Articulation  errors are commonly present in children with DiGeorge syndrome. These errors include a limited phonemic (speech sound) inventory and the use of compensatory articulation strategies resulting in reduced intelligibility. The  phonemic  inventory typically produced consists of sounds made in the front or back of the oral cavity such as:  /p/ ,  /w/ ,  /m/ ,  /n/ , and glottal stops. Sound made in the middle of the mouth are completely absent. Compensatory articulation errors made by this population of children include:  glottal stops , nasal substitutions, pharyngeal fricatives, linguapalatal sibilants, reduced pressure on consonant sounds, or a combination of these symptoms. Of these errors, glottal stops have the highest frequency of occurrence. It is reasoned that a limited  phonemic inventory  and the use of compensatory articulation strategies is present due to the structural abnormalities of the palate. The speech impairments exhibited by this population are more severe during the younger ages and show a trend of gradual improvement as the child matures. [ 24 ] [ 28 ]


DiGeorge syndrome is caused by a  heterozygous  deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2). Approximately 80-90% of patients have a deletion of 3  Mb  and 8% have a deletion of 1.5Mb. [ 31 ] [ 32 ]  The number of genes affected by the deletion has been cited as approximately 30 to 50. [ 33 ] [ 34 ]  Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10. [ 35 ]  The disorder has an autosomal dominant inheritance pattern.


A French study of 749 people diagnosed between 1995 and 2013 found that the mutation was inherited in 15% of patients, of which 85.5% was from the mother. [ 36 ]  Other studies have found inheritance rates of 6–10%. The majority cases are a result of a  de novo  (new to the family) deletion. [ 13 ]  This is because the 22q11 region has a structure that makes it highly prone to rearrangements during sperm or egg formation. [ 37 ]


The exact mechanism that causes all of the associated features of the syndrome is unknown. [ 31 ]  Of the 30–50 genes in the deleted region, a number have been identified as possibly playing a role in the development of some of the signs and symptoms.


Haploinsufficiency  of the  TBX1  gene (T-box transcription factor TBX1) is thought to be the cause of some of the symptoms observed.  Point mutations  in this gene have also been observed in individuals with DiGeorge syndrome. [ 31 ]   TBX1  is part of the  T-box  family of genes which have an important role in tissue and organ formation during embryonic development and it may have a role in the regulation of  differentiation  of post migration  neural crest cells . The neural crest forms many of the structures affected in DiGeorge syndrome, including  the skull bones,  mesenchyme  of the face and palate, the outflow tract of the heart, and the thymus and parathyroid  stroma . When there is a loss of expression of  FGF18  during the development of the  pharyngeal arches , neural crest cell death is seen. Although neither  FGF18  or  TBX1  is expressed in the neural crest cells,  TBX1  might have a role in the regulation of FGF18 expression, ensuring that the differentiation of these cells in the pharyngeal region is correct.  Therefore, dysfunction of  TBX1  may be responsible for some of the symptoms in DiGeorge syndrome. [ 32 ]


Research in mouse models has shown that deletion of  Tbx1  leads to several defects similar to those seen in humans, mainly affecting development of the  great arteries  and the  thymus . [ 38 ] [ 39 ]


The abnormalities seen in the great arteries of mice deficient of  Tbx1  are a consequence of abnormal formation and remodelling of the  aortic arches  during early development. The role of  Tbx1  for correct formation and remodelling of the aortic arches has been extensively studied in various mouse models suggesting the key role of  Tbx1  for cardiovascular development and the phenotypes seen in DiGeorge syndrome.


In mice, haploinsufficiency of the  Dgcr8  gene has been linked to improper regulation of the microRNA  miR-338  and 22q11.2 deletion phenotypes. [ 40 ]


Transport and golgi organization 2 homolog ( TANGO2 ) also known as chromosome 22 open reading frame 25 (C22orf25) is a protein that in humans is encoded by the  TANGO2  gene. [ citation needed ]


The gene coding for C22orf25 is located on chromosome 22 and the location q11.21, so it is often associated with 22q11.2 deletion syndrome. [ 41 ]  But with TANGO2 disorder being autosomal recessive, will not occur in all cases. [ citation needed ]


Mutations in the  TANGO2  gene may cause defects in mitochondrial  β-oxidation [ 42 ]  and increased  endoplasmic reticulum  stress and a reduction in  Golgi  volume density. [ 43 ]   These mutations results in early onset  hypoglycemia ,  hyperammonemia ,  rhabdomyolysis ,  cardiac arrhythmias , and  encephalopathy  that later develops into cognitive impairment. [ 42 ] [ 43 ]


22q11.2DS has been associated with a higher risk of early onset  Parkinson's disease  (PD). The neuropathology seen is similar to  LRRK2 -associated PD. None of the genes affected in individuals with 22q11.2DS have previously been linked to PD but there are a number that are likely candidates. These include  DGCR8 , which is important for biogenesis of brain microRNA,  SEPT5 , which encodes a protein that interacts with the  PARK2  protein,  COMT , which is involved in regulating dopamine levels, and microRNA miR-185, which is thought to target known PD locus  LRRK2 . [ 22 ]


Diagnosis of DiGeorge syndrome can be difficult due to the number of potential symptoms and the variation in phenotypes between individuals. It is suspected in patients with one or more signs of the deletion. In these cases a diagnosis of 22q11.2DS is confirmed by observation of a deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2. Genetic analysis is normally performed using  fluorescence  in situ  hybridization   (FISH), which is able to detect microdeletions that standard karyotyping (e.g.  G-banding ) miss. Newer methods of analysis include  multiplex ligation-dependent probe amplification  assay (MLPA) and  quantitative polymerase chain reaction  (qPCR), both of which can detect atypical deletions in 22q11.2 that are not detected by FISH. [ 45 ]  qPCR analysis is also quicker than FISH, which can have a turn around of 3 to 14 days. [ 13 ]


A 2008 study of a new high-definition MLPA probe developed to detect  copy number variation  at 37 points on chromosome 22q found it to be as reliable as FISH in detecting normal 22q11.2 deletions. It was also able to detect smaller atypical deletions that are easily missed using FISH. These factors, along with the lower expense and easier testing mean that this MLPA probe could replace FISH in clinical testing. [ 46 ]


Genetic testing using BACs-on-Beads has been successful in detecting deletions consistent with 22q11.2DS during prenatal testing. [ 47 ] [ 48 ]   Array-comparative genomic hybridization  (array-CGH) uses a large number of probes embossed in a chip to screen the entire genome for deletions or duplications. It can be used in post and pre-natal diagnosis of 22q11.2. [ 49 ]


Fewer than 5% of individuals with symptoms of DiGeorge syndrome have normal routine cytogenetic studies and negative FISH testing. In these cases, atypical deletions are the cause. [ 50 ]  Some cases of 22q11.2 deletion syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14. [ 35 ]


No cure is known for DiGeorge syndrome. Certain individual features are treatable using standard treatments. [ 51 ]  The key is to identify each of the associated features and manage each using the best available treatments. [ citation needed ]


For example, in children, it is important that the immune problems are identified early, as special precautions are required regarding blood transfusion and immunization with live vaccines. [ 52 ]   Thymus transplantation  can be used to address absence of the thymus in the rare, so-called "complete" DiGeorge syndrome. [ 53 ]   Bacterial  infections  are treated with  antibiotics .  Cardiac surgery  is often required for congenital heart abnormalities. Hypoparathyroidism causing hypocalcaemia often requires lifelong vitamin D and calcium supplements. Specialty clinics that provide multi-system care allow for individuals with DiGeorge syndrome to be evaluated for all of their health needs and allow for careful monitoring of the patients. An example of this type of system is the 22q Deletion Clinic at  SickKids Hospital  in Toronto, Canada, which provides children with 22q11 deletion syndrome ongoing support, medical care and information from a team of health care workers. [ 54 ]


Metirosine  (methyltyrosine) is used as an off-label treatment for DiGeorge syndrome. [ 55 ]


DiGeorge syndrome is estimated to affect between one in 2000 and one in 4000 live births. [ 56 ] [ 57 ]  This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed.  It is one of the most common causes of  intellectual disability  due to a genetic deletion syndrome. [ 58 ]


The number of people affected has been expected to rise because of multiple reasons: (1) surgical and medical advances, an increasing number of people are surviving heart defects associated with the syndrome. These individuals are in turn having children. The chances of a person with DiGeorge syndrome having an affected child is 50% for each pregnancy; (2) Parents who have affected children, but who were unaware of their own genetic conditions, are now being diagnosed as genetic testing become available; (3) Molecular genetics techniques such as FISH (fluorescence in situ hybridization) have limitations and have not been able to detect all 22q11.2 deletions.  Newer technologies have been able to detect these atypical deletions. [ 59 ]


The signs and symptoms of DiGeorge syndrome are so varied that different groupings of its features were once regarded as separate conditions. These original classifications included velocardiofacial syndrome, Shprintzen syndrome, DiGeorge sequence/syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome. All are now understood to be presentations of a single syndrome.


ICD-10 2015 version mentions DiGeorge syndrome using two codes:  D82.1 (Di George syndrome) [ 60 ]  and Q93.81 (Velo-cardio-facial syndrome). [ 61 ]  The ICD-11 Beta Draft discusses the syndrome under “LD50.P1 CATCH 22 phenotype". [ 61 ]  However, since this syndrome is caused by the deletion of a small piece of chromosome 22, some recommend that the name "22q11.2 deletion syndrome (22q11.2DS)" be used. [ 62 ] [ 13 ]  Some experts support changing the name of both DiGeorge and velocardiofacial syndromes to CATCH-22. [ citation needed ]  The International 22q11.2 Foundation, through its "Same Name Campaign", advocates for the name 22q11.2 deletion syndrome. [ 63 ]


peripheral:   Purine nucleoside phosphorylase deficiency


Fragile X-associated primary ovarian insufficiency  (FXPOI) is the most common genetic cause of  premature ovarian failure  in women with a normal karyotype 46,XX. [ 1 ]  The expansion of a CGG repeat in the 5' untranslated region of the  FMR1  gene  from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. [ 2 ]  About 1:150-1:200 women in the US population carry a premutation. [ 3 ]  Women who carry an  FMR1  premutation have a roughly 20% risk of being diagnosed with FXPOI, compared to 1% for the general population, and an 8-15% risk of developing the neurogenerative  tremor/ataxia disorder (FXTAS) . [ 4 ] [ 5 ]   FMR1  premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats (a  full mutation ). [ 6 ]  Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the  FMR1  gene and have  fragile X syndrome  as a result.


