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At least 19 recordsLinked to original sources
PubMed2026

Three-Year Experience of Cytogenetic and Molecular Genetic Evaluation in Patients With Disorders of Sex Development at a Tertiary Care Centre in Eastern India.

OBJECTIVES: Disorders of sex development (DSD) include a range of conditions in which chromosomal, gonadal, or anatomical sex deviates from the typical developmental pathway. The diagnostic approach to DSD has shifted from karyotyping to molecular genetic tools. This study evaluated the clinical presentation, cytogenetic spectrum, and diagnostic utility of conventional and advanced molecular genetic investigations in patients with suspected DSD managed at a tertiary care facility in Eastern India over a three-year period. METHODS: A retrospective observational study was conducted at the Genetics Laboratory of a tertiary care teaching hospital in Eastern India. Consecutive patients with clinically suspected DSD referred between January 2022 and December 2024 were included. Demographic and clinical data were obtained from referral records, and peripheral blood samples were analysed using standard G-banded karyotyping according to the International System for Human Cytogenomic Nomenclature (ISCN 2020). Fluorescence in situ hybridisation (FISH), chromosomal microarray analysis (CMA), and whole-genome sequencing (WGS) were selectively performed in cases with inconclusive cytogenetic findings, suspected structural chromosomal abnormalities, or complex phenotypes. RESULTS: A total of 98 suspected DSD cases were evaluated during the study period. The most frequent chromosomal constitution was 46,XY DSD (37, 37.8%), followed by 46,XX DSD (30, 30.6%) and sex chromosome DSD (21, 21.4%). Culture failure occurred in 10 (10.2%) samples. Advanced genetic techniques, including FISH, CMA, and WGS, improved diagnostic clarification in selected complex cases. CONCLUSION: This experience highlights the importance of integrating contemporary high-resolution technologies with conventional cytogenetics to enhance the assessment, counselling, and treatment of individuals with DSD.

chromosomal analysis↗
PubMed2026

The role of the external genitalia score (EGS) in evaluation of disorders of sex development.

OBJECTIVE: To investigate the utility of the External Genitalia Score (EGS) in the diagnosis of disorders of sex development (DSD) and decision-making regarding gender assignment in affected patients. METHODS: A retrospective cohort study was conducted, enrolling 114 DSD patients aged <2 years (88 reared as males, 26 reared as females) treated at our hospital between April 2005 and June 2023, alongside 40 hypospadias patients aged <2 years who underwent surgery at our institution from January to July 2023. Demographic data (age) and EGS assessments of external genitalia were collected for all participants. Statistical analyses included independent samples t-tests, Mann-Whitney U tests and Receiver Operating Characteristic (ROC) curve analysis. Specifically, EGS scores were compared between the hypospadias group and the male-reared subgroup of the DSD cohort; additionally, EGS scores were contrasted between male-reared and female-reared DSD subgroups. RESULTS: The mean age was 20.3 months in the hypospadias group, 17.9 months in the male-reared DSD group, and 18.8 months in the female-reared DSD group. EGS ranged from 5.5 to 11.5 (median 10.5) in the hypospadias group and from 1 to 12 (median 4.75) in the DSD group. ROC curve analysis was performed to compare EGS scores between the hypospadias group and the male-reared DSD subgroup. The optimal diagnostic threshold was determined by maximizing the Youden index (sensitivity + specificity - 1), which balances sensitivity and specificity. A cut-off value of &#x2264;8.50 was identified as indicative of DSD; clinically, patients with an EGS score <9 should be prioritized for DSD screening. Further comparison between male-reared and female-reared DSD subgroups yielded a threshold of 4.00. Clinically, an EGS score &#x2264;4 may suggest a preference for female gender assignment. DISCUSSION: The EGS scale is a reliable, valid, and clinically feasible tool for characterizing external genitalia in DSD patients. An EGS score of 9 can serve as an indicator for initiating detailed sex development evaluation in hypospadias patients. While gender assignment in DSD is a complex, multifactorial process, EGS scores showed a significant association with the sex of rearing in our cohort. In settings where major determinants are balanced, EGS may serve as an adjunctive descriptive parameter rather than a standalone decision-making tool.

