Dataset Information

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

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.

SUBMITTER: Rojas RA

PROVIDER: S-EPMC8335791 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Rojas Rebecca A RA Kutateladze Anna A AA Plummer Lacey L Stamou Maria M Keefe David L DL Salnikov Kathyrn B KB Delaney Angela A Hall Janet E JE Sadreyev Ruslan R Ji Fei F Fliers Eric E Gambosova Katarina K Quinton Richard R Merino Paulina M PM Mericq Veronica V Seminara Stephanie B SB Crowley William F WF Balasubramanian Ravikumar R

Genetics in medicine : official journal of the American College of Medical Genetics 20210113 4

<h4>Purpose</h4>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.<h4>Methods</h4>Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadi ...[more]

PMID: 33442024

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Project description:Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in RAB3GAP2 and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous RAB3GAP2 variants were also reviewed. The ES identified pathogenic compound heterozygous RAB3GAP2 variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the RAB3GAP2 allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported RAB3GAP2 variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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