Primary ovarian insufficiency requires that a diagnosis be made prior to the age of 40, since it is considered premature relative to the average age of  menopause  of 51 in the US. [ 7 ]  The two criteria are the repeated elevation of the  follicle stimulating hormone  (FSH), which increases dramatically when a woman enters menopause, and the loss of  menstruation  for at least 4–6 months. [ 8 ]  In  FMR1  premuation carriers, the likelihood of receiving a clinical diagnosis of FXPOI is about 20% and increased FSH levels and altered menstrual cycles become particularly evident between 30 and 40 years of age. [ 4 ]  Even if  menses  are lost, women diagnosed with FXPOI may experience a spontaneous "escape"  ovulation . This means that there is some chance for  conception , around 10%, even if menstruation has been absent for extended periods in women with FXPOI. [ 9 ]  Women planning to conceive before the cessation of periods are often encouraged to consult a  genetic counselor  or  medical geneticist  to understand their individual risk for having a child with fragile X syndrome.


The  FMR1  premutation is commonly identified using reflexive  genetic testing  after identification of a child with fragile X syndrome found in a family. This genetic diagnosis accounts for 10-15% of women who will receive a FXPOI diagnosis. [ 9 ]  Women may also experience  infertility  and receive genetic testing in the course of  reproductive care . Roughly 1-3% of FXPOI cases are identified through this process. [ 9 ]


FXPOI is the most common known genetic cause of ovarian insufficiency for women with a normal chromosome number (46,XX) and accounts for 5-10% of these cases of  premature ovarian failure . [ 10 ]  Not all women who are carriers for an  FMR1  premutation allele, an expansion of the CGG repeat in the  FMR1  gene to 55-199 repeats, will be diagnosed with FXPOI. About 20% of premutation carriers will be diagnosed, but this risk represents a significant increase over the general population who have a roughly 1% risk of POI. [ 11 ]  Women with highest risk of POI have 70-100 CGG repeats, meaning there is a non-linear association between CGG-repeat size and FXPOI risk. [ 7 ] [ 12 ]  This relationship is different than the  linear association  seen between CGG repeat size and age of onset of  FXTAS . Other variations in premutation alleles, like AGG interruptions within the CGG repeats, are not correlated with risk of a FXPOI diagnosis. [ 13 ]  The AGG interruptions are correlated with the risk that the premutation-length allele could expand in the  oocyte, or egg cell , and lead to a child with  fragile X syndrome . [ 14 ] [ 15 ]


Though the greatest risks for female carriers of an  FMR1  premuation are developing POI and having a child with fragile X syndrome, there are other possible  neurological  and  neuropsychiatric conditions  that may occur. [ 16 ] [ 17 ]  Roughly 8-15% of female premutation carriers will develop the late-onset  neurodegenerative   tremor/ataxia disorder  FXTAS. [ 16 ]  More recently, increased interest in neurological features and cognition of female premutation carriers has suggested a broader range of neuropsychiatric conditions associated with premutation-sized CGG repeats. Women with an  FMR1  premutation exhibit higher incidences of  depression ,  anxiety ,  autoimmune dysfunction , and  neuromuscular pain . [ 17 ] [ 18 ] [ 19 ] [ 20 ]  The prevalence of depression and anxiety in premutation females is, notably, higher than that observed in premutation males. [ 21 ]  Interpretation of studies that examine women with a premutation, who may have complex and challenging needs, is difficult since it is unclear whether the premutation leads to increased anxiety and depression or it is increased environmental stressors within the home. [ 22 ]  Research to understand these differences between males and females with the same genetic change is developing, but there are no studies that point to a definitive driver of these differences.


An additional challenge for women with an  FMR1  premutation is determining the risk for having a child with fragile X syndrome.  Epidemiological  data show that the risk of a premutation allele (55-199 CGGs) expanding to a full mutation (>200 CGGs) increases as the length of the CGG tract grows. [ 23 ]  This risk assessment for expansion to a full mutation is critical for women, but not men, with a premutation since the premutation allele in males does not show large expansion and transmission through generations. [ 14 ] [ 23 ]  Expansion from a premutation to full mutation only occurs within the  egg cells  of a female premutation carrier. [ 23 ] [ 24 ]  Additional factors influencing the stability of  FMR1  premutation alleles are the presence of AGG interruptions. [ 25 ]  The loss of 1 or 2 AGG interruptions in the 5' region of the CGG repeat allele leads to increased likelihood that a premutation will expand to a full mutation from one generation to the next. [ 23 ] [ 14 ] [ 25 ]  Studies have also indicated that increasing maternal age may be a contributor to increased risk of expansion of a premutation to a full mutation, but the molecular mechanism through which this expansion process occurs are not yet understood. [ 14 ] [ 23 ] [ 26 ]


Individuals with  FMR1 -related disorders and families have access to several communities to find support groups and information about ongoing research and new therapies. Concise information designed for patients, families, or people outside of medical fields are available. The National Fragile X Foundation is a private foundation that focuses on raising awareness about fragile X-associated disorders, research, and treatments. [ 27 ]  The FRAXA Research Foundation is another resource for families and is primarily focused on funding and helping amplify research and treatment options for fragile X to the community. [ 28 ]


Genetic incompatibility  describes the process by which mating yields offspring that are nonviable, prone to disease, or genetically defective in some way. In nature, animals can ill afford to devote costly resources for little or no reward, ergo, mating strategies have evolved to allow females to choose or otherwise determine mates which are more likely to result in viable offspring.


Polyandry , for instance, when a female mates with two or more males during a period of sexual receptivity, reduces the chance that a singular mate is genetically incompatible. Exactly how females determine compatible genes prior to mating is not completely understood, but various mechanisms have been proposed, such as pheromones and male appearance and/or courtship behavior.


It is also surmised that sexual selection can continue after copulation, the so called 'cryptic female choice', so named because it takes place within the body and cannot be directly observed. In this scenario, incompatible male sperm can be rejected by the female.


Genetic incompatibility can be engineered by scientists in order to control pests such as mosquitos and fruit flies.


Introduced to the scientific community in the early 1990s, the concept of  cryptic female choice  is complicated and offers a new explanation for infertility. [ 1 ]  Non-additive genetic effects have been thought of to be the main reason for reproductive isolation between species. [ 2 ]  More recent studies have concluded that in comparison to additive genetic effects, non-additive genetic effects have a more important role in fertility and embryo survival. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  As a result, some scientists have concluded that rather than the genes of the female alone or the genes of the male alone being the reason for the pair to be infertile, it is a result of the relationship and compatibility of their genes. [ 2 ]  Thus, some male genotypes may have a higher success rate of fertilization with some female genotypes rather than others. [ 2 ]


Certain alleles being paired together can lead to complete reproductive failure/incompatibility as a result of differential compatibility between different variants. [ 2 ]  Another contributing factor to incompatibility is based on the surface carbohydrates of the gametes. [ 2 ]  Multiple studies have shown that the physical contact between the sperm and the egg can cause a chemical reaction in the female. [ 2 ]  This reaction occurs when the egg comes in contact with non-compatible surface glycans and can impact the sperm's potential for fertilization by causing structural changes in the sperm's surface glycans. [ 2 ]


There are numerous other factors that can likewise contribute to the incompatibility of male and female haplotypes within an embryo. [ 7 ]  For example, certain male  Drosophila melanogaster  (Fruit Flies) carry a drive allele that on average results in them producing 50% less viable sperm than their counterparts who are not heterozygous for the allele. [ 7 ]  Not only are offspring of heterozygous males less genetically competitive, if both the male and female are heterozygous, their offspring will be either inviable or infertile [ 7 ]


One example of how indirect non additive genes impact fertility comes from a team of researchers who investigated how female  rhodeus ocellatus  (rosy bitterlings) employ mate choice and the role of the MHC gene in that decision. [ 3 ]  After allowing females and males to mate, they collected DNA from all the adult bitterlings as well as their offspring. [ 3 ]  The data showed that females were more likely to choose males whose MHC gene was dissimilar to theirs. [ 3 ]  The offspring that came from a pair who had dissimilar MHC genes had higher survival rates. [ 3 ]  Although these researchers did not test this theory, they speculated that perhaps during the male's courtship, he dissipates odor cues from the MHC gene that assist the female in her decision-making process [ 3 ]


DDK is a lethal phenotype in  Mus Domesticus  ( house mice) that leads to developmental abnormalities and eventually deterioration of the embryo when females with the phenotype mate with males who carry other inbred strains. [ 8 ]  Scientists have discovered that expression of this incompatibility within the embryo depends on the paternal allele of the DDK syndrome. [ 8 ]  If the paternal allele is compatible, meaning the male is not carrying an inbred strain (ex. DDK female x non-DDK male), the embryo will survive. [ 8 ]  However if the male carries the incompatible allele, the embryo will not survive. [ 8 ]


Genetic color polymorphisms are genetically defined color forms between animals of the same species. [ 9 ]  For the most part, color morphs within a population can interbreed without any issues. However, evidence shows that in certain cases, the viability of interbred color morph offspring is drastically lower than those that present the same color. [ 9 ]  While coloration is the most pronounced exhibition of a certain phenotype as individuals can be easily and quickly differentiated to the human eye, there are other factors that may be affected but not as easily identified. [ 10 ]


