Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants



SOX10 variants 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.


Exome sequencing from 1,309 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 and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.


Thirty-seven SOX10-associated IHH cases were identified as follows: 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 versus gnomAD.


SOX10 variants 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.

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Fig. 1: Family pedigrees of probands with SOX10 rare sequence variants (RSVs) identified in the Massachusetts General Hospital (MGH) idiopathic hypogonadotropic hypogonadism (IHH) cohort.
Fig. 2: SOX10 protein domains and positions of SOX10 rare sequence variants (RSVs) identified in idiopathic hypogonadotropic hypogonadism (IHH), Waardenburg syndrome (WS), and gnomAD.

Data availability

Data and materials will be made available by the authors individually upon request subject to the data sharing plan and consent provided by the study participants.


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We thank the families and referring clinicians for their participation in this study. This work was supported by US National Institutes of Health (NIH) grants P50HD028138 (S.B.S., W.F.C., R.B.); K23HD077043 (R.B.) and R01HD096324.

Author information




Conceptualization: R.B.; Data curation: R.A.R., A.A.K., L.P, K.B.S., M.S., D.L.K.,; Formal analysis: R.A.R., A.A.K., R.B.; Funding acquisition: R.B., S.B.S., W.F.C.; Investigation: R.B., S.B.S., W.F.C., V.M., P.M.M., R.Q., K.G., E.F., J.E.H., A.D.; Methodology: R.B., F.J., R.S.; Validation: L.P., R.A.R.; Visualization: L.P., R.A.R., F.J., R.S.; Writing – original draft: R.A.R., A.A.K., R.B.; Writing – review & editing: S.B.S, W.F.C., R.Q., R.B.

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Correspondence to Ravikumar Balasubramanian.

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Rojas, R.A., Kutateladze, A.A., Plummer, L. et al. Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants. Genet Med (2021).

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