Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development

Abstract

Background Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic. Methods To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed. Results Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients. Conclusion Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.

Whole‐genome resequencing reveals novel sex‐related markers and candidate gene in the Chinese soft‐shelled turtle (Pelodiscus sinensis)

“…Correspondingly, RSPO1 has been reported to be highly expressed in the female ovaries of P. sinensis (Liang, Meng, et al, 2019b). This study, however, revealed a surprising female‐biased expression of PsZNRF3 , with significantly higher expression levels in ovaries than in testes, diverging from mammalian patterns yet aligning with findings in Neocaridina denticulate (Harris et al, 2018; Muncaster et al, 2023; Rjiba et al, 2023). Additionally, the study compared expression levels (FPKM values) of PsZNRF3 across different embryonic development stages between females and males, revealing consistently higher expression in females.…”

“…These sex‐specific loci were annotated, revealing that 19 SNPs were situated within the Zinc and ring finger 3 ( ZNRF3 ) gene, known for its role in testis determination in mammals and which has been the focus of significant research in recent years (Rjiba et al, 2023). Mammalian sex determination is governed by the antagonistic interplay between the testis‐determining (SRY‐SOX9‐FGF9) pathway and the ovary‐promoting (RSPO1‐WNT/β‐catenin‐FOXL2) pathway.…”

<i>PTPN11</i> and <i>FLNA</i> variants in a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features

“…Loss-of-function variants of FLNA have been causally associated with neurodevelopmental and skeletal disorders ( 15 , 16 ). Although 46,XY DSD is not a common symptom of patients with FLNA mutations, hypospadias and cryptorchidism have been reported in a few cases ( 7 , 8 , 17 ). Importantly, Carrera-Garcia et al .…”

“…FLNA is known as a causative gene for neurodevelopmental and skeletal abnormalities ( 6 ). Rare variants in FLNA have been identified in a few patients with 46,XY DSD without neuronal or skeletal anomalies ( 7 , 8 ).…”