Humans↗
PubMed2025

Detection of copy number variations by chromosomal microarray analysis in disorders of sex development of unexplained molecular etiology and association with clinical findings.

PURPOSE: Despite advances in genetic diagnostics, the molecular cause of a significant proportion of DSDs remains unknown. The aim of this study was to identify copy number variations (CNVs) using chromosomal microarray analysis (CMA) technology in DSD patients with previously undetected molecular genetic etiology and to investigate their phenotypic associations with these variations. METHODS: This study included DSD cases without chromosomal abnormalities and without any variants detected by sequence analysis methods, including whole-exome sequencing analysis. We evaluated variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines and recorded the phenotypic findings of the cases. All pathogenic variants were subjected to segregation analysis. RESULTS: Of the 20 patients included in the study, 16 (80%) were classified as 46,XY DSD and 4 (20%) as 46,XX DSD. Initial clinical diagnoses in this 46,XX DSD group included gonadal dysgenesis in two patients (50%) and androgen excess in the remaining two (50%). Among the 46,XY DSD patients, five patients (31.25%) were presumed to be androgen insensitive, nine (56.25%) were diagnosed with defects in androgen biosynthesis, and two (12.5%) had gonadal dysgenesis. CMA detected 38 CNVs in 16 patients (80%), comprising 12 deletions (31.6%) and 26 duplications (68.4%). Three pathogenic CNVs were detected in 3 patients (15%), whereas 27 variants of uncertain significance were identified in 13 patients (65%). CONCLUSION: In selected cases, the diagnostic approach should incorporate CMA to elucidate the molecular etiology of DSD. Furthermore, CMA may prove to be an invaluable tool in the search for new genes responsible for DSD.

Humans↗
PubMed2025

DHX37 variants in patients with 46,XY disorders or differences of sex development.

Here, using whole-exome sequencing of a cohort of 17 Japanese patients with 46,XY disorders or differences of sex development, we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in three patients. We also identified a patient with a likely pathogenic variant in SOX9 and a rare likely benign variant in DHX37. This Data Report highlights the genetic and phenotypic diversity of DXH37 variants.

Journal Article↗
PubMed2026

Novel compound heterozygous POR variants in a neonate with Antley-Bixler syndrome and 46,XY DSD: a case report and literature review.

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities. CASE PRESENTATION: We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the POR gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in cis, c.1447G>A (p.Gly483Ser) and c.1806&#xa0;+&#xa0;4_1806&#xa0;+&#xa0;28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)-binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806&#xa0;+&#xa0;4_1806&#xa0;+&#xa0;28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)-binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806&#xa0;+&#xa0;4_1806&#xa0;+&#xa0;28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS). CONCLUSIONS: This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.

Humans↗
PubMed2026

Molecular analysis of individuals with suspected 46,XY differences of sex development in a homogenous and understudied population.

Differences of sex development (DSD) are a group of rare congenital conditions defined by atypical chromosomal, gonadal, and/or hormonal sex. Despite advances in massively parallel sequencing (MPS), more than half of DSD cases have an unknown genetic aetiology. We recruited and analysed 21 individuals with 46,XY DSD from the Greater Middle East population using chromosomal microarray and whole exome sequencing. Participants had DSD ranging from micropenis to anorchia (absence of testes) with extra-genital features reported in four individuals (19%). Using a combination of microarray and WES, a genetic diagnosis (variants curated as likely pathogenic or pathogenic) was identified in 12/21 (57%) individuals. Microarray analysis showed two DSD participants with extra genital features had chromosomal abnormalities (48,XXXY and mosaic Y chromosomal rearrangement). Microarray also indicated a high degree of consanguinity, with extensive long contiguous stretches of homozygosity (LCSH) (>3% of the genome) in 6/21 (28.6%) individuals, all of whom received a genetic diagnosis. WES analysis revealed variants in the NR5A1 (three individuals), SRD5A2 (three individuals), TALDO1 (one individual) and AR (two individuals) genes. This includes the novel frameshift variant, c.1309del (p.Leu437Cysfs*59), in NR5A1. This study contributes to the characterisation of clinical features and molecular findings in individuals with DSD in this understudied and homogenous population and highlights the challenges with DSD diagnosis in the region. The genetic diagnoses identified may contribute to improved patient care and management.