A group of researchers investigated how the survival rates of offspring of  Erythrura Gouldiae  (Gouldian finch) are impacted when the mating pair have genes for different colors. [ 9 ]  They bred both pure and mixed pairs of the finches (in this species the gene for producing a red-headed finch is dominant to the one that produces a black headed finch). [ 9 ]  After incubation, eggs that were produced from mixed pairs were 34.3% less likely to hatch compared to those that were produced from pure pairs. [ 9 ]  The mixed-pair offspring that did survive the incubation stage were still at a disadvantage, being burdened with a 32.1% increase in mortality between the time that they hatched and 60 days after (during which time they were still in the care of parents). [ 9 ]  Even after becoming independent, the offspring mortality of mixed pairs was still higher. Specifically the rate of mortality of daughters from mixed-genotypes was much higher. [ 9 ]


Polyandry  is a mating pattern that is identified in species when a female mates with two or more males during a period of sexual receptivity. [ 11 ]  Females may engage in this behavior in the event that their singular mate is a genetically incompatible match. [ 12 ]  If that were to be the case, she would lose the chance to become pregnant during that season and not be able to try again until the next mating window. [ 12 ]


Creating offspring requires the female to allocate a large portion of her resources to both the formation of the embryo. [ 7 ]  Partaking in polyandry allows her to ensure that the offspring that she will be providing for is going to be viable, and not be a waste of her time, energy, and resources. [ 7 ]


Another experiment was done with Gouldian finches, during which researchers wanted to determine the effect of compatibility and incompatibility on the relationship between socially monogamous pairs of finches. [ 13 ]  They discovered that by participating in "extra-pair" mating relationships, the females were able to more accurately target compatible genes, thus increasing the amount of viable offspring that they produce. [ 13 ]  Researchers paired females with both compatible and incompatible males as their social partner. However, they also made available both compatible and incompatible males as the extra-pair partner. [ 13 ]  The data collected revealed that 77.5% of the females mated outside of their pairs. If their extra-pair was compatible (unlike their social partner), the female experienced a 38.9% increase in offspring survival. [ 13 ]  Although females are unable to tell the difference between compatible and incompatible partners, by participating in polyandry, their likelihood of yielding more and healthier offspring is increased. [ 13 ]


Selfish genetic elements  are genes that will use various methods to ensure that they are transferred on to new generations. [ 14 ]  Selfish elements have the potential to create genetic incompatibilities because their effects frequently depend on interactions with the host genotype and according to whether selfish elements are present in both parents. [ 15 ]  There has been some debate over whether these selfish genetic elements can actually influence the post-copulatory sperm selection that some females go through in order to determine the best (most compatible) match for her genes. [ 14 ]


Mice, carry a particular type of selfish genetic element known as a segregation distorter. [ 16 ]  This specific classification is able to establish themselves in over 50% of offspring after the meiosis period. [ 16 ]  Specific to mice, the distorter that they can carry is known as the t-complex. [ 17 ]  This specific allele is recessive lethal, meaning that it can have a serious effect on the fitness of offspring as well and is most likely deadly. [ 17 ]  After multiple experiments, it was found that both males and females will avoid mating with those of the opposite sex who are heterozygous for the allele but showed a strong preference for those that were not carriers of the allele. [ 17 ]  If they were to mate with a heterozygous partner, it could potentially lead to half of their offspring dying as a result of the lethal allele [ 17 ]


Engineered Genetic Incompatibility (EGI) is a technique that is being developed to manufacture incompatibility between species in order to aid in population suppression. [ 18 ]  Mimicking the  Sterile Insect Technique , by introducing EGI males into a population, a sex-sorting incompatible male system is generated. [ 18 ]  Males that have been genetically modified are able to compete for the attention of females at the same level as those that have not been modified. [ 18 ]  Because the EGI males are equal rivals to their wild counterparts, they are able to use the female's time and energy reproducing but only to create non-viable offspring. [ 18 ]


A team of researchers from the University of Minnesota were successful in genetically engineering a population of fruit flies that would not be able to generate viable progeny when mating with wild-types specifically. [ 18 ]  The researchers manufactured flies that would express a dCas9-based programmable transcription activator or PTA. [ 18 ]  By this method, the promoter of any gene could be affected. [ 18 ]  When the EGI flies mate with each other, they are able to avoid the negative effects the PTA generates because they were also given the gene for a mutation that could combat the overexpression of the gene. [ 18 ]  Their offspring would go on to carry the same incompatibilities to the next generation, furthering the impact on the population. [ 18 ]  However, the offspring that are produced by hybrid pairs (one EGI and one wild type) have a heterozygous pair of both the PTA and resistance genes and do not survive long after hatching, if they ever do as a result of the PTA's disabling effect on the gene promoter. [ 18 ]


A great deal of research has gone into trying to use this technology as a tool in order to try and control the spread of diseases that are carried by mosquitoes such as Dengue, Zika, and Chikungunya. [ 19 ]  Because of the successful research done on fruit flies, a team of researchers was able to manipulate some aspects of the experiment and effectively control a simulated population of  Aedes aegypti  (mosquitoes). [ 19 ]  For their experiment, they used female lethality meaning that the engineered female mosquitoes will not survive the initial stages of their lives. [ 19 ]  The researchers titled this new approach the Self-Sorting Incompatible Male System (SSIMS). [ 19 ]  They observed an increase in population suppression as they increased the number of SSIMS mosquitoes released because the offspring conceived from the SSIMS males were inviable. [ 19 ]  After this success, a new strategy was modeled, Field-Amplified Male Sterility System (FAMSS). [ 19 ]  This led to an even bigger impact on population control as the offspring were viable but sterile. [ 19 ]


Intersex  is a general term for an organism that has  sex  characteristics that are between  male  and  female . [ 1 ]  It typically applies to a minority of members of  gonochoric  animal species such as mammals (as opposed to  hermaphroditic  species in which the majority of members can have both male and female sex characteristics). [ 2 ]  Such organisms are usually  sterile . [ 3 ]


Intersexuality can occur due to both genetic and environmental factors [ 4 ]  and has been reported in  mammals ,  fishes ,  nematodes , and   crustaceans .


Intersex can occur in mammals such as  pigs , with it being estimated that 0.1% to 1.4% of pigs are intersex. [ 5 ]  In  Vanuatu ,  Narave pigs  are sacred intersex pigs that are found on  Malo Island . An analysis of Narave pig mitochondrial DNA by Lum et al. (2006) found that they are descended from Southeast Asian pigs. [ 6 ] [ 7 ] [ 8 ]


At least six different  mole  species have an intersex adaption where by the female mole has an  ovotestis , "a hybrid organ made up of both  ovarian  and  testicular  tissue. This effectively makes them intersex, giving them an extra dose of  testosterone  to make them just as muscular and aggressive as male moles". The ovarian part of the ovotestis is reproductively functional. [ 9 ] [ 10 ]


Intersexuality in humans is relatively rare. Depending on the definition, the  prevalence  of  intersex  among humans has been reported to range around a figure of 0.018%. [ 11 ] [ 12 ]


Intersex is known to occur in all main groups of  nematodes . Most of them are functionally female. Male intersexes with female characteristics have been reported but are less common. [ 13 ]


Gonadal intersex occurs in fishes, where the individual has both ovarian and testicular tissue. Although it is a rare anomaly among gonochoric fishes, it is a transitional state in fishes that are  protandric  or  protogynous . [ 14 ]  Intersexuality has been reported in 23 fish families. [ 15 ]


The oldest evidence for intersexuality in crustaceans comes from fossils dating back 70 million years ago. [ 4 ]  Intersex has been reported in  gonochoric   crustaceans  as early as 1729. A large amount of literature exists on intersexuality for  isopoda  and  amphipoda , with there being reports of both intersex males and intersex females. [ 16 ]


Klinefelter syndrome  ( KS ), also known as  47,XXY , is a chromosome anomaly where a male has an extra  X chromosome . [ 10 ]  These complications commonly include infertility and small, poorly functioning  testicles  (if present). These symptoms are often noticed only at puberty, although this is one of the most common  chromosomal disorders , occurring in one to two per 1,000 live births. It is named after American  endocrinologist   Harry Klinefelter , who identified the condition in the 1940s, along with his colleagues at  Massachusetts General Hospital . [ 4 ] [ 5 ] [ 11 ] [ 12 ]


The syndrome is defined by the presence of at least one extra X chromosome in addition to a  Y chromosome , yielding a total of 47 or more  chromosomes  rather than the usual 46. Klinefelter syndrome occurs randomly. The extra X chromosome comes from the father and mother nearly equally. An older mother may have a slightly increased risk of a child with KS. The syndrome is diagnosed by the  genetic test  known as  karyotyping . [ 4 ] [ 6 ] [ 13 ] [ 14 ]


Klinefelter syndrome has different manifestations and these will vary from one patient to another. Among the primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. In other cases, symptoms are more prominent and may include weaker muscles, greater height, poor motor coordination, less body hair,  gynecomastia  (breast growth), and low libido. In the majority of the cases, these symptoms are noticed only at  puberty . [ 4 ] [ 6 ] [ 15 ]


Chromosomal abnormalities, including Klinefelter syndrome, are the most common cause of spontaneous abortion. [ 16 ]  Generally, the severity of the malformations is proportional to the number of extra X chromosomes present in the karyotype. For example, patients with 49 chromosomes (XXXXY) have a lower IQ and more severe physical manifestations than those with 48 chromosomes (XXXY). [ 17 ]


As babies and children, those with XXY chromosomes may have lower muscle tone and reduced strength. They may sit up, crawl, and walk later than other infants. An average KS child will start walking at 19 months of age. They may also have less muscle control and coordination than other children of their age. [ 18 ]


During puberty, KS subjects show less muscular body, less facial and body hair, and broader hips as a consequence of low levels of testosterone. Delays in motor development may occur, which can be addressed through occupational and physical therapies. As teens, males with XXY may develop  breast tissue , have weaker bones, and a lower energy level than others. Testicles are affected and are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4ml in volume. Those with XXY chromosomes may also have  microorchidism  (i.e., small testicles). [ 18 ] [ 19 ]


By adulthood, individuals with KS tend to become taller than average, with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, narrower shoulders. Some will show little to no symptomology, a lanky, youthful build and facial appearance, or a rounded body type. Gynecomastia (increased breast tissue) in males is common, affecting up to 80% of cases. [ 20 ]  Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery. [ citation needed ]


