The genetic background of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: A systematic review.

The Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome.The MRKH syndrome affects at least 1 in 4000 to 5000 female new-borns. Although most of the cases are sporadic, familial clustering has also been described, indicating a genetic cause of the disease. However, the mode of inheritance is autosomal-dominant inheritance with reduced penetrance. High-resolution array-CGH and MLPA analysis revealed recurrent aberrations in different chromosomal regions such as TAR susceptibility locus in 1q21.1, chromosomal regions 16p11.2, and 17q12 and 22q11.21 microduplication and -deletion regions in patients with MRKH. Sequential analysis of the genes LHX1, TBX6 and RBM8A, which are located in chromosomal regions 17q12, 16p11.2 and 1q21.1, yielded in the detection of MRKH-associated mutations. In a subgroup of patients with signs of hyperandrogenaemia mutations of WNT4 have been found to be causative. Analysis of another member of the WNT family, WNT9B, resulted in the detection of some causative mutations in MRKH patients.

Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for 1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.

Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome)

The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. It affects at least one out of 4,500 women. MRKH may be isolated (type I) but it is more frequently associated with renal, vertebral and, to a lesser extent, auditory and cardiac defects (MRKH type II or MURCS association). The first sign of MRKH syndrome is a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia, with normal and functional ovaries, and karyotype 46, XX without visible chromosomal anomaly. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or associations and thus require accurate delineation. For a long time, the syndrome has been considered as a sporadic anomaly, but increasing number of familial cases now supports the hypothesis of a genetic cause. In familial cases, the syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. This suggests that the involvement of either mutations in a major developmental gene or a limited chromosomal imbalance. However, the etiology of MRKH syndrome still remains unclear. Treatment of vaginal aplasia, which consists in creation of a neovagina, can be offered to allow sexual intercourse. As psychological distress is very important in young women with MRKH, it is essential for the patients and their families to attend counseling before and throughout treatment.

Recurrent aberrations identified by array-CGH in patients with Mayer-Rokitansky-Küster-Hauser syndrome

STUDY QUESTIONIs there an increased prevalence of male microchimerism in women with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives?SUMMARY ANSWERPredominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADYThe etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATIONAn observational case–control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients’ association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODSAfter written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome–specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCEThe final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59–21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTIONWe are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGSThis is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERDutch trial register, NTR5961.

Disclosure: A. Navitski: None. L.P. Chorich: None. Z. Hawkins: None. J. Theisen: None. L.C. Layman: None. Background: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare congenital disorder, characterized by the absence/underdevelopment of the uterus and vagina. It may be associated with cardiac, renal, skeletal, and/or auditory defects. Evidence suggests genetic factors in some persons with MRKH (e.g., pathogenic variants in HNF1B, WNT4, and ZNHIT3). Additional genes essential for Müllerian and Wolffian duct development may play a key role in MRKH etiology. Compared to exome sequencing, genome sequencing (GS) provides a broader genomic coverage. This study aimed to use GS of well-characterized families with MRKH to detect clinically relevant pathogenic variants and to determine inheritance. Methods: GS was performed on 31 unrelated individuals with MRKH: type 1 (n=7); type 2 (n=20); unspecified (n=4) and their direct family members (n=93). The average depth was 36.7X. Variants were filtered by mapping quality >30, allelic frequency < 0.01 in gnomAD and 1000 genome databases, top consequence (frameshift, splice acceptor, splice donor, start-lost, stop-gain, stop-lost, transcript ablation), and a Combined Annotation-Dependent Depletion (CADD) score ≥ 20, which predicts high likelihood of deleterious functional consequences. Varsome, which contains >145 databases, was used to categorize variants. Variants were filtered by potential involvement in Mullerian, renal, skeletal, auditory, or cardiac development and function. Likely deleterious variants were confirmed by Sanger sequencing. Results: Of 31 probands, 7 had de novo coding heterozygous variants of uncertain significance (VUS) in: GLS, SF3B1, IPO11-LRRC70, TCP1, NR6A1, SIRT1, SUPT6H, and 10 probands had inherited coding heterozygous VUS, likely pathogenic, or pathogenic variants in ITIH5, AKR1A1, NPHP3, PDGFRA, TENT2, LY6L, RECQL4, TPRN, RESF1, C16orf95, with none of the carrier family members being affected. Five de novo non-coding and 9 inherited non-coding heterozygous VUS with a regulatory function were also detected. Two variants were predicted to be likely deleterious in MRKH. One patient and her healthy mother had a splice-donor variant in HOXA11-AS-205, encoding a long non-coding RNA. Another person and her healthy father had a stop-gain variant in ITIH5. Both variants were confirmed with Sanger sequencing. Conclusion: This comprehensive genetic analysis by GS in 31 well-characterized MRKH families revealed no clear pathogenic variants in the genes with known association to the MRKH phenotype. Two probands had likely deleterious variants in HOXA11-AS-205 and ITIH5 inherited from one parent, suggesting an autosomal dominant inheritance with reduced penetrance, variable expressivity, and/or a sex-limited phenotype to females. More comprehensive analysis of variants in non-coding regulatory regions may provide novel insights to better understand the complex genetic landscape of MRKH. Presentation: 6/2/2024

