Expanding the phenotypic spectrum of LHCGR signal peptide insertion variant: novel clinical and allelic findings causing Leydig cell hypoplasia type II.

PURPOSE: Leydig cell hypoplasia (LCH) type II is a rare disease with only a few cases reported. Patients presented with hypospadias, micropenis, undescended testes, or infertility. In this study, we report a new patient with compound heterozygous variants in the LHCGR gene and LCH type II phenotype. METHODS: Whole exome sequencing (WES) was performed followed by Sanger sequencing to confirm the detected variants in the patient and his parents. RESULTS: A novel missense variant (p.Phe444Cys) was identified in a highly conserved site and is verified to be in trans with the signal peptide's 33-bases insertion variant. CONCLUSION: Our research provides a more comprehensive clinical and genetic spectrum of Leydig cell hypoplasia type II. It highlighted the importance of WES in the diagnosis of this uncommon genetic disorder as well as the expansion of the genotype of LCH type II.

Congenital leptin and leptin receptor deficiencies in nine new families: identification of six novel variants and review of literature.

Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients' managements specially with the availability of drugs for LEP and LEPR deficiencies.

In vitro cellular reprogramming to model gonad development and its disorders.

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.

A Homozygous Missense Variant in Hedgehog Acyltransferase (HHAT) Gene Associated with 46,XY Gonadal Dysgenesis.

INTRODUCTION: Disorders of gonadal development represent a clinically and genetically heterogeneous group of DSD, and the etiology in many cases remains unknown, indicating that our knowledge of factors controlling sex determination is still limited. METHODS: We describe a 46,XY DSD patient from Egypt. The patient was reared as female, born to consanguineous parents, and was referred to us at the age of 5 years because of ambiguous genitalia. On examination, the girl was microcephalic (head circumference -3 SD), but her height and weight were normal for her age and sex. RESULTS: Exome sequencing identified a homozygous variant in the hedgehog acyltransferase (HHAT) gene, which encodes an enzyme that is required for multimerization and signaling potency of the hedgehog secreted proteins. The variant is a novel homozygous missense change c.1329C>A (p.N443K), located within transmembrane domain 9, which segregated with the phenotype in the family. DISCUSSION/CONCLUSION: Our results expand the phenotypic spectrum associated with HHAT variants to include 46,XY gonadal dysgenesis and reinforce the role of exome sequencing in unraveling new genes that play a pivotal role in sexual development.

Chromosome 9p terminal deletion in nine Egyptian patients and narrowing of the critical region for trigonocephaly.

BACKGROUND: This study aimed to delineate the clinical phenotype of patients with 9p deletions, pinpoint the chromosomal breakpoints, and identify the critical region for trigonocephaly, which is a frequent finding in 9p terminal deletion. METHODS: We investigated a cohort of nine patients with chromosome 9p terminal deletions who all displayed developmental delay, intellectual disability, hypotonia, and dysmorphic features. Of them, eight had trigonocephaly, seven had brain anomalies, seven had autistic manifestations, seven had fair hair, and six had a congenital heart defect (CHD). RESULTS: Karyotyping revealed 9p terminal deletion in all patients, and patients 8 and 9 had additional duplication of other chromosomal segments. We used six bacterial artificial chromosome (BAC) clones that could identify the breakpoints at 17-20 Mb from the 9p terminus. Array CGH identified the precise extent of the deletion in six patients; the deleted regions ranged from 16 to 18.8 Mb in four patients, patient 8 had an 11.58 Mb deletion and patient 9 had a 2.3 Mb deletion. CONCLUSION: The gene deletion in the 9p24 region was insufficient to cause ambiguous genitalia because six of the nine patients had normal genitalia. We suggest that the critical region for trigonocephaly lies between 11,575 and 11,587 Mb from the chromosome 9p terminus. To the best of our knowledge, this is the minimal critical region reported for trigonocephaly in 9p deletion syndrome, and it warrants further delineation.

Testosterone Therapy and Its Monitoring in Adolescent Boys with Hypogonadism: Results of an International Survey from the I-DSD Registry.