Humans↗
PubMed2026

Post-translational modification of proteins in the human testis development pathway.

BACKGROUND: The foetal testes produce the androgens necessary to masculinise the developing embryo and support the maturation of germ cells, that will eventually develop into sperm, thus ensuring future reproductive capacity. The testes develop from the bi-potential gonads in a highly orchestrated process resulting in the differentiation of a complex tissue with multiple cellular lineages. While recent transcriptomic and chromatin-based analyses of human foetal testes have provided an unprecedented level of insight into signalling pathways activated during this process, proteomic studies of the human foetal gonads remain limited. Proteins are active molecules and post-translational modification (PTM) of proteins influences protein activity, stability and localisation. Studies have shown that PTMs regulate critical proteins in testis development, and their disruptions are implicated in congenital disorders including differences of sex development (DSD), in which sex development is atypical. Despite this, the role and regulation of protein PTM during human testis development remains poorly understood due to limited access to human foetal gonadal tissue, a paucity of large-scale proteomics studies, and a lack of robust of human gonad in vitro models. OBJECTIVE AND RATIONALE: This review aims to provide a comprehensive analysis of validated PTMs affecting proteins critical for testicular development. We discuss PTMs with evidence for a role in normal testis development, and highlight those disrupted in DSD. We review emerging techniques, including proteomic technologies and organ modelling systems that may advance our understanding of PTMs in foetal testis development. We discuss challenges that have restricted the application of these technologies and how overcoming these will significantly improve our understanding of testis development and disease, diagnostics and patient outcomes. SEARCH METHODS: We searched PubMed and the University of Melbourne library for peer-reviewed English-language studies using keywords such as phosphorylation, SUMOylation, acetylation, ubiquitination alongside each protein of interest. PTM sites in proteins involved in testis development were identified using the PhosphoSitePlus database focusing those confirmed in in vitro or animal model studies. ClinVar and the Human Gene Mutation Database were used to identify patient variants that may disrupt PTM sites. OUTCOMES: Our review finds that proteins required for human foetal testis development are subject to extensive PTM. Several PTM sites and PTM-mediated pathways [e.g. MAPK (mitogen-activated protein kinase) pathway] are disrupted in patients with DSD or related conditions. While recent advances in proteomics technologies hold considerable promise, their application to human foetal gonads has been constrained by technical, ethical, and logistical challenges. Encouragingly, emerging high-sensitivity and low-input technologies, alongside stem cell-based approaches, offer viable pathways to overcoming these barriers. WIDER IMPLICATIONS: The relationship between gene regulation, protein expression, and cellular outcome is inherently non-linear, shaped by additional regulatory layers-most notably PTMs. The contribution of PTMs to human testis development in both typical and atypical contexts is a major knowledge gap. Addressing this gap has broad clinical and biological relevance: it may help improve genetic diagnosis or shed light on how proteins or pathways critical for testis development respond to environmental signals-an increasingly pressing question as declining global fertility rates bring testicular function under greater scrutiny. REGISTRATION NUMBER: N/A.

Humans↗
PubMed2025

Sex differences in the developing human cortex intersect with genetic risk of neurodevelopmental disorders.