Individuals with KS are often infertile or have reduced fertility. Advanced reproductive assistance is sometimes possible in order to produce an offspring since approximately 50% of males with Klinefelter syndrome can produce  sperm . [ 11 ] [ 21 ]


Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in  executive functions , although these deficits can often be overcome through early intervention. It is estimated that 10% of those with Klinefelter syndrome are  autistic . Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing. [ 22 ] [ 23 ]


The overall  IQ  tends to be lower than average. Language milestones may also be delayed, particularly when compared to other people their age. Between 25% and 85% of males with XXY have some kind of language problem, such as delay in learning to speak, trouble using language to express thoughts and needs, problems reading, and trouble processing what they hear. They may also have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers. [ 18 ] [ 24 ]


Compared to individuals with a normal number of chromosomes, males affected by Klinefelter syndrome may display behavioral differences. These are phenotypically displayed as higher levels of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood, and low frustration tolerance. [ 25 ] [ 26 ] [ 27 ]  These neurocognitive disabilities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome. [ 28 ]


In 1995, a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. It demonstrated that males with XXY tend to be quiet, shy and undemanding; they are less self-confident, less active, and more helpful and obedient than other children their age. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other kids. [ 24 ] [ 29 ]


As adults, they live lives similar to others without the condition; they have friends, families, and normal social relationships. Nonetheless, some individuals may experience social and emotional problems due to problems in childhood. They show a lower sex drive and low self-esteem, in most cases due to their feminine physical characteristics. [ 4 ] [ 24 ]


Those with XXY are more likely than others to have certain health problems, such as  autoimmune disorders ,  breast cancer ,  venous thromboembolic disease , and  osteoporosis . Nonetheless, the risk of breast cancer is still below the normal risk for women. These patients are also more prone to develop  cardiovascular disease  due to the predominance of metabolic abnormalities such as  dyslipidemia  and  type 2 diabetes . It has not been demonstrated that hypertension is related with KS. [ 30 ] [ 31 ] [ 32 ]


In contrast to these potentially increased risks, rare  X-linked recessive  conditions are thought to occur less frequently in those with XXY than in those without, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only  carriers  rather than affected by these X-linked recessive conditions. [ 33 ]


Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases. Maternal age is the only known risk factor. Women at 40 years have a four-times-higher risk of a child with Klinefelter syndrome than women aged 24 years. [ 14 ] [ 34 ] [ 35 ]


The extra chromosome is retained because of a  nondisjunction  event during paternal  meiosis I , maternal meiosis I, or maternal  meiosis II , also known as  gametogenesis . The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY or Klinefelter offspring. Fertilizing a double X egg with a normal sperm also produces an XXY or Klinefelter offspring. [ 34 ] [ 36 ]


Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in approximately one in 500 live male births. [ 4 ] [ 13 ] [ 36 ]


In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as  X inactivation . This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the  pseudoautosomal regions  of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed. [ 37 ] [ 38 ]


The condition 48, XXYY  or 48, XXXY  occurs in one in 18,000–50,000 male births. The incidence of 49, XXXXY  is one in 85,000 to 100,000 male births. [ 39 ]  These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, urinogenital and other anomalies. [ citation needed ]  Thirteen cases of individuals with a 47,XXY karyotype and a female phenotype have been described. [ 40 ]


Approximately 15–20% [ 41 ]  of males with KS may have a  mosaic  47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. [ 41 ]  Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only approximately 10 cases of 47,XXY/46,XX have been described in literature. [ 42 ]


Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelter's, including in both cases a small proportion of individuals with a skewed ratio between the two Xs. [ 43 ]


The term " hypogonadism " in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum  testosterone  level, but high serum  follicle-stimulating hormone  and  luteinizing hormone  levels,  hypergonadotropic hypogonadism . [ 44 ]  Despite this misunderstanding of the term, testicular growth is arrested. [ 44 ]


Destruction and hyalinization of the  seminiferous tubules  cause a reduction in the function of  Sertoli cells  and  Leydig cells , leading to decreased production of  FSH  and  testosterone . This results in impaired  spermatogenesis  and further endocrine dysfunction. [ 45 ]


The standard diagnostic method is the analysis of the chromosomes' karyotype on  lymphocytes . A small blood sample is sufficient as test material. In the past, the observation of the  Barr body  was common practice, as well. [ 46 ]  To investigate the presence of a possible  mosaicism , analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair, and occasionally an enlargement of the breast. Usually, a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml) occurs. [ 32 ]  During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A  spermiogram  can also be part of the further investigation. Often, an azoospermia is present, or rarely an oligospermia. [ 14 ]  Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). Approximately 10% of KS cases are found by  prenatal diagnosis . [ 47 ]


The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual. [ 4 ]


The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population. [ 48 ]  These results are still questioned data, are not absolute, and need further testing. [ 49 ]


As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy. [ 50 ]  Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the  surgical removal of the breast  may be considered for psychological benefits and to reduce the risk of breast cancer. [ 51 ] [ 52 ]


The use of  behavioral therapy  can mitigate any language disorders, difficulties at school, and socialization. An approach by  occupational therapy  is useful in children, especially those who have  dyspraxia . [ 53 ]


Methods of reproductive medicine, such as  intracytoplasmic sperm injection  (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring. [ 54 ]  By 2010, over 100 successful pregnancies have been reported using  in vitro fertilization  technology with surgically removed sperm material from men with KS. [ 55 ]


The syndrome was named after American endocrinologist  Harry Klinefelter , who in 1942 worked with  Fuller Albright  and E. C. Reifenstein at  Massachusetts General Hospital  in  Boston, Massachusetts , and first described it in the same year. [ 11 ] [ 56 ]  The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter–Reifenstein–Albright syndrome. [ 57 ]  In 1956, Klinefelter syndrome was found to result from an extra chromosome. [ 58 ]  Plunkett and Barr found the sex chromatin body in cell nuclei of the body. This was further clarified as XXY in 1959 by  Patricia Jacobs  and  John Anderson Strong . [ 59 ]  The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at  Western General Hospital  in  Edinburgh, Scotland , in 1959. [ 59 ]  This karyotype was found in a 24-year-old man who had signs of KS. Jacobs described her discovery of this first reported human or mammalian chromosome  aneuploidy  in her 1981 William Allan Memorial Award address. [ 60 ]


Klinefelter syndrome has been identified in ancient burials. In August 2022, a team of scientists published a study of a skeleton found in  Bragança , north-eastern  Portugal , of a man who died around 1000 AD and was discovered by their investigations to have a 47,XXY karyotype. [ 61 ]  In 2021,  bioarchaeological investigation  of the individual buried with the  Suontaka sword , previously assumed to be a woman, concluded that person "whose gender identity may well have been non-binary", had Klinefelter syndrome. [ 62 ]


In many societies, the symptoms of Klinefelter syndrome have contributed to significant  social stigma , particularly due to infertility and gynecomastia. Historically, these traits were often associated with a perceived lack of  masculinity , which could result in social ostracism. [ citation needed ]  However, in recent years, increased awareness and advocacy have led to a reduction in stigma, with individuals diagnosed with KS more likely to receive proper medical care and support. Advocacy organizations, such as the American Association for Klinefelter Syndrome Information and Support (AAKSIS), have played a crucial role in promoting understanding and improving the quality of life for affected individuals. [ 63 ]


This syndrome, evenly distributed in all  ethnic groups , has a  prevalence  of approximately four subjects per every 10,000 (0.04%) males in the general population. [ 35 ] [ 64 ] [ 65 ] [ 66 ]  However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. [ 50 ]  The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is the main cause of male hypogonadism. [ 67 ]  One survey in the United Kingdom found that the majority of people with KS identify as male, however, a significant number have a different  gender identity . [ 68 ]  The prevalence of KS is higher than expected in  transgender women . [ 69 ]


Koolen–De Vries syndrome  ( KdVS ), also known as  17q21.31 microdeletion syndrome , is a rare  genetic disorder  caused by a  deletion  of a segment of  chromosome 17  which contains six genes. This deletion syndrome was discovered independently in 2006 by three different research groups. [ 1 ] [ 2 ] [ 3 ] [ 4 ]


The symptoms associated with this syndrome are variable, but common features include:  low birthweight ,  low muscle tone  at birth,  poor feeding  in infancy (often requiring  feeding by tube  for a period) and  oromotor dyspraxia  together with moderate  developmental delays  and  learning disabilities  but amiable behaviour. Other clinically important features include  epilepsy , heart defects ( atrial septal defect ,  ventricular septal defect ) and kidney/urological anomalies. Silvery  depigmentation  of strands of hair have been noted in several patients. With age, there is an apparent coarsening of facial features. [ 5 ]


17q21.3 was reported simultaneously in 2006 by three independent groups, with each group reporting several patients, and is now recognised to be one of the more common recurrent  microdeletion syndromes . [ 6 ]  In 2007, a patient with a small  duplication  in same segment of DNA was described. [ 7 ]  An overview of the clinical features of the syndrome, by reviewing 22 individuals with a 17q21.31 microdeletion, estimated the disorder is present in 1 in every 16,000 people. [ 8 ]


The recurrent deletion is between 500 and 650  kilobases  (Kb) in size encompassing at least six genes, among them the microtubule-associated protein tau ( MAPT ). A review of five patients found the parental chromosome from which the deletion originated carried a common 900kb  inversion   polymorphism . [ 8 ]  The orientation of  low copy repeats  flanking the deleted segment suggests the inversion in the parental chromosome influences the deletion in the child's chromosome via a  non-allelic homologous recombination  (NAHR) mechanism. [ 9 ]


The deletion that causes this disease can remove up to six different genes. These include: [ 10 ]


Diagnosis is established with a chromosome microarray analysis. The symptoms of Koolen–de Vries syndrome can be very variable, and there is no single  clinical sign  required to establish the diagnosis. [ 11 ]


Treatment centres around the symptoms in each individual and can include: early  physiotherapy  for feeding and motor problems, physiotherapy for strengthening the muscles,  speech therapy ,  sign language , alternative or augmentative communication devices,  special education , routine  antiepileptic  medications,  orthopaedic  care for  scoliosis ,  hip dislocation  and positional deformities of the feet, treatment for cardiac, renal,  urologic  and other medical issues and surgery for  cryptorchidism  if indicated. [ 11 ]


