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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Hormozdiari, F. et al. Widespread allelic heterogeneity in complex traits. Am. J. Hum. Genet. 100, 789–802 (2017).
Walsh, C. A. & Engle, E. C. Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron. 68, 245–253 (2010).
Chaoui, A. et al. Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. Hum. Mutat. 32, 1436–1449 (2011).
Pingault, V. et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am. J. Hum. Genet. 92, 707–724 (2013).
Balasubramanian, R. & Crowley, W. F. Jr. Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the GnRH neuronal network. Mol. Cell. Endocrinol. 346, 4–12 (2011).
Elmaleh-Berges, M. et al. Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations. AJNR Am. J. Neuroradiol. 34, 1257–1263 (2013).
Suzuki, E. et al. Loss-of-function SOX10 mutation in a patient with Kallmann syndrome, hearing loss, and iris hypopigmentation. Horm. Res. Paediatr. 84, 212–216 (2015).
Dai, W. et al. Functional analysis of SOX10 mutations identified in Chinese patients with Kallmann syndrome. Gene. 702, 99–106 (2019).
Vaaralahti, K. et al. De novo SOX10 nonsense mutation in a patient with Kallmann syndrome and hearing loss. Pediatr. Res. 76, 115–116 (2014).
Amato, L. G. L. et al. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. Eur. J. Endocrinol. 181, 103–119 (2019).
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443 (2020).
Fokkema, I. F. et al. LOVD v.2.0: the next generation in gene variant databases. Hum. Mutat. 32, 557–563 (2011).
Touraine, R. L. et al. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am. J. Hum. Genet. 66, 1496–1503 (2000).
Guo, M. H., Plummer, L., Chan, Y. M., Hirschhorn, J. N. & Lippincott, M. F. Burden testing of rare variants identified through exome sequencing via publicly available control data. Am. J. Hum. Genet. 103, 522–534 (2018).
Adzhubei, I., Jordan, D. M. & Sunyaev, S. R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. 20 (2013).
Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47, D886–D894 (2019).
Ioannidis, N. M. et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99, 877–885 (2016).
Biesecker, L. G., Harrison, S. M. & ClinGen Sequence Variant Interpretation Working Group. The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet. Med. 20, 1687–1688 (2018).
Vivekanandan, S., Moovarkumudalvan, B., Lescar, J. & Kolatkar, P. R. Crystallization and X-ray diffraction analysis of the HMG domain of the chondrogenesis master regulator Sox9 in complex with a ChIP-Seq-identified DNA element. Acta Crystallogr. F Struct. Biol. Commun. 71, 1437–1441 (2015).
Sykiotis, G. P. et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc. Natl. Acad. Sci. U S A. 107, 15140–15144 (2010).
Chong, J. X. et al. The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities. Am. J. Hum. Genet. 97, 199–215 (2015).
Chaoui, A. et al. Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations. Hum. Mol. Genet. 24, 4933–4947 (2015).
Inoue, K. et al. Translation of SOX10 3’ untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum. Mol. Genet. 16, 3037–3046 (2007).
Inoue, K. et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36, 361–369 (2004).
Barraud, P., St John, J. A., Stolt, C. C., Wegner, M. & Baker, C. V. Olfactory ensheathing glia are required for embryonic olfactory axon targeting and the migration of gonadotropin-releasing hormone neurons. Biol. Open 2, 750–759 (2013).
Whitlock, K. E., Wolf, C. D. & Boyce, M. L. Gonadotropin-releasing hormone (GnRH) cells arise from cranial neural crest and adenohypophyseal regions of the neural plate in the zebrafish, Danio rerio. Dev. Biol. 257, 140–152 (2003).
Forni, P. E., Taylor-Burds, C., Melvin, V. S., Williams, T. & Wray, S. Neural crest and ectodermal cells intermix in the nasal placode to give rise to GnRH-1 neurons, sensory neurons, and olfactory ensheathing cells. J. Neurosci. 31, 6915–6927 (2011).
Noisa, P. & Raivio, T. Neural crest cells: from developmental biology to clinical interventions. Birth Defects Res. C Embryo Today 102, 263–274 (2014).
Grumbach, M. M. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J. Clin. Endocrinol. Metab. 90, 3122–3127 (2005).
Kohva, E. et al. Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys. Hum. Reprod. 34, 863–871 (2019).
Izumi, Y. et al. Hypogonadotropic hypogonadism in a female patient previously diagnosed as having waardenburg syndrome due to a sox10 mutation. Endocrine. 49, 553–556 (2015).
Iso, M. et al. SOX10 mutation in Waardenburg syndrome type II. Am. J. Med. Genet. A. 146A, 2162–2163 (2008).
Stevenson, R. E., Vincent, V., Spellicy, C. J., Friez, M. J. & Chaubey, A. Biallelic deletions of the Waardenburg II syndrome gene, SOX10, cause a recognizable arthrogryposis syndrome. Am. J. Med. Genet. A. 176, 1968–1971 (2018).
Matera, I. et al. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum. Mol. Genet. 17, 2118–2131 (2008).
Maione, L., Brailly-Tabard, S., Nevoux, J., Bouligand, J. & Young, J. Reversal of congenital hypogonadotropic hypogonadism in a man with Kallmann syndrome due to SOX10 mutation. Clin. Endocrinol. (Oxf.) 85, 988–989 (2016).
Shin, S. J. et al. Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience. Ann. Pediatr. Endocrinol. Metab. 20, 27–33 (2015).
Siomou, E. et al. A 725 kb deletion at 22q13.1 chromosomal region including SOX10 gene in a boy with a neurologic variant of Waardenburg syndrome type 2. Eur. J. Med. Genet. 55, 641–645 (2012).
Bondurand, N. et al. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am. J. Hum. Genet. 81, 1169–1185 (2007).
Korsch, E., Steinkuhle, J., Massin, M., Lyonnet, S. & Touraine, R. L. Impaired autonomic control of the heart by SOX10 mutation. Eur. J. Pediatr. 160, 68–69 (2001).
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.
All subjects provided written informed consent and research activities were approved by the Human Research Committee at the MGH, Boston, Massachusetts.
The authors declare no competing interests.
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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