Disclosure: A. Navitski: None. L.P. Chorich: None. Z. Hawkins: None. J. Theisen: None. L.C. Layman: None. Background: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare congenital disorder, characterized by the absence/underdevelopment of the uterus and vagina. It may be associated with cardiac, renal, skeletal, and/or auditory defects. Evidence suggests genetic factors in some persons with MRKH (e.g., pathogenic variants in HNF1B, WNT4, and ZNHIT3). Additional genes essential for Müllerian and Wolffian duct development may play a key role in MRKH etiology. Compared to exome sequencing, genome sequencing (GS) provides a broader genomic coverage. This study aimed to use GS of well-characterized families with MRKH to detect clinically relevant pathogenic variants and to determine inheritance. Methods: GS was performed on 31 unrelated individuals with MRKH: type 1 (n=7); type 2 (n=20); unspecified (n=4) and their direct family members (n=93). The average depth was 36.7X. Variants were filtered by mapping quality >30, allelic frequency < 0.01 in gnomAD and 1000 genome databases, top consequence (frameshift, splice acceptor, splice donor, start-lost, stop-gain, stop-lost, transcript ablation), and a Combined Annotation-Dependent Depletion (CADD) score ≥ 20, which predicts high likelihood of deleterious functional consequences. Varsome, which contains >145 databases, was used to categorize variants. Variants were filtered by potential involvement in Mullerian, renal, skeletal, auditory, or cardiac development and function. Likely deleterious variants were confirmed by Sanger sequencing. Results: Of 31 probands, 7 had de novo coding heterozygous variants of uncertain significance (VUS) in: GLS, SF3B1, IPO11-LRRC70, TCP1, NR6A1, SIRT1, SUPT6H, and 10 probands had inherited coding heterozygous VUS, likely pathogenic, or pathogenic variants in ITIH5, AKR1A1, NPHP3, PDGFRA, TENT2, LY6L, RECQL4, TPRN, RESF1, C16orf95, with none of the carrier family members being affected. Five de novo non-coding and 9 inherited non-coding heterozygous VUS with a regulatory function were also detected. Two variants were predicted to be likely deleterious in MRKH. One patient and her healthy mother had a splice-donor variant in HOXA11-AS-205, encoding a long non-coding RNA. Another person and her healthy father had a stop-gain variant in ITIH5. Both variants were confirmed with Sanger sequencing. Conclusion: This comprehensive genetic analysis by GS in 31 well-characterized MRKH families revealed no clear pathogenic variants in the genes with known association to the MRKH phenotype. Two probands had likely deleterious variants in HOXA11-AS-205 and ITIH5 inherited from one parent, suggesting an autosomal dominant inheritance with reduced penetrance, variable expressivity, and/or a sex-limited phenotype to females. More comprehensive analysis of variants in non-coding regulatory regions may provide novel insights to better understand the complex genetic landscape of MRKH. Presentation: 6/2/2024

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder of sex development which affects 1 in 4,500 females and is characterized by agenesis of müllerian structures, including the uterus, cervix, and upper vagina. It can occur in isolation (type 1) or in conjunction with various anomalies (type 2), with a subset of these comprising müllerian, renal, and cervicothoracic abnormalities (MURCS) association. The genetic causes of MRKH have been investigated previously yielding limited results, with massive parallel sequencing becoming increasingly utilized. We sought to identify genetic contributions to MRKH using a combination of microarray and whole exome sequencing (WES) on a cohort of 8 unrelated women with MRKH and MURCS. WES data were analysed using a candidate gene approach to identify potential contributing variants. Microarray analysis identified a 0.6-Mb deletion in the previously implicated 16p11.2 region in a patient with MRKH type 2. WES revealed 16 rare nonsynonymous variants in MRKH candidate genes across the cohort. These included variants in several genes, such as LRP10 and DOCK4, associated with disorders with müllerian anomalies. Further functional studies of these variants will help to delineate their biological significance and expand the genotypic spectrum of MRKH.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. It affects at least 1 out of 4500 women. MRKH may be isolated (type I) but it is more frequently associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects (MRKH type II or MURCS association). The first sign of MRKH syndrome is a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia, with normal and functional ovaries, and karyotype 46, XX without visible chromosomal anomaly. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or associations and thus require accurate delineation. For a long time the syndrome has been considered as a sporadic anomaly, but increasing number of familial cases now support the hypothesis of a genetic cause. In familial cases, the syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. This suggests the involvement of either mutations in a major developmental gene or a limited chromosomal imbalance. However, the etiology of MRKH syndrome still remains unclear. Treatment of vaginal aplasia, which consists in creation of a neovagina, can be offered to allow sexual intercourse. As psychological distress is very important in young women with MRKH, it is essential for the patients and their families to attend counseling before and throughout treatment.

