TY - JOUR
T1 - Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants
AU - Rojas, Rebecca A.
AU - Kutateladze, Anna A.
AU - Plummer, Lacey
AU - Stamou, Maria
AU - Keefe, David L.
AU - Salnikov, Kathyrn B.
AU - Delaney, Angela
AU - Hall, Janet E.
AU - Sadreyev, Ruslan
AU - Ji, Fei
AU - Fliers, Eric
AU - Gambosova, Katarina
AU - Quinton, Richard
AU - Merino, Paulina M.
AU - Mericq, Veronica
AU - Seminara, Stephanie B.
AU - Crowley, William F.
AU - Balasubramanian, Ravikumar
N1 - Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100142805&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-020-01051-3
DO - https://doi.org/10.1038/s41436-020-01051-3
M3 - Article
C2 - 33442024
SN - 1098-3600
VL - 23
SP - 629
EP - 636
JO - Genetics in medicine
JF - Genetics in medicine
IS - 4
ER -