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. 2021 Apr;23(4):629-636.
doi: 10.1038/s41436-020-01051-3. Epub 2021 Jan 13.

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

Rebecca A Rojas  1 , Anna A Kutateladze  1 , Lacey Plummer  1 , Maria Stamou  1 , David L Keefe Jr  1 , Kathyrn B Salnikov  1 , Angela Delaney  2 , Janet E Hall  3 , Ruslan Sadreyev  4 , Fei Ji  4 , Eric Fliers  5 , Katarina Gambosova  6 , Richard Quinton  7 , Paulina M Merino  8 , Veronica Mericq  8 , Stephanie B Seminara  1 , William F Crowley Jr  1 , Ravikumar Balasubramanian  9
Affiliations

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

Rebecca A Rojas et al. Genet Med. 2021 Apr.

Erratum in

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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Conflict of interest statement

Disclosure: The authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:. Family pedigrees of probands with SOX10 RSVs identified in the MGH IHH cohort.
Pedigrees are sorted by presence (Panel A) or absence (Panel B) of WS-associated features. Probands are identified by arrows. “+” indicates Wild-type (WT) allele and M indicates the mutant allele.
Figure 2:
Figure 2:. SOX10 protein domains and positions of SOX10 RSVs identified in IHH, WS and gnomAD.
Heterozygous loss-of-function alleles are shown in red circles; heterozygous missense alleles are shown in black circles; homozygous missense alleles are shown in green circles. *Only single nucleotide variants associated with WS are shown and SOX10 structural variants are not depicted. DM, Dimerization Domain; HMG, High Mobility Group; Cons, Conserved in SOX-E Family; TA, Transactivation Domain
See this image and copyright information in PMC

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