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

Genetics in Medicine (2021)Cite this article

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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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Acknowledgements

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

Affiliations

  1. Harvard Reproductive Sciences Center, The Reproductive Endocrine Unit and The Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Rebecca A. Rojas, Anna A. Kutateladze, Lacey Plummer, Maria Stamou, David L. Keefe Jr, Kathyrn B. Salnikov, Stephanie B. Seminara, William F. Crowley Jr & Ravikumar Balasubramanian

  2. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Angela Delaney

  3. National Institute of Environmental Health Sciences, Research Triangle, NC, USA

    Janet E. Hall

  4. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    Ruslan Sadreyev & Fei Ji

  5. Amsterdam University Medical Center, location AMC, Department of Endocrinology and Metabolism, Amsterdam, The Netherlands

    Eric Fliers

  6. Stormont-Vail Health, Cotton O’Neil Diabetes and Endocrinology, Topeka, KS, USA

    Katarina Gambosova

  7. Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-tyne, UK

    Richard Quinton

  8. Institute of Maternal and Child Research, University of Chile, Santiago, Chile

    Paulina M. Merino & Veronica Mericq

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  1. Rebecca A. Rojas
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  2. Anna A. Kutateladze
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  18. Ravikumar Balasubramanian
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Contributions

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.

Corresponding author

Correspondence to Ravikumar Balasubramanian.

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All subjects provided written informed consent and research activities were approved by the Human Research Committee at the MGH, Boston, Massachusetts.

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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). https://doi.org/10.1038/s41436-020-01051-3

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