The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006. [ 12 ]


Müllerian duct anomalies  are those structural anomalies caused by errors in  Müllerian duct  development as an embryo forms. Factors contributing to them include genetics and maternal exposure to substances that interfere with fetal development. [ 1 ] [ 2 ]


Genetic causes of Müllerian duct anomalies are complicated and uncommon. Inheritance patterns can be  autosomal dominant ,  autosomal recessive , and X-linked disorders. Müllerian anomalies can be part of a multiple malformation syndrome. [ 1 ] [ 3 ]  Studies have estimated that Mullerian anomalies can affect between 4 percent and nearly 7 percent of the female population.  [ 4 ] [ 5 ]


Müllerian anomalies occur as a congenital malformation of the Müllerian ducts during  embryogenesis . The Müllerian ducts are also referred to as  paramesonephric ducts , referring to ducts next to (para) the mesonephric (Wolffian) duct during foetal development.  Paramesonephric ducts  are paired ducts derived from the embryo, and for females develop into the  uterus ,  uterine tubes ,  cervix  and upper two-thirds of the vagina. [ 6 ]  Embryogenesis of the Müllerian ducts play important roles in ensuring normal development of the female reproductive tract. However, when defects in each of the three phases of embryogenesis occur, it results in specific structural malformations which are distinguished according to anatomy into seven classes based on the American Society for Reproductive Medicine (ASRM) classification system. [ 7 ]  Class I and II anomalies result from underdevelopment of the two separate primitive uterine, vaginal and cervical pockets due to an arrest of stage one of  organogenesis , resulting in underdevelopment of both left and right primitive uterus (class I) or underdevelopment of one of the primitive uterus (class II). Class III and IV anomalies result from failure of midline fusion of the two separate primitive pockets due to an arrest of stage two of organogenesis. Class V and VI anomalies result from failure of degeneration of the midline due to an arrest at stage three of organogenesis. Class VII anomalies are malformations caused by  Diethylstilbestrol  (DES). [ 8 ]


Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome is a class I developmental disorder of the Müllerian ducts where the vagina and uterus are underdeveloped or absent. Females with MRHK syndrome have normal chromosome pattern of 46,XX karyotype, with normal functioning ovaries and  secondary sex characteristics . [ 9 ]  Females with MRKH are unable to carry a pregnancy due to a malformed uterus, but can have children via assisted reproduction. MRKH syndrome type 1 results when only reproductive organs such as vagina are affected (vaginal agenesis) and type 2 results when abnormalities develop in other parts of the body such as abnormal kidney formation (unilateral renal agenesis). [ 8 ]


MRKH syndrome occurs from an arrest in the embryonic development in the first phase of  organogenesis , resulting in underdevelopment of one or both the left and right primitive uterus and vagina (agenesis). Specifically, an arrest in the development of the paramesonephric ducts at week seven of gestation is linked to MRKH syndrome. [ 9 ]  During embryological development of the first phase, two separate uterine, cervical and vaginal pockets develop, following which a transverse septum forms across the caudal aspect in the upper two thirds of the vagina, which will dissolve when the lower one third of the vagina (developed from the  urogenital sinus ) fuses with the upper two thirds. An arrest at this stage means midline fusion of pockets do not occur and subsequently are unable to develop into a whole uterus, cervix and vagina. [ 10 ]


Changes in the sequences of DNA bases due to mutations in  WNT3, HNF1b  and  LHX1  are decreased in people with MRKH. [ 11 ]  Mice with mutant alleles for  Wnt4, Wnt5a, Wnt7a  and  Wnt9b  display varying extents of Müllerian duct  hypoplasia  indicating these genes may cause MRKH-like  phenotypes  in humans. [ 12 ]  A commonly identified  copy number variants  (CNVs) deletion of 17q12 is present in both type 1 and type 2 MRKH patients. The deletion of 17q12 results in a loss of 2 specific genes,  HNFB  and  LHX1  at position q12 on chromosome 17 which are linked to Müllerian anomalies. Most 17q12 deletions result from genetic mutations in people with no known history of MRHK syndrome in their family. [ 11 ]


Patients who have not reached puberty are asymptomatic and diagnosis is difficult at this stage as the vagina and uterus are not fully developed. Estrogenization during puberty will increase the size of the uterus and allow for accurate evaluation. Symptomatic patients will present with pain at the uterus area due to infections or abnormal vaginal bleeding with cyclical pelvic pain. [ 13 ]


Diagnosis of  septate uterus  is based on ultrasound findings of two endometrial cavities and a smooth contouring of the fundus. The septum separating both endometrial cavities is thin and may descend into the cervix and the vagina. [ 14 ]  An over extended septum can cause the cervix to be obstructed, allowing pathogens to infect the region resulting in pelvic pain due to inflammation of the cervix. The Müllerian duct can be partially obstructed or fully obstructed. In the case where the Müllerian duct is partially obstructed, a reduced cervix opening obstructs menstrual bleeding flow, causing prolonged menstrual bleeding (hypermenorrhea). When there is complete obstruction, patients will present with absence of menstruation (amenorrhea). [ 15 ]  For patients where the septum extends longitudinally, bleeding will persist when a tampon is used as there are two vaginal openings, and dyspareunia (pain during intercourse) is common. [ 16 ]


Magnetic resonance imaging  (MRI) is useful in detecting obstruction of the endometrium due to  hematometra , which appears as cavitated uterine buds on images, and are unable to be detected by ultrasound. MRI provides three-dimensional information of both internal and external contours and can differentiate septate from  bicornuate uterus  and other complex anomalies. [ 17 ]


Malformation of the Müllerian ducts in foetuses can result in exhibition of extragenital anomalies such as  urological  anomalies that includes unilateral renal agenesis,  horseshoe kidneys  or malformation of collecting ducts. Skeletal malformations which include congenital dislocation of the hip, malformations of the arms, foot, ribs,  hemivertebrae  in the lumbar spine and cervical  spina bifida  are associated with Müllerian anomalies. [ 18 ]  Mutations of homeobox genes  HOXA10 ,  HOXA11  and  HOXA13  in uterus malformations are also responsible for renal and skeletal developmental anomalies. [ 19 ]  However, the mechanism of action of these genes has not been established.


The Frank and Ingram procedure is a common non-operative procedure used to increase function of the vaginal via dilators. The method uses graduated dilators to progressively invaginate the mucosa to dilate the opening, increasing depth and functionality of the vaginal over time. The Ingram modification involves using a bicycle seat positioned between the legs allowing direct contact with the perineum creating pressure on the vagina. Thus, by applying pressure to the mucosa, a  neovagina  forms. It takes between four months up to several years for complete successful treatment. [ 20 ]


The McIndoe procedure uses a split-thickness skin graft from the patient where it is placed over an obturator and sewn at the ends to from a tube with one closed end. A transverse incision at the vaginal dimple and a small cavity is made at the level of the peritoneum by the surgeon. The skin graft and obturator are inserted into the vagina vault and secured to the  labia minora . Synthetic skin grafts are also an alternative, eliminating the need for skin grafts from patients. [ 21 ]  The use of dilators post operation for three to six months is required to prevent contraction of the vagina. Complications include skin graft failure due to the formation of a  hematoma  beneath the graft, postoperative hematoma that prevents the graft from receiving adequate nourishment, rectal perforation and fistula formation. Patients with prior history of vaginal or perineal surgery have higher complication rates. [ 10 ]


The Sigmoid vaginaplasty procedure uses a segment of the patient's  sigmoid colon  where one end is pulled down to form a neovagina while the other end is sealed forming a blind pouch. Complications include narrowing of the vaginal (stenosis) and weakening of pelvic floor muscles and ligaments which are unable to support the uterus (uterine prolapse). As the use of dilators are not required for sigmoid vaginoplasty, this treatment is favoured over the McIndoe procedure. [ 22 ]


Diethylstilbestrol  (DES) was a synthetic oestrogen supplement introduced in 1938 to decrease miscarriage in the first trimester by enhancing the oestrogen dependent  follicular phase  and implantation of  blastocysts . DES is a known  teratogen , by crossing the  placenta  DES disrupts organogenesis by disorganising uterine muscle layers causing maldevelopment of uterus and uterine tube junctions. This prevents normal columnar ciliated cell formation of the vaginal epithelium and reabsorption of vaginal glands. [ 23 ]  When absorbed, DES is broken down to produce a transient quinone-like reactive intermediate that alters normal gene function of  HOX  and  WNT,  affecting differentiation of Müllerian ducts.  In utero  DES exposure has additionally been linked to epigenetic changes responsible for uterine anomalies such as dysregulation of the homeobox gene  HOXA10  by  hypermethylation  of  HOXA10 , altering long term expression of genes which controls uterine organogenesis. [ 24 ]


DES is also an endocrine disrupting compound (EDC) which alters normal hormone responses required for reproductive tract development in foetuses. A dose–response association for DES has not been establish but an association with the time of exposure  in utero  suggest exposure to DES at a certain embryological stage leads to increase susceptibility to Müllerian anomalies. [ 23 ]


Female foetuses exposed to DES  in utero  (DES daughters) have abnormalities in development in three areas of the Müllerian duct, namely of their  uterus ,  cervix  and  vagina . DES uterine anomalies include hypoplastic uterus (small uterus), T-shaped uterine cavity and constrictions of the endometrial cavity. [ 25 ]  DES uterine anomalies vary in extent in different races, with foetuses of African American females being more prone to fibroids development during organogenesis. [ 26 ]  DES cervical and vaginal anomalies include hypoplasia, collar and hood malformation of the vagina and cervix and is seen in 20% of women exposed to DES. [ 25 ]


The prevalence of vaginal agenesis or class I uterine anomalies is 1:5000 female live births globally. The most prevalent form of vaginal agenesis is Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome and results in congenital aplasia or hypoplasia of Müllerian derived structures. [ 9 ]  MRKH syndrome account for 5% to 10% of all Müllerian anomalies. While septate uterus or class II uterine anomalies account for 3% to 7% of all Müllerian anomalies. The prevalence of Müllerian anomalies also differs within the female population, occurring in 5.5% of the general population, 8% in sterile females and 13.3% in females with a history of miscarriage. [ 27 ]


The human  female reproductive system  consists of the  gonads ,  external genitalia  and the  Müllerian duct  system. [ 28 ]  Initially in the embryo, both the Wolffian (mesonephric) and Müllerian (paramesonephric) ducts are present, where development of the Wolffian ducts give rise to the male reproductive tract and development of the Müllerian ducts give rise to the female reproductive tract. [ 28 ] [ 8 ]  These ducts are identical until approximately week 6 of  embryonic development . In males, the sex-determining region Y ( SRY ) gene on the Y chromosome suppresses Müllerian duct development, by initiating the production of  anti-Müllerian hormone  by the  Sertoli cells  of the  testicle . The Müllerian ducts only develop in the absence of anti-Müllerian hormone, where the Wolffian ducts regress. [ citation needed ]


Development of the female reproductive tract begins at approximately week 8 of embryonic development, and development of the Müllerian duct system is typically complete by the end of the  first trimester . [ 8 ] [ 29 ]  The Müllerian ducts develop to give rise to the  fallopian tubes ,  uterus ,  cervix  and upper two-thirds of the  vagina . The  ovaries  are not part of the Müllerian system and arise from primordial  germ cells , which develop at the  genital ridge .


