Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin?

Abstract

SF-1/NR5A1 is a transcriptional regulator of adrenal and gonadal development. NR5A1 disease-causing variants cause disorders of sex development (DSD) and adrenal failure, but most affected individuals show a broad DSD/reproductive phenotype only. Most NR5A1 variants show in vitro pathogenic effects, but not when tested in heterozygote state together with wild-type NR5A1 as usually seen in patients. Thus, the genotype-phenotype correlation for NR5A1 variants remains an unsolved question. We analyzed heterozygous 46,XY SF-1/NR5A1 patients by whole exome sequencing and used an algorithm for data analysis based on selected project-specific DSD- and SF-1-related genes. The variants detected were evaluated for their significance in literature, databases and checked in silico using webtools. We identified 19 potentially deleterious variants (one to seven per patient) in 18 genes in four 46,XY DSD subjects carrying heterozygous NR5A1 disease-causing variants. We constructed a scheme of all these hits within the landscape of currently known genes involved in male sex determination and differentiation. Our results suggest that the broad phenotype in these heterozygous NR5A1 46,XY DSD subjects may well be explained by an oligogenic mode of inheritance, in which multiple hits, individually non-deleterious, may contribute to a DSD phenotype unique to each heterozygous SF-1/NR5A1 individual.

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

“…Given the wide phenotypic variation observed in individuals with NR5A1 variants, recent reports hypothesize that oligogenic inheritance is likely to be at play (Camats, Fernandez‐Cancio, Audi, Schaller, & Fluck, ; Robevska et al., ). We filtered our massively parallel sequencing data with a list of 116 NR5A1 ‐related genes to identify variants that may act additively with the NR5A1 variants in these four patients.…”

“…Additional genomic variants may act as modifiers of expression and thus explain some of the variable expressivity observed. A recent report on 46,XY DSDs with NR5A1 variants explored oligogenic inheritance by filtering exome sequencing variants with a list of NR5A1 ‐associated genes (Camats et al., ). Using a similar, albeit targeted, approach, we identified an additional 2–6 variants per patient that may modify NR5A1 expression or act additively with NR5A1 to generate the wide phenotypic variation observed ().…”

Novel<b><i> NR5A1</i></b> Pathogenic Variants Cause Phenotypic Heterogeneity in 46,XY Disorders of Sex Development

“…Though the pathogenic variants (in family 1 and proband 2) are different, their impacts on the protein function, such as binding to target DNA and transactivation abilities, look very similar. The observed phenotypic heterogeneity in 46,XY DSD individuals could be due to varied degrees of penetrance or possible digenic/oligogenic inheritance [Camats et al, 2018]. The third pathogenic variant, p.Ser143Asn, located in the flexible linker region of NR5A1, was identified in proband 3 with ambiguous genitalia and who was brought up as a female.…”

Mutation update for theNR5A1gene involved in DSD and infertility

“…Apparently, the residual activity or the dosage in which NR5A1 is expressed will influence the expression of a wide range of proteins in different forms, leading to each of those phenotypes. Another feasible reason that could explain several different clinical features is the oligogenic inheritance for NR5A1 cases, which was already discussed in the literature (Camats, Fernández‐Cancio, Audí, Schaller, & Flück, ; Mazen et al, ) and endorses the idea of the existence of genetic modifiers influencing phenotypic severity, since the same mutation can be associated with different phenotypes. There are some classic examples for that: the already mentioned p.Arg92Trp mutation whose heterozygosis was described associated with different phenotypes such as SRY ‐negative 46,XX OTDS and TDSD and SRY ‐positive 46,XY PGD, including a boy with SRY ‐negative 46,XX OTDS and a girl with SRY ‐positive 46,XY PGD who were siblings (Baetens et al, ; Bashamboo et al, ; Igarashi et al, ; Wang et al, ); the also mentioned p.Asp293Asn mutation whose homozygosis was reported in cases with PGD, CGD, and POI, whereas heterozygous carriers were normal or have PGD in the same family (Lourenço et al, ; Soardi et al, ); and the p.Arg313His associated with POI and PGD (Janse et al, ; Saraco et al, ; Wang et al, ).…”