Mutations in novel gene tied to rare disorder of sex development

see page NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development

Another player in the complicated molecular choreography that determines male or female sex has been traced through a series of patient studies. Dutch and Belgian researchers studied 11 unrelated patients and two sisters who presented with both testis and ovarian tissue. Chromosome studies identified them as 46,XX with ovo-testicular or testicular disorder of sexual development. Genomic analysis revealed a novel variant (Arg92Trp) in the Nuclear Receptor family 5 subfamily A member 1 (NR5A1) gene. Mutations or copy-number variants in this gene had previously been associated with other disorders of male sexual development or male infertility. Previous studies with both male and female Nr5a1 knockout mice showed that absence of the protein results in total lack of gonadal and adrenal development. Here, the research team used molecular modeling and animal models to work out a potential molecular explanation for the clinical outcomes seen in this patient cluster. The newly identified mutation was found in unaffected XX individuals in each of the three families studied, suggesting that its effects vary widely among individuals. Molecular studies indicate that NR5A1 plays an important role in multiple stages of gonadal development, acting as a regulator of sex determination and of differentiation in both sexes. Modeling work suggested that the newly identified mutation downregulates pro-ovarian pathways, tipping the balance toward male development. The researchers conclude that disturbances in the timing, tissue distribution, or expression of NR5A1 might shift the balance between the male and female sex determination pathways leading from the ovarian developmental program to the testicular pathway. —Karyn Hede, News Editor

Small copy-number variants matter too

see page Clinical relevance of small copy-number variants in chromosomal microarray clinical testing

A comprehensive review of small copy-number variants (CNVs) identified during chromosomal microarray analysis suggests that many are clinically significant and merit further study. Hollenbeck and colleagues evaluated 4,417 patients at the University of Alabama at Birmingham’s clinical cytogenetics laboratory from 2009 to 2014. Within this group, 8.67% had at least one small CNV and 2.12% carried more than one. Overall, the research team identified 435 unique CNVs. As is the case with most of these small (<500 kb) variants, most turned out not to have any clinical significance. The relatively common presence of benign CNVs in healthy people makes interpreting their presence in individuals being evaluated for congenital defects all the more confounding. However, the authors found that when combined with robust clinical data, one-third of the CNVs could be assigned as pathogenic or likely pathogenic in 3% of the patients tested. These small deletions were concentrated in 54 genes involved mainly in developmental delay and/or intellectual disability. The investigators credited having access to patients’ detailed clinical information for the ability to make better correlations with available understanding of the genes’ roles in development. They suggest that similar future studies could add to their yield of novel genes involved in the pathogenesis of neurodevelopmental disorders and/or congenital anomalies. The study also highlights the importance of having phenotypic information available to genetic testing laboratories. Without the ability to compare identified variants with clinical findings, laboratories can’t match rare CNVs with patient indications. The investigators call for better sharing of patients’ clinical information among academic clinical laboratories through depositing well-characterized phenotypes into publicly available clinical CNV databases. —Karyn Hede, News Editor