The formation of the female reproductive tract via the Müllerian ducts has 3 distinct stages. An array of Müllerian anomalies can occur if any of these processes are arrested or impaired. [ 8 ] [ 29 ] [ 30 ]


The first stage of Müllerian duct development is  organogenesis , where both Müllerian ducts are formed. [ 29 ]  If the formation of the Müllerian ducts is impaired or does not occur, this can give rise to uterine, cervical and/or vaginal  hypoplasia  or  agenesis . [ 8 ]   Müllerian agenesis , also known as the Mayer–Rokitansky–Kuster–Hauser ( MRKH ) syndrome, results in the  congenital  absence of the vagina or uterus. [ 31 ]  Women with  MRKH  syndrome commonly present with  primary amenorrhea , where  menstruation  does not occur by the age of 16. In the first stage of development, it is also possible for only one Müllerian duct to develop, giving rise to a single uterine horn ( unicornuate uterus ). [ 8 ]  Unicornuate uteri commonly develop on the right side, although the reason for this preference remains elusive. [ 28 ]


The second stage of Müllerian duct development involves the fusion of the inferior portion of the ducts to form the uterus, cervix and upper two-thirds of the vagina. [ 29 ]  The superior part of the Müllerian ducts do not fuse and form the left and right fallopian tubes. Disruptions to this stage of development can result in  didelphys  or  bicornuate  uteri anomalies. [ 8 ]  In both didelphys and bicornuate uteri, the non-fusion of the Müllerian ducts results in two distinct  uterine cavities .


The third and final stage of Müllerian duct development is septal resorption. [ 8 ]  After the lower Müllerian ducts fuse, a central septum is left behind, and this partition must be eliminated to give rise to a single  uterine cavity ,  cervical canal  and  vaginal canal . Defects in septal resorption may produce a  septate uterus  or  arcuate uterus , where the septum divides the uterine cavity. More than 50% of women with reported Müllerian anomalies have septate uteri. [ 28 ]
It is common for other developmental defects to occur in conjunction with Müllerian anomalies, including renal, skeletal, auditory and cardiac abnormalities. [ 30 ] [ 31 ]


The causes of Müllerian anomalies are not well-understood. [ 29 ] [ 30 ] [ 31 ] [ 32 ]  The aetiology of this congenital disease may be multifactorial, with  genetics , socioeconomic factors and geographic factors playing a role in dysfunctional Müllerian duct development. [ 29 ]  Müllerian anomalies likely occur early in development, as the congenital disorder often occurs in association with renal and anorectal disorders. [ 30 ] [ 31 ]


Typically, women with Müllerian abnormalities have a normal female  karyotype  (46, XX). Most incidences of Müllerian anomalies occur sporadically, with instances of familial  inheritance  patterns being less common. [ 30 ]  The genetic component of the disease classically follows an  autosomal dominant  pattern, with variable rates of genotypic expression.


WNT4  is a gene that has a crucial role in embryonic development, particularly to ensure the normal formation of the female reproductive system, the kidneys and several  endocrine  organs. [ 33 ]   The  Wnt4  gene pathway promotes female  sexual differentiation , while suppressing male sexual differentiation. Mice lacking  Wnt4  display androgenisation, the presence of Wolffian ducts and absence of Müllerian ducts. This effect is mirrored in humans, where mutations in the WNT4 gene has been observed in MRKH syndrome patients, who display  hyperandrogenism . Mutations in WNT4 gene are not always present in individuals with Müllerian anomalies or MRKH syndrome, but the WNT4 gene is the only gene that has been clearly implicated in MRKH. [ 30 ]


TP63  is a tumour protein encoded by the  EMX2  gene, which is expressed in uterine and vaginal  epithelium . [ 32 ]  The TP63 protein is required for epithelial differentiation during Müllerian duct development  in utero , by promoting the  transcription  of particular genes. EMX2 mutations result in incomplete Müllerian fusion. Some women with unicornuate uteri exhibit mutant EMX2 and significantly decreased expression of TP63, implicating TP63 in the fusion stage of Müllerian development. [ 9 ]


DES  is a synthetic non-steroidal  estrogen  that was used during 1940–1971, to prevent  premature births ,  miscarriage  and other  pregnancy complications . [ 34 ] [ 35 ]  The use of DES was discontinued after it was established that approximately 69% of females who were exposed to DES in utero had uterine abnormalities. [ 35 ]  DES has been marked as a  teratogen  as it results in malformation of the embryo. DES is more  potent  than  steroidal estrogen  and binds to cytosolic receptors after crossing the  placenta . [ 36 ]
DES is not  metabolised  as quickly as endogenous  estrogen . DES remains bound to cytosolic receptors for a longer period of time. The extended binding time of DES and the subsequent prolonged activation of its cognate receptors has been suggested to disrupt Müllerian development, resulting in uterine abnormalities. Exposure to DES induced multiple uterine abnormalities including constriction bands, hypoplasticity in the uterine cavity and irregular borders. Females exposed to this teratogen in utero presented most commonly with a  T-shaped uterus , resulting in increased rates of  ectopic pregnancy ,  spontaneous abortions , and an overall increased risk of adverse pregnancy outcome. [ 35 ]


The incidence of individuals with Müllerian anomalies is twice as high in the  infertile  population than in the  fertile  population. [ 28 ]  Women who do experience some obstetric complications usually have trouble maintaining full-term  pregnancy , rather than issues with  conception . Due to improper development of the uterus and fallopian tubes, pregnancies in women with Müllerian anomalies could result in  spontaneous abortions ,  preterm birth ,  intrauterine growth restriction ,  perinatal mortality , placental abruption and other malpresentations. [ 37 ] [ 38 ] [ 39 ]


Advancements in the  epidemiology  of Müllerian anomalies has resulted in earlier diagnosis and treatment. Uterine obstructions can be surgically repaired or managed to result in successful perinatal outcomes. [ 38 ]


Normal ovarian function is not interrupted in females with Müllerian anomalies and women with the anomaly have been able to utilise  assisted reproductive technologies  and a  gestational carrier  to increase the chance of successful reproductive outcomes. [ 40 ]


Physiological changes that occur in conjunction with Müllerian anomalies explain why some women with the disorder experience difficulties maintaining pregnancy. These physiological changes include compromised blood flow to the uterus, low uterine muscle mass and an insufficient cervix. [ 38 ] [ 39 ]


An insufficient flow of blood to the uterus would compromise nutritional supply to the foetus and waste removal from the foetus, and this can explain the heightened occurrence of low foetal birth weight ( intrauterine growth restriction ) and  spontaneous abortions  in women with Müllerian anomalies. [ 38 ] [ 40 ]  Women with anomalies such as  didelphys  and  bicornuate  uteri present with a decreased uterine size and subsequent lower muscle mass. [ 37 ] [ 38 ]  A diminished uterine capacity reduces the likelihood of the foetus reaching full-term development due to spatial constraints, explaining the higher rates of preterm births observed in women with Müllerian anomalies. [ citation needed ]


The degree to which the Müllerian anomaly impairs the reproductive potential of a woman varies between individuals, and is dependent on the type of anomaly and its severity. [ 28 ]  Women with minor fusion defects such as arcuate uteri and septate uteri tend to have a lower risk of aversive pregnancy outcome, compared to patients with major fusion defects, such as unicornuate uteri,  bicornuate  uteri and  didelphys  uteri. [ 41 ]  Females with severe  agenesis  and/or  hypoplasia , such as in  MRKH  syndrome, have an increased chance of poor reproductive outcomes without surgical intervention. [ 31 ]


Women with Müllerian anomalies often utilise assisted reproductive technologies such as  in vitro fertilisation  (IVF),  intracytoplasmic sperm injection  (ICSI) and  embryo transfer  (ET), and/or a  gestational carrier . [ 42 ]  Compared to individuals with no  uterine anomalies , women with Müllerian anomalies exhibit no differences in number of follicles produced, number of  oocytes  retrieved, or levels of  estrogen  produced. [ 43 ]  The normal follicular function, oocyte population and estrogen levels in women with Müllerian anomalies occurs as normal ovarian function is not compromised in the disease.


In patients with uterine anomalies, there may be a chance that the  endometrial cavity  can be compromised, such that implantation following  IVF  does not always lead to a successful pregnancy. [ 42 ] [ 43 ]  If an individual has a reduced likelihood of effective implantation, a  gestational carrier  can be appointed to increase the chance of a successful pregnancy. [ 40 ] [ 44 ]


Women that present with unicornuate uteri may have an increased risk of  spontaneous abortions ,  premature labour  and  preterm delivery , while individuals with unicornuate uteri may be at risk of  ectopic pregnancy . [ 34 ] [ 38 ]  These risks can be minimised if assisted reproductive technologies are utilised.


