Biallelic Germline Inactivation of HROB Causes Primary Gonadal Insufficiency and is Potentially Associated with...

The Homologous Recombination Factor With OB-Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8-MCM9 helicase complex activity. Recent findings link biallelic germline HROB variants to primary gonadal insufficiency (hypergonadotropic hypogonadism), a phenotype also associated with MCM8/MCM9 deficiency. Here, we describe a family where two individuals with biallelic HROB variants presented with hypergonadotropic hypogonadism and colonic polyposis. Exome sequencing identified three unique HROB variants: a likely pathogenic nonsense variant (c.1267C>T [p.(Gln423*)]) in exon four, and two missense variants (c.1363C>G [p.(Leu455Val)] and c.1318A>G [p.(Ser440Gly)]) in exon five. RNA analysis and protein mapping indicate that the nonsense variant is likely pathogenic, whereas the missense variants remain of uncertain significance. Mutational signature analysis of polyposis tissue did not reveal signatures directly linked to HROB deficiency, yet a review of published cases and analyses of cohorts with unexplained polyposis/cancer identified additional individuals with HROB variants exhibiting hypergonadotropic hypogonadism or colonic polyposis. These findings reinforce the association between biallelic germline HROB variants and hypergonadotropic hypogonadism and suggest a potential role in colonic polyposis predisposition. We recommend incorporating HROB into diagnostic gene panels for hypergonadotropic hypogonadism, especially in cases where colonic polyposis is also present. Furthermore, we emphasize the importance of additional studies to comprehensively characterize HROB's phenotypic impact and assess its contribution to disease risk.