The evolving role of whole-exome sequencing in the management of disorders of sex development

Abstract

Objective: Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two patients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management, and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome

“…According to a series of 19 cases, distinct facial features seem to be present in 100% of cases, followed by digital abnormalities (89%), neurologic findings (79%), micropenis (33%), and cryptorchidism (20%) [34]. Reviewing WITKOS cases reported in the literature, it is possible to point out several characteristics that are present in the patients described here [18–20, 36–39, 60–64]. CHH diagnosis is challenging in these cases, as the majority of patients described were individuals at prepubertal age [18, 19].…”

Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development

“…In light of our finding, suggesting that TEs may participate in sex determination, it will be interesting to re-analyze human patients suffering of difference of sexual development (DSDs) with unexplained etiology (more than 50%: (Rakover et al 2021)) to see whether reshuffle of TEs loci might be the cause for their phenotypes. Indeed, development of long-reads technologies of sequencing, and dedicated bioinformatic tools for analysis of repeated sequenced, would allow to better resolve these questions.…”

Clinical utility of early rapid genome sequencing in the evaluation of patients with differences of sex development

“…Despite clear benefits, these technologies have been slow to be incorporated in pediatric medicine owing to perceived deficiencies in turnaround time, cost, standardization, and genotype–phenotype correlation. However, as advances in clinical informatics infrastructure and quality control are made, there is increasing evidence to support rapid result availability, cost–benefit, and medical and psychosocial clinical impact of these genomic diagnostic modalities, including for patients with DSD (Barseghyan et al, 2018; Diaby et al, 2022; Manolio et al, 2015; Parivesh et al, 2019; Stark et al, 2018; Tenenbaum‐Rakover et al, 2021).…”