Correcting the anomaly prior to commencing assisted reproductive technologies can increase the possibility of reproductive success by increasing the chance of implantation and reducing the likelihood of complications occurring after pregnancy occurs. [ 38 ]  A greater rate of successful pregnancies are observed in women with septate uteri when the septum is operated on prior to implantation of the embryo. [ 45 ]


Smith–Magenis syndrome  ( SMS ), also known as  17p-microdeletion syndrome , is a  microdeletion syndrome  characterized by an abnormality in the short (p) arm of  chromosome 17 . [ 1 ]  It has features including  intellectual disability , facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals. [ 2 ]


Facial features of children with Smith–Magenis syndrome include a broad and square face, deep-set eyes, large cheeks, and a prominent jaw, as well as a flat nose bridge (in the young child; as the child ages it becomes more ski-jump shaped). Eyes tend to be deep-set, close together, and slanted upwards. Eyebrows are heavy with lateral extension. The mouth is the most noticeable feature; both upper and lower lips are full, and the mouth is wide. The mouth curves downwards and the upper lip curves outwards, due to a fleshy  philtrum . These facial features become more noticeable as the individual ages, as  mandible  growth outstrips that of the  maxilla  leading to a clear midface  hypoplasia . There is also a mild  brachycephaly . [ 3 ]


Disrupted sleep patterns are characteristic of Smith–Magenis syndrome, typically beginning early in life. Affected individuals may be very sleepy during the day, but have trouble falling asleep and awaken several times each night due to an inverted  circadian rhythm  of  melatonin . [ 4 ]


Those affected by Smith–Magenis typically have behavioral problems, which include frequent temper  tantrums , meltdowns and outbursts, aggression, anger, fidgeting, compulsive behavior, anxiety, impulsiveness, and difficulty paying attention. Self-harm behaviours, including biting, hitting, head banging, and skin picking, are very common. Behavioral complications in Smith-Magenis syndrome are thought to be worsened by issues with sleeping.  [ 5 ]  Repetitive self-hugging is a behavioral trait that may be unique to Smith–Magenis syndrome. People with this condition may also compulsively lick their fingers and flip pages of books and magazines (a behavior known as "lick and flip"), as well as possessing an impressive ability to recall a wide range of small details about people or subject-specific trivia. [ citation needed ]


Other symptoms can include short stature, abnormal curvature of the spine ( scoliosis ), reduced sensitivity to  pain  and  temperature , and a hoarse voice. Some people with this disorder have ear abnormalities that lead to hearing loss. Affected individuals may have eye abnormalities that cause nearsightedness ( myopia ),  strabismus , and other problems with vision. Heart and kidney defects also have been reported in people with Smith–Magenis syndrome, though they are less common.


Smith–Magenis syndrome is a chromosomal condition related to  low copy repeats  of specific segments of chromosome 17. [ 6 ]  Most people with SMS have a deletion of genetic material from a specific region of chromosome 17 (17p11.2). Although this region contains multiple genes, recently researchers discovered that the loss of one particular gene, the  retinoic acid  induced 1 or  RAI1 ,  is responsible for most of the characteristic features of this condition. [ 7 ] [ 8 ]  Also, other genes within the chromosome 17 contribute to the variability and severity of the clinical features. The loss of other genes in the deleted region may help explain why the features of Smith–Magenis syndrome vary among affected individuals. A small percentage of people with Smith–Magenis syndrome have a mutation in the  RAI1  gene instead of a chromosomal deletion.


These deletions and mutations lead to the production of an abnormal or nonfunctional version of the  RAI1  protein.  RAI1  is a  transcription factor  that regulates the expression of multiple genes, including several that are involved in controlling  circadian rhythm , such as  CLOCK . [ 9 ]  The groups led by  James Lupski  (Baylor College of Medicine) and Sarah Elsea (Virginia Commonwealth University) are in the process of studying the exact function of this gene in relation to Smith-Magenis syndrome. [ 10 ] [ 11 ]


SMS is typically not inherited. This condition usually results from a genetic change that occurs during the formation of reproductive cells (eggs or sperm) or in early fetal development. People with Smith–Magenis syndrome most often have no history of the condition in their family.


SMS is usually confirmed by blood tests called chromosome ( cytogenetic ) analysis and utilize a technique called FISH ( fluorescent in situ hybridization ). The characteristic micro-deletion was sometimes overlooked in a standard FISH test, leading to a number of people with the symptoms of SMS with negative results. [ citation needed ]


The recent development of the FISH for 17p11.2 deletion test has allowed more accurate detection of this deletion. [ 12 ]  However, further testing is required for variations of Smith–Magenis syndrome that are caused by a mutation of the  RAI1  gene as opposed to a deletion.


Children with SMS are often given psychiatric diagnoses such as  autism ,  attention deficit/hyperactivity disorder  (ADHD),  obsessive-compulsive disorder  (OCD),  attention deficit disorder  (ADD), and/or  mood disorders .


Treatment for Smith–Magenis syndrome relies on managing its symptoms. Children with SMS often require several forms of support, including  physical therapy ,  behaviour therapy ,  occupational therapy , and  speech therapy . Support is often required throughout an affected person's lifetime.


Medication is often used to address some symptoms.  Melatonin  supplements and  trazodone  are commonly used to regulate sleep disturbances. In combination with exogenous melatonin, blockade of endogenous melatonin production during the day by the adrenergic antagonist  acebutolol  can increase concentration, improve sleep and sleep timing and aid in improvement of behaviour. [ 13 ]  Other medications (such as  risperidone ) are sometimes used to regulate violent behavior.


The eponym Smith–Magenis refers to two scientists who described the condition in 1986, namely,  Ann C. M. Smith , a  genetic counselor  at the  National Institutes of Health , and  R. Ellen Magenis , a pediatrician, medical geneticist, and cytogeneticist at the  Oregon Health Sciences University . [ 14 ] [ 15 ]


Witteveen–Kolk syndrome , also known as WITKOS and 15q24 microdeletion syndrome, is a rare  neurodevelopmental disorder  characterized by developmental delay/ intellectual disability ,  facial dysmorphisms , and  short stature . The syndrome is caused by loss of function of switch‐insensitive 3 transcription regulator family member A ( SIN3A ). [ 1 ] [ 2 ]  The syndrome was discovered by developmental neuroscientists Josefine S. Witteveen, PhD and Sharon M. Kolk, PhD, in 2016. [ 1 ]


Classical genetics  is the branch of  genetics  based solely on visible results of reproductive acts. It is the oldest discipline in the field of genetics, going back to the experiments on  Mendelian inheritance  by  Gregor Mendel  who made it possible to identify the basic mechanisms of heredity. Subsequently, these mechanisms have been studied and explained at the molecular level.


Classical genetics consists of the techniques and methodologies of genetics that were in use before the advent of  molecular biology . A key discovery of classical genetics in  eukaryotes  was  genetic linkage . The observation that some  genes  do not segregate independently at  meiosis  broke the laws of Mendelian inheritance and provided science with a way to map characteristics to a location on the  chromosomes . Linkage maps are still used today, especially in breeding for  plant improvement .


After the discovery of the  genetic code  and such tools of  cloning  as  restriction enzymes , the avenues of investigation open to geneticists were greatly broadened. Some classical genetic ideas have been supplanted with the mechanistic understanding brought by molecular discoveries, but many remain intact and in use. Classical genetics is often contrasted with  reverse genetics , and aspects of molecular biology are sometimes referred to as  molecular genetics .


At the base of classical genetics is the concept of a  gene , the hereditary factor tied to a particular simple feature (or character). [ citation needed ]


The set of genes for one or more characters possessed by an individual is the  genotype . A  diploid  individual often has two  alleles  for the determination of a character. [ citation needed ]


Classical genetics is the aspect of  genetics  concerned solely with the transmission of genetic traits via reproductive acts. Genetics is, generally, the study of genes,  genetic variation , and  heredity . The process by which characteristics are passed down from parents to their offspring is called heredity. In the sense of classical genetics, variation is known as the lack of resemblance in related individuals and can be categorized as discontinuous or continuous. Genes are a fundamental part of DNA that is aligned linearly on a eukaryotic chromosome. Chemical information that is transported and encoded by each gene is referred to as a trait. Many organisms possess two genes for each individual trait that is present within that particular individual. These paired genes that control the same trait is classified as an allele. In an individual, the allelic genes that are expressed can be either homozygous, meaning the same, or heterozygous, meaning different. Many pairs of alleles have differing effects that are portrayed in an offspring's  phenotype  and  genotype . The phenotype is a general term that defines an individual's visible, physical traits. The genotype of an offspring is known as its genetic makeup. The alleles of genes can either be dominant or recessive. A dominant allele needs only one copy to be expressed while a recessive allele needs two copies (homozygous) in a diploid organism to be expressed. Dominant and recessive alleles help to determine the offspring's genotypes, and therefore phenotypes. [ citation needed ]


Classical genetics is often referred to as the oldest form of genetics, and began with  Gregor Mendel's  experiments that formulated and defined a fundamental biological concept known as  Mendelian inheritance . Mendelian inheritance is the process in which genes and traits are passed from a set of parents to their offspring. These inherited traits are passed down mechanistically with one gene from one parent and the second gene from another parent in sexually reproducing organisms. This creates the pair of genes in diploid organisms. Gregor Mendel started his experimentation and study of  inheritance  with phenotypes of garden peas and continued the experiments with plants. He focused on the patterns of the traits that were being passed down from one generation to the next generation. This was assessed by  test-crossing  two peas of different colors and observing the resulting phenotypes. After determining how the traits were likely inherited, he began to expand the amount of traits observed and tested and eventually expanded his experimentation by increasing the number of different organisms he tested.