It is unclear whether testosterone replacement therapy (TRT) in adolescent boys, affected by a range of endocrine diseases that may be associated with hypogonadism, is particularly common. The aim of this study was to assess the contemporary practice of TRT in boys included in the I-DSD Registry. All participating centres in the I-DSD Registry that had boys between 10 and 18 years of age and with a condition that could be associated with hypogonadism were invited to provide further information in 2019. Information on 162 boys was collected from 15 centres that had a median (range) number of 6 boys per centre (1.35). Of these, 30 (19%) from 9 centres were receiving TRT and the median (range) age at the start was 12.6 years (10.8-16.2), with 6 boys (20%) starting at <12 years. Median (range) age of boys not on TRT was 11.7 years (10.7-17.7), and 69 out of 132 (52%) were <12 years. TRT had been initiated in 20 of 71 (28%) boys with a disorder of gonadal development, 3 of 14 (21%) with a disorder of androgen synthesis, and all 7 (100%) boys with hypogonadotropic hypogonadism. The remainder who did not have TRT included 15 boys with partial androgen insensitivity, 52 with non-specific XY DSD, and 3 with persistent Müllerian duct syndrome. Before starting TRT, liver function and blood count were checked in 19 (68%) and 18 boys (64%), respectively, a bone age assessment was performed in 23 (82%) and bone mineral density assessment in 12 boys (43%). This snapshot of contemporary practice reveals that TRT in boys included in the I-DSD Registry is not very common, whilst the variation in starting and monitoring therapy is quite marked. Standardisation of practice may lead to more effective assessment of treatment outcomes.

IGF1R, IGFALS, and IGFBP3 gene copy number variations in a group of non-syndromic Egyptian short children.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is required for normal intrauterine and postnatal growth, and this action is mediated through IGF1 receptor (IGF1R). IGF1R copy number variants (CNVs) can cause pre- and postnatal growth restriction, affecting an individual's height. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to detect CNVs in IGF1R, IGFALS, and IGFBP3 genes in the diagnostic workup of short stature for 40 Egyptian children with short stature. RESULTS: We detected a heterozygous deletion of IGF1R (exons 4 through 21) in 1 out of the 40 studied children (2.5%). Meanwhile, we did not detect any CNVs in either IGFALS or IGFBP3. CONCLUSION: The diagnostic workup of short stature using MLPA for CNVs of IGF1R and other recognized height-related genes, such as SHOX and GH, in non-syndromic short stature children can be a fast and inexpensive diagnostic tool to recognize a subcategory of patients in which growth hormone treatment can be considered.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.

Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X-linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.

Gonadectomy in conditions affecting sex development: a registry-based cohort study.

OBJECTIVES: To determine trends in clinical practice for individuals with DSD requiring gonadectomy. DESIGN: Retrospective cohort study. METHODS: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. RESULTS: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. CONCLUSIONS: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Assessment of the most common CYP21A2 point mutations in a cohort of congenital adrenal hyperplasia patients from Egypt.

Objectives Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by defects in the CYP21A2 gene. We aimed to determine the prevalence of the most commonly reported mutations among 21-OHD Egyptian patients and correlate genotype with phenotype. Methods Molecular analysis of the CYP21A2 gene was performed for the detection of the six most common point mutations (p.P30L, p.I172N, p.V281L, p.Q318X, the splice site mutation Int2 [IVS2-13A/C>G], and the cluster of three mutations [p.I236N, p.V237E, and p.M239K] designed as CL6). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed on 47 unrelated Egyptian 21α-OH deficiency patients and their available parents to detect the presence of the six most common point mutations. Results Screening for the six most common point mutations in CYP21A2 gene, revealed mutations in 87.2% (82/94) of the studied alleles corresponding to 47 Egyptian patients. The most common mutation among the studied cases was IVS2-13C/A>G that was found to be presented in a frequency of 46.8% (44/94). The genotype/phenotype correlations related to null, A, and B groups were with PPV of 100, 55.5, and 83.3%, respectively. Conclusions The described method diagnosed CAH in 80.8% of the studied patients. Good correlation between genotype and phenotype in salt wasting and simple virilizing forms is determined, whereas little concordance is seen in nonclassical one. Furthermore, studying the carrier frequency of 21-OHD among the normal population is of great importance.

Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene.

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P = 4.4 × 10-6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 × 10-4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1Arg495Gly/Arg495Gly XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor ß-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.

Detection of low-grade mosaicism and its correlation with hormonal profile, testicular volume, and semen quality in a cohort of Egyptian Klinefelter and Klinefelter-like patients.

Klinefelter syndrome (KS) is the most common chromosomal syndrome, causing infertility in men and leading to non-obstructive azoospermia. Previous studies on mosaicism have shown contradictory results on its correlation with both serum hormone levels and the presence of spermatozoa in the ejaculate of KS, KS-like, and non-KS-like infertile patients. So, the present study was designed to detect low-grade mosaicism in the peripheral blood lymphocytes and buccal mucosa cells of 14 KS and 8 KS-like patients by using fluorescence in situ hybridization (FISH) and to investigate its correlation with luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) levels, testicular volume, and semen analysis compared with 10 normal healthy fertile men. Our results indicated that mosaicism was only found in 42.9 % of the KS patients and completely absent in all KS-like patients. Moreover, mosaicism has led to complete azoospermia and non-significant differences in both hormone levels and testicular volume between mosaic and non-mosaic KS patients. All KS patients demonstrated significant differences in both hormone levels and testicular volume compared with normal men. Conversely, they revealed non-significant differences in hormone levels and significant differences in testicular volume compared with KS-like patients. Additionally, the KS-like patients exhibited non-significant variations in both LH and FSH levels and significant variations in T level and testicular volume compared with normal men. Moreover, all KS-like patients had azoospermia, except for one patient who showed oligozoospermia. Therefore, no correlations were found either between mosaicism and serum hormone levels or with testicular volume and semen analysis.

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.

PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.

We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense (c.770T>C, p.[Leu257Pro]) variant in the hedgehog acyl-transferase gene (HHAT), encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling. There is a report of one family with Nivelon-Nivelon-Mabille syndrome in which HHAT was proposed as the likely candidate gene. The phenotypic overlap with the family we report herein provides further evidence implicating HHAT in cerebellar development and the pathogenesis of this rare spectrum.

Cytogenetic Spectrum of Ovotesticular Difference of Sex Development (OT DSD) among a Large Cohort of DSD Patients and Literature Review.

Ovotesticular difference of sex development (OT DSD) is a rare genetic disorder with an incidence of about 1/100,000 live births. The majority of OT DSD patients show a 46,XX karyotype, others may have 46,XX/46,XY chimerism or exhibit various mosaic sex chromosome combinations, and less commonly they may have a 46,XY karyotype. The aim of this work is to report the clinical, pathological, and karyotypic variations in OT DSD patients diagnosed among a large cohort of DSD patients. The study included 10 patients thoroughly evaluated for clinical, genital, and hormonal abnormalities and subjected to imaging studies, laparoscopy with gonadal biopsy, karyotype, and FISH analysis. The current study revealed a greater percentage of mosaic cell line combinations than previously reported and showed variable cytogenetic abnormalities, including the rare isodicentric (Y)(p11.32) abnormality and X;Y translocation. The study also revealed a unique pattern of gonadal type and combination frequencies. To our knowledge, this is the first study on OT DSD patients among a large cohort of DSD patients in Egypt and the Middle East.

GAPO syndrome in seven new patients: Identification of five novel ANTXR1 mutations including the first large intragenic deletion.

GAPO syndrome is a very rare disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy. It is caused by biallelic mutations in the ANTXR1 gene. Herein, we describe the clinical and molecular findings of seven new patients with GAPO syndrome. Our patients presented with the characteristic clinical features of the syndrome except for one patient who did not display total alopecia till the age of two years. Strikingly, optic atrophy and glaucoma were observed in all patients and one patient showed keratopathy in addition. Moreover, craniosynstosis was an unusual associated finding in one patient. Mutational analysis of ANTXR1 gene identified five novel homozygous mutations including two frameshift, two splice site and a large intragenic deletion of exon 3. Our results reinforce the clinical characteristics of the syndrome, expand the mutational spectrum and provide more insights into the role of the ANTXR1 protein in the regulation of extracellular matrix.