Müllerian Agenesis in a patient with Rubinstein-Taybi Syndrome: A Case Series and Review of the Overlapping Developmental Biologic Pathways

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by congenital absence of the uterus and upper 2/3 rd of vagina with a normal 46, XX karyotype and normally developed secondary sexual characteristics. It affects 1:4000 women. It may be isolated (Type I) or frequently associated with renal, vertebral anomalies and less frequently associated with auditory, cardiac defects (Type II). It presents with primary amenorrhea in young women with normal external genitalia and normal development of secondary sexual characteristics with normal functioning ovaries and karyotype 46, XX without visible chromosomal anomaly. It was considered as sporadic anomaly but an increasing number of familial cases is suggestive of genetic cause in whom it is transmitted as autosomal dominant trait with incomplete penetrance and variable expressibility. This is suggestive of involvement of mutation in a major development gene or a limited chromosomal imbalance. Etiology of MRKH syndrome is still unclear. In order to allow sexual intercourse, treatment is aimed at creation of neovagina. Patients and their families must attend counseling before and throughout treatment as psychological distress is very important in young women with MRKH. We hereby report a rare case of MRKH syndrome in a 19-year-old married female patient presenting with primary amenorrhea, coital difficulty and no other clinical disorder.

BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare syndrome that is characterized by congenital aplasia of the uterus and the upper portion (2/3) of the vagina. Previous attempts to identify causal mutations of MRKH syndrome have primarily resulted in negative outcomes. We investigated whether these reported variants are associated with MRKH syndrome (types I and II) in a relatively large sample size of Chinese Han patients, and whether any gene-gene epistatic interactions exist among these variants.MethodsThis study included 182 unrelated Chinese women with MRKH syndrome (155 with type I and 27 with type II) and 228 randomized female controls. Seventeen candidate loci in the AMH, PBX1, WNT4, WNT7A, WNT9B, HOXA10, HOXA11, LHXA1 and GALT genes were genotyped using the Sequenom MassARRAY iPLEX platform. Single-marker association, additive effects and multifactor interactions were investigated.ResultsThe gene frequency distributions of MRKH type 1 and type 2 were similar. Rs34072914 in WNT9B was found to be associated with MRKH syndrome (P = 0.024, OR = 2.65, 95%CI = 1.14–6.17). The dominant models of rs34072914 and rs2275558 in WNT9B and PBX1, respectively, were significantly associated with MRKH syndrome risk in the Chinese Han patients. Additive gene-gene interaction analyses indicated a significant synergetic interaction between WNT9B and PBX1 (RERI = 1.397, AP = 0.493, SI = 4.204). Multifactor dimensionality reduction (MDR) analysis revealed novel dimensional epistatic four-gene effects (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome.ConclusionsThis association study successfully identified two susceptibility SNPs (WNT9B and PBX1) associated with MRKH syndrome risk, both separately and interactively. The discovery of a four-gene epistatic effect (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome provides novel information for the elucidation of the genetic mechanism underlying the etiology of MRKH syndrome.

We have searched the literature for information on the risk of breast cancer (BC) in relation to gender, breast development, and gonadal function in the following 8 populations: 1) females with the Turner syndrome (45, XO); 2) females and males with congenital hypogonadotropic hypogonadism and the Kallmann syndrome; 3) pure gonadal dysgenesis (PGD) in genotypic and phenotypic females and genotypic males (Swyer syndrome); 4) males with the Klinefelter syndrome (47, XXY); 5) male-to-female transgender individuals; 6) female-to-male transgender individuals; 7) genotypic males, but phenotypic females with the complete androgen insensitivity syndrome, and 8) females with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (müllerian agenesis). Based on this search, we have drawn 3 major conclusions. First, the presence of a Y chromosome protects against the development of BC, even when female-size breasts and female-level estrogens are present. Second, without menstrual cycles, BC hardly occurs with an incidence comparable to males. There is a strong correlation between the lifetime number of menstrual cycles and the risk of BC. In our populations the BC risk in genetic females not exposed to progesterone (P4) is very low and comparable to males. Third, BC has been reported only once in genetic females with MRKH syndrome who have normal breasts and ovulating ovaries with normal levels of estrogens and P4. We hypothesize that the oncogenic glycoprotein WNT family member 4 is the link between the genetic cause of MRKH and the absence of BC women with MRKH syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterizing females with absence of the uterus and part of the vagina. Several genetic defects have been correlated with the presence of MRKH; however, the exact etiology is still unknown due to the complexity of the genetic pathways implicated during the embryogenetic development of the Müllerian ducts. A systematic review (SR) of the literature was conducted to investigate the genetic causes associated with MRKH syndrome and Congenital Uterine Anomalies (CUAs). This study aimed to identify the most affected chromosomal areas and genes along with their associated clinical features in order to aid clinicians in distinguishing and identifying the possible genetic cause in each patient offering better genetic counseling. We identified 76 studies describing multiple genetic defects potentially contributing to the pathogenetic mechanism of MRKH syndrome. The most reported chromosomal regions and the possible genes implicated were: 1q21.1 (RBM8A gene), 1p31-1p35 (WNT4 gene), 7p15.3 (HOXA gene), 16p11 (TBX6 gene), 17q12 (LHX1 and HNF1B genes), 22q11.21, and Xp22. Although the etiology of MRKH syndrome is complex, associated clinical features can aid in the identification of a specific genetic defect.