Phenotypic continuum between Waardenburg syndrome and Idiopathic Hypogonadotropic Hypogonadism in humans with SOX10 mutations

PURPOSE: SOX10 mutations previously implicated in Waardenburg syndrome (WS), have now been linked to Kallmann Syndrome [KS], the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. METHODS: Exome sequencing from 1309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH:677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study & literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. RESULTS: Thirty-seven SOX10-associated IHH cases were identified: Current study:16 KS; 4 nIHH; literature:16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease-states vs. gnomAD. CONCLUSIONS: SOX10 mutations contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.