ESPE Abstracts

The widespread availability of relatively inexpensive and rapidly evolving genetic screening by whole exome sequencing (WES) has transformed diagnosis in DSD. WES has identified many new genetic causes of DSD (e.g. ZFPM2, NR2F2, ZNRF3), several of which would not have been possible by classic candidate gene approaches (e.g. DHX37 or SART3). However, despite these advances, pathogenic variants in each gene affect only a comparatively...

Disorders of sex development (DSD) constitute an array of rare disorders affecting the genito-urinary tract and the endocrine-reproductive system and are often identified in the newborn or adolescent. Gene mutations causing DSD are slowly being identified using high-throughput sequencing, but the interpretation of the data and ascribing causality to novel variants is challenging. This is because DSD mutations occur in multiple genes with each gene affecting a small number of i...

Background: The age of onset of puberty is known to be influenced by poorly understood genetic and environmental factors. Familial forms of precocious puberty suggest the involvement of autosomal genetic factors.Objective and hypotheses: We evaluated the mode of inheritance of precocious puberty in a large series of familial cases of both central precocious puberty (CPP) and advanced puberty.Method: A retrospective, single-centre s...

Background: RSPO1 is an activator of the canonical Wnt signalling pathway by acting as a ligand for LGR4–6 receptors and an a 46,XX individual it represses testicular development. Only three families have been reported in the literature with recessive mutations in RSPO1 and syndromic 46,XX sex-reversal.Objective and hypotheses: We identified a consanguineous family from Southern Morocco with two sibs presenting with 46,XX testicular and ovo...

MYRF is known to regulate the myelination of the central nervous system and mice with a conditional deletion of MYRF in oligodendrocyte precursors has anomalies of motor skill. Recently, several loss-of-function and missense mutations in MYRF have been reported in association with syndromic forms of congenital heart disease (CHD) with elements of Scimitar syndrome and/or with congenital diaphragmatic hernia (CDH). In most 46,XY individuals a range of...

The Polycomb Repressive Complex 1 (PRC1) represses gene expression through CBX2, which binds to H3K27me3 and promotes chromatin expression. Recently, CBX2 has been shown to function in testis-formation by directly repressing Wnt4's downstream target, Lef1, in Sertoli cells rather than positively controlling Sry expression, as previously thought. Here, we describe two new cases carrying missense mutations in CBX2. The first is a female with 46,XY ...

The genomic analysis of 46,XX individuals with testes (known as testicular Disorders/Differences of Sex Development (TDSD) or ovotestes (ovotesticular DSD (OTDSD)) supports the hypothesis that ‘pro-testis/anti-ovary’ or ‘pro-ovary/anti-testis’ genetic pathways exist. These children typically present with virilized genitalia due to testosterone production from the presence of testicular tissue. Many individuals with TDSD and a minority with OTDSD have a tran...

Background: 46,XX DSD (Disorder of Sex Development) includes individuals with ovotestes (ovotesticular DSD (OTDSD)) or testes (testicular DSD (TDSD)). Most individuals with 46,XX TDSD carry the SRY gene. Other known causes of TDSD/OTDSD include chromosomal rearrangements involving SOX9 or SOX3 and mutations of WNT4 and a WNT regulator, R-SPONDIN 1. However, our understanding of the molecular causes of TDSD and OTDSD remain incomplete.<p ...

Background: The genetic causes of disorders of sex development (DSD) are difficult to identify since these conditions are refractory to classic genetic approaches. In particular the underlying genetic mutations of most cases of 46,XY DSD is unknown.Objective and hypotheses: Using an exome sequencing approach we aimed to identify new genetic factors involved in 46,XY gonadal dysgenesis.Method: Exon enrichment was performed using Agi...

Background: Disorders of sex development (DSD) are classified as a congenital discrepancy between external genitalia, and gonadal and chromosomal sex. Despite extensive laboratory and imaging investigations, the etiology of DSD is unknown in more than 50% of patients. We aimed to evaluate the etiology of DSD using whole exome sequencing (WES) technique.Methods: Eleven patients with DSD (ten with 46,XY and one with 46...