A de novo deletion mutation in SOX10 in a Chinese family with Waardenburg syndrome type 4

Abstract

Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare genetic disorder with a prevalence of <1/1,000,000 and characterized by the association of congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. There are three types of WS4 (WS4A–C) caused by mutations in endothelin receptor type B, endothelin 3, and SRY-box 10 (SOX10), respectively. This study investigated a genetic mutation in a Chinese family with one WS4 patient in order to improve genetic counselling. Genomic DNA was extracted, and mutation analysis of the three WS4 related genes was performed using Sanger sequencing. We detected a de novo heterozygous deletion mutation [c.1333delT (p.Ser445Glnfs*57)] in SOX10 in the patient; however, this mutation was absent in the unaffected parents and 40 ethnicity matched healthy controls. Subsequent phylogenetic analysis and three-dimensional modelling of the SOX10 protein confirmed that the c.1333delT heterozygous mutation was pathogenic, indicating that this mutation might constitute a candidate disease-causing mutation.

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

“…However, the subjects were prepubertal and formal testing for anosmia was not reported. Interestingly, SOX10 mutations, unlike PAX3 mutations, most commonly arise de‐novo, which may be related to infertility . Future studies focusing on genotype should include a comprehensive phenotype profile and, if appropriate, long‐term follow‐up.…”

“…Interestingly, SOX10 mutations, unlike PAX3 mutations, most commonly arise de-novo, which may be related to infertility. [110][111][112] All neonates born to parents with CHH should be formally evaluated by an endocrinologist. Referral should not be delayed because the window for hormone profiling is narrow.…”

Case Report: A Novel Gross Deletion in PAX3 (10.26 kb) Identified in a Chinese Family With Waardenburg Syndrome by Third-Generation Sequencing

“…The four types of WS exhibit common phenotypes and differences. Compared with WS1, the inner canthi of both eyes in patients with WS2 were normal, those with WS3 exhibit upper limb abnormalities, and those with WS type IV (WS4) had Hirschsprung disease (Wang et al, 2017 ; Ahmed Jan et al, 2021 ). Symptoms in I:1 and II:3 were more consistent with those in WS3, whereas II:2 was diagnosed with WS1.…”

A Novel Spontaneous Mutation of the SOX10 Gene Associated with Waardenburg Syndrome Type II

“…In addition, through analysis of the reported cases and the literature, we found that when the SOX10 mutation site occurred behind the 180th amino acid, or you could say after the HMG domain, it caused more severe symptoms of type IV WS [ 5 , 6 , 36 – 39 ] ( Table 2 ). We speculate that the reason may be due to the truncated mutation which means that the HMG domain loses the normal function of the protein, but can combine with the target gene promoter.…”

“…The clinical manifestations of type II are basically the same as type I, but without dystopia of the canthus. The clinical manifestations of type III are the same as type I, but combined with upper limb deformity, while type IV exhibits basically the same symptoms as type II, but combined with Hirschsprung disease (gastrointestinal malformation) [3][4][5][6]. Mutations of the PAX3, SOX10, MITF, SNAI2, EDNRB, and EDN3 genes have been found in cases of the different types of WS [7,8].…”