Unbalanced 14;X Translocation and Pattern of X Inactivation in a Female Patient with Multiple Congenital Anomalies.

We report on a female patient who was first evaluated at the age of 6 years with developmental delay, dysmorphic facial features, seizures, and autistic behavior. A brain CT showed complete agenesis of the corpus callosum, and EEG recorded bilateral epileptogenic foci. Karyotype analysis revealed 45,X,psu dic(14;X)(p11;p22). FISH using 14q and Xp subtelomeric probes, combined with a SHOX gene-specific probe, and centromere X and XIST gene analysis revealed ish psu dic(14;X)(D14S1420+; DXYS129-, SHOX-, DXZ1+, XIST+). Array CGH detected a 2-Mb loss at Xp22.33 and a 4.6-Mb gain at Xp22.2p22.12. The deletion contains 34 genes, of which CSF2RA and SHOX are OMIM morbid genes. The duplication also contains some OMIM morbid genes, of which CDKL5, NH5, RPS6KA3, and AP1S2 are the most important. The late replicating chromatin technique was used to detect the pattern of X inactivation in the normal X and in the translocated chromosome. The translocated X was found to be inactive in 70% of the studied blood lymphocytes with patchy extension of inactivation to chromosome 14. In conclusion, the phenotype of the patient may be partially affected by the haploinsufficiency of the genes that are known to escape X inactivation and that lie within the deleted region and by other deleted or duplicated genes on the abnormal X chromosome due to an alternative pattern of X inactivation. The phenotype of the patient was significantly aggravated and complicated by the functional monosomy of some genes on chromosome 14 due to partial spreading of inactivation and silencing of those genes. This case report indicates the importance of structural and functional studies and emphasizes the clinical importance of the follow-up of abnormal microarrays.

Clinical and Cytogenetic Study of Egyptian Patients with Sex Chromosome Disorders of Sex Development.

Disorders of sex development (DSD) are conditions with an abnormal development of chromosomal, gonadal, or anatomical sex. Sex chromosome DSD involve conditions associated with either numerical or structural abnormalities of the sex chromosomes. This study included patients comprising a wide spectrum of presenting features suggestive of DSD and aimed at studying the frequency of sex chromosome abnormalities among 108 Egyptian DSD patients who presented to the Clinical Genetics and Endocrinology Clinics, National Research Centre (NRC) over the 2-year period of 2013 and 2014. The age of the studied patients ranged from 2 months to 39 years. The patients exhibited various presentations, including ambiguous genitalia, undescended testis, hypogonadism, short stature with Turner manifestations, primary or secondary amenorrhea, primary infertility, edema of the dorsum of the hands and feet, and dysmorphic features. The patients were subjected to detailed clinical examination, pubertal staging, and cytogenetic analysis. Our study reported a wide karyotypic diversity and a high frequency of sex chromosome DSD, reaching 44.44% (48/108). In conclusion, we showed a high incidence of sex chromosome DSD among Egyptian DSD patients with wide karyotype/phenotype diversity. The most frequent sex chromosome DSD detected among patients of the present study was Turner syndrome and variants (52.08%; 25/48) followed by Klinefelter syndrome and variants (43.75%; 21/48). Further long term studies are necessary for accurate detection of frequencies of different types of sex chromosomal anomalies and associated phenotypes.

A Homozygous Missense Mutation in FANCA Gene in a 46,XY Female with Gonadal Dysgenesis.

Fanconi anemia (FA) is a pleiotropic condition with 2 characteristic phenotypic markers of hematological and cytogenetic changes. The phenotype of patients with FA is very heterogeneous, associated with an array of congenital malformations affecting the skeletal, renal, genital, and/or central nervous systems. Here, we report on a 46,XY female who presented with gonadal dysgenesis and microcephaly. Exome sequencing showed that she was homozygous for a rare variant in the FANCA gene (c.4232C>T, p.P1411L, rs201494304). Both parents were heterozygous for the mutation. The FA mutation was associated with an atypical clinical presentation, and thus exome sequencing provided essential data that otherwise would have been overlooked in the diagnosis of this patient.