About 150 years ago, Gregor Mendel published his first experiments with the test crossing of  Pisum  peas. Seven different phenotypic characteristics were studied and tested in the peas, including seed color, flower color and seed shape. The seven different characteristics which Mendel selected / checked for the experiment were as follows:


Mendel took peas that had differing phenotypic characteristics and test-crossed them to assess how the parental plants passed the traits down to their offspring. He started by crossing a round, yellow and round, green pea and observed the resulting phenotypes. The results of this experiment allowed him to see which of these two traits was dominant and which was recessive based upon the number of offspring with each phenotype. Mendel then chose to further his experiments by crossing a pea plant homozygous dominant for round and yellow phenotypes with a pea plant that was homozygous recessive for wrinkled and green. The plants that were originally crossed are known as the parental generation, or P generation, and the offspring resulting from the parental cross is known as the first filial, or F1, generation. The plants of the F1 generation resulting from this hybrid cross were all heterozygous round and yellow seeds.


Classical genetics is a hallmark of the start of great discovery in biology, and has led to increased understanding of multiple important components of molecular genetics, human genetics, medical genetics, and much more. Thus, reinforcing Mendel's nickname as the father of modern genetics.


In other words, we can say that classical genetics is basis of the modern genetics. Classical genetics is the Mendelian genetics or the older concepts of the genetics, which solely expressed based on the phenotypes resulted from breeding experiments while the modern genetics is the new concept of genetics, which allows the direct investigation of genotypes together with phenotypes.


Monohybrid Cross (3:1)  [ 2 ]


y


Dihybrid Cross (9:3:3:1)


yR


Yr


yr


An  acentric fragment  is a segment of a  chromosome  that lacks a  centromere . [ 1 ]


Because the centromere is the point of attachment for the  mitotic apparatus , acentric fragments are not evenly distributed to the  daughter cells  in cell division ( mitosis  and  meiosis ).  As a result, one of the daughters will lack the acentric fragment.


Lack of the acentric fragment in one of the daughter cells may have deleterious consequences, depending on the function of the DNA in this region of the chromosome.  In the case of a  haploid  organism or a  gamete , it will be fatal to one of the daughter cells if essential DNA is contained in the lost DNA segment.  In the case of a  diploid  organism, the daughter cell lacking the acentric fragment will show expression of any  recessive genes  found in the homologous chromosome.  Developmental geneticists look for cells and cell lineages lacking  unpaired chromosome  segments produced this way as a means of identifying essential genes for specific functions.


Acentric fragments are commonly generated by chromosome-breaking events, such as  irradiation . Such acentric fragments are unequally distributed between the daughter cells after cell division. Acentric fragments can also be produced when an  inverted  segment is present in one member of a chromosome pair. In that case, a crossover event will result in one chromosome with two centromeres and an acentric fragment. The acentric fragment will be lost as explained above, and chromosomes with two centromeres will break unevenly during mitosis, resulting in one daughter lacking essential genes. [ 2 ]


Achiasmate meiosis  refers to  meiosis  without  chiasmata , which are structures that are necessary for  recombination  to occur and that usually aid in the  segregation  of non-sister homologs. [ 1 ]  The  pachytene  stage of  prophase I  typically results in the formation of chiasmata between homologous non-sister  chromatids  in the tetrad chromosomes that form. [ 1 ]  The formation of a chiasma is also referred to as  crossing over . When two homologous chromatids cross over, they form a chiasma at the point of their intersection. However, it has been found that there are cases where one or more pairs of homologous chromosomes do not form chiasmata during  pachynema . [ 2 ] [ 3 ] [ 4 ]  Without a chiasma, no recombination between  homologs  can occur.


The traditional line of thinking was that without at least one  chiasma  between homologs, they could not be properly segregated during  metaphase  because there would be no tension between the homologs for the  microtubules  to pull against. [ 5 ]  This tension between the homologs is typically what allows the chromosomes to align along an axis of the cell (the  metaphase plate ) and to then properly segregate to opposite sides of the cell. Despite this, achiasmate homologs are still found to line up with the  chiasmate  chromosomes at the  metaphase plate . [ 6 ]


Chiasmata play a crucial role in correctly segregating the chromosomes during meiosis I to maintain correct  ploidy ; when chiasmata fail to form, it typically results in  aneuploidy  and nonviable  gametes . [ 2 ]  However, some species have been found to employ alternative methods to segregate chromosomes. [ 5 ]  They all involve linking the homologs together with some structure. These structures provide the same needed tension that chiasmata usually provide.


One segregation strategy is to create a  centromere -centromere interaction between achiasmate homologous chromosomes. Residual proteins from the  synaptonemal complex  (SC) ‘stick’ between the homologs' centromeres after  diplotene , when the SC typically dissociates, allowing the homologs to achieve  biorientation  and attach correctly to the microtubules during  anaphase I . [ 2 ]  This has been observed in budding yeast,  Drosophila melanogaster , and mouse  spermatocytes . [ 2 ]


Heterochromatin  is a tightly grouped type of DNA. Threads of heterochromatin have been observed in  Drosophila melanogaster , connecting achiasmate homologs and allowing them to move pull back and forth by  spindles  as a connected duo. [ 6 ] [ 7 ]


While multiple species of budding yeast have been found to have residual SC proteins that connect the centromeres together when needed, nearly all of said species are chiasmatic and have been simply used as convenient model organisms. [ 2 ] [ 3 ]  However,  Saccharomycodes ludwigii  also displays centromere-centromere interactions with SC proteins and is also almost entirely achiasmatic. It employs the breeding strategy of  automixis  (commonly used by many budding yeasts) in addition with a nearly complete lack of genetic mixing via crossovers to gain the genetic/evolutionary advantages of cloning ( asexual reproduction ) while maintaining the  heterozygosity  typically afforded by  sexual reproduction . [ 8 ]   S. ludwigii  also creates strong connections between the tetrads produced by meiosis to promote the breeding (automixis) within the tetrad. This breeding strategy may have evolved “through mutual selection between suppression of meiotic recombination and frequent intratetrad mating", which would have helped the trait spread to fixation. [ 8 ]


In  Drosophila melanogaster , both  oocytes  and  spermatocytes  display achiasmy. In oocytes, neither the 4th nor the sex-determining chromosomes form chiasmata; in spermatocytes, no chiasmata form on any of the chromosomes. [ 7 ] [ 9 ]  Heterochromatin threads have been observed in  D. melanogaster  oocytes. [ 6 ]  Unusually,  D. melanogaster  lack SCs all together, so SC proteins likely do not play a role in this species' segregation strategy. [ 9 ]


Amazon Mollies  ( Poecilia formosa ) reproduce without recombination via  gynogenesis . They mate with males of other species and the sperm triggers the development of their eggs, but the Amazon Mollies create diploid eggs that have copies of only their own genes. [ 4 ]  There is no crossing over during their meiosis, indicating that they have achiasmate meiosis. It is theorized that this failure during the meiotic cycle is what creates the diploid eggs and that likely sister chromatids are separated during meiosis instead of the homologs in this species. [ 4 ]  If sister chromatids are being separated instead of homologs, than proper segregation of homologs has failed in this species.


True bugs (order  Heteroptera ) are partially of achiasmate species and partially of chiasmate species in reference to  spermatogenesis . The infraorder  Cimicomorpha , specifically its families  Anthocoridae ,  Microphysidae ,  Cimicidae ,  Miridae , and  Nabidae  are achiasmate. Additionally, achiasmy has been reported in the infraorder  Leptopodomorpha  and in the family  Micronectidae  on the infraorder  Nepomorpha . [ 10 ] [ 11 ]  A deeper understanding of how meiosis proceeds in these achiasmate species is still under investigation.


It is thought that achiasmatic meiosis is  polyphyletic , as there is no distinct pattern to its occurrence, nor to the methods through which it occurs. It appears to instead be multiple instances of secondary loss of meiotic recombination that resulted in either the evolution of new segregation processes, or a shift to an existing backup system for segregation. [ 5 ]  Current evidence suggests the latter, that there are existing mechanisms to segregate homologs without chiasmata, as these mechanisms (heterochromatin and centromere-centromere interaction) have been observed in chiasmate species. [ 12 ] [ 2 ]


An  allele [ 1 ] , or  allelomorph , is a variant of the sequence of  nucleotides  at a particular location, or  locus , on a  DNA  molecule. [ 2 ]


Alleles can differ at a single position through  single nucleotide polymorphisms  (SNP), [ 3 ]  but they can also have insertions and deletions of up to several thousand  base pairs . [ 4 ]


Most alleles observed result in little or no change in the function of the  gene  product it codes for. However, sometimes different alleles can result in different observable  phenotypic traits , such as different  pigmentation . A notable example of this is  Gregor Mendel 's discovery that the white and purple flower colors in  pea  plants were the result of a single gene with two alleles.


Nearly all  multicellular organisms  have two sets of  chromosomes  at some point in their  biological life cycle ; that is, they are  diploid . For a given locus, if the two chromosomes contain the same allele, they, and the organism, are  homozygous  with respect to that allele. If the alleles are different, they, and the organism, are  heterozygous  with respect to those alleles.


Popular definitions of 'allele' typically refer only to different alleles within genes. For example, the  ABO blood grouping  is controlled by the  ABO gene , which has six common alleles (variants). In  population genetics , nearly every living human's  phenotype  for the ABO gene is some combination of just these six alleles. [ 5 ] [ 6 ]


The word "allele" is a short form of "allelomorph" ("other form", a word coined by British geneticists  William Bateson  and  Edith Rebecca Saunders ) in the 1900s, [ 7 ] [ 8 ]  which was used in the early days of  genetics  to describe variant forms of a  gene  detected in different  phenotypes  and identified to cause the differences between them. It derives from the  Greek  prefix ἀλληλο-,  allelo- , meaning "mutual", "reciprocal", or "each other", which itself is related to the Greek adjective ἄλλος,  allos  (cognate with  Latin   alius ), meaning "other".


In many cases, genotypic interactions between the two alleles at a locus can be described as  dominant  or  recessive , according to which of the two homozygous phenotypes the  heterozygote  most resembles. Where the heterozygote is indistinguishable from one of the homozygotes, the allele expressed is the one that leads to the "dominant" phenotype, [ 9 ] [ 10 ]  and the other allele is said to be "recessive". The degree and pattern of dominance varies among loci. This type of interaction was first formally-described by  Gregor Mendel . However, many traits defy this simple categorization and the phenotypes are modelled by  co-dominance  and  polygenic inheritance . [ 11 ]