Autism is highly heritable and diagnosed more frequently in males than females. To identify neurodevelopmental processes that might present sex-biased vulnerability, we generated transcriptomic and epigenomic profiles of cell types present in the prenatally developing human cerebral cortex of 27 males and 21 females. By intersecting sex-biased molecular signatures and genes with de novo mutations in male and female autistic probands, we reveal two points of vulnerability contributing to the sex-biased penetrance in neurodevelopmental disorders (NDDs). First, we show that NDD risk genes are biased towards higher expression in females, identifying the NDD gene MEF2C as a critical transcription factor for female-biased expression. Second, we identify a significant contribution of X chromosome genes to NDD pathobiology. We construct a gene regulatory map of X-linked risk genes to enable functional studies of genetic variants that likely disrupt gene expression in the developing brains of autistic males. Together, these results point towards an outsized contribution of the X-chromosome to both the origin of sex differences in the developing human cortex and NDD vulnerability. We propose a model where female-biased vulnerability is driven by coding variation within genes while male-biased vulnerability is driven by noncoding variation in regulatory elements that affect gene expression.

Sex differences↗
PubMed2024

Consider CUX1 variants in children with a variation of sex development: a case report and review of the literature.

BACKGROUND: The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. CASE PRESENTATION: The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4-10 of the CUX1 gene. CONCLUSIONS: Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.

Humans↗
PubMed1978

The urologic manifestations of XO/XY mosaicism.

The mosaic karyotype XO/XY is expressed by a spectrum of genital phenotypes, ranging from normal male through ambiguous genitalia to normal female. The urologist may see some of these patients because of the following clinical presentations: 1) ambiguous genitalia with a chromatin-negative buccal smear, 2) hypospadias with cryptorchidism or 3) cryptorchidism with müllerian remnants, discovered unexpectedly during inguinal operations. Reliable karyotyping is mandatory for diagnosis of XO/XY patients. Management should include laparotomy with excision of any intra-abdominal gonads (testis and/or streak gonad) because these are prone to develop malignancies that may occur before puberty. Female sex assignment and a reconstructive operation are advised in cases with severely deficient virilization of the genitalia.

Cryptorchidism↗
PubMedDate not supplied

Sexual development and activity of men with disturbances of somatic development.

By means of Questionnaires HTDM and SAM the heterosexual development and sexual activity were investigated in the following groups of males: 1. the control group consists of 345 married men from sterile marriages, who were adequately developed somatosexually, had normozoospermia in the ejaculate and a good potency; 2. in 48 unilateral and 57 bilateral adult cryptorchids; 3. in 101 married men with a distinct testicular hypoplasia, the long axis of both sexual glands being shorter than 30 mm; 4. in 110 patients with a Klinefelter's syndrome; 5. in 14 patients with hypogonadotropic hypogonadism. Whereas the retardation of heterosexual development was found only in two groups (group 4 and 5), a distinctly lowered activity in sex life was ascertained in all four pathological samples.

Adult↗
PubMed1976

HCG stimulation test in children with abnormal sexual development.

Plasma testosterone was estimated by radioimmunoassay in 60 children with disorders of sexual development before and after stimulation with human chorionic gonadotrophin (HCG). In 21 children the testosterone levels after 3 and 5 daily injections of 1000 units HCG were compared and good correlation was found between the paired results (r =0-93), suggesting that the 5-day HCG test has no advantage over the 3-day test. In 7 boys with apparently normal genital development the increments in plasma testosterone ranged from 2-0 to 8-5 nmol/1 after 3 injections of HCG. 10 boys with anorchia showed little response to HCG stimulation, but in patients with other disorders, such as micropenis (10), cryptorchidism (8), hermaphroditism (3), male pseudohermaphroditism (13), hypospadias (3), and sex chromosome anomalies (6), there was considerable variation in the plasma testosterone level after HCG. In 2 boys with suspected anorchia the results suggested that testes were present and this was confirmed at operation.

Adolescent↗