Waardenburg syndrome type 4: Report of two new cases caused by SOX10 mutations in Spain

Abstract

Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases.

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

“…WS is clinically and genetically heterogeneous and is classified into four types (WS1–4) caused by mutations of paired box 3 ( PAX3 ), melanogenesis-associated transcription factor ( MITF ), endothelin 3 ( EDN3 ), endothelin receptor type B ( EDNRB ), snail-family transcriptional repressor 2 ( SNAI2 ), and SRY-box 10 ( SOX10 ) 3 4 . WS1 and WS2 are the most frequent types, whereas WS4 constitutes a rare disorder 5 6 .…”

“…WS4 includes three subtypes [WS4A–C (OMIM 277580, 613265, and 613266)] caused by mutations in EDNRB, EDN3 , and SOX10 , respectively 7 8 9 . Mutations in EDNRB and EDN3 are inherited in the autosomal recessive (AR) or autosomal dominant (AD) form, whereas the SOX10 mutation is inherited as AD 10 11 12 13 and found in ~50% of WS4 patients 1 6 , with >30 WS4-related mutations reported in the Human Gene Mutation Database. SOX10 is a critical transcription factor, targeting MITF , tyrosinase, myelin protein zero, gap junction protein beta 1, ret proto-oncogene, and EDNRB during neural-crest-derived cell migration and differentiation.…”

Estudo genético e molecular da síndrome de Waardenburg

“…As mutações mais recentemente descritas foram encontradas em 2 pacientes com SW4, no exon 5, em um estudo de pacientes espanhóis; ambas as mutações levam a uma parada prematura da tradução [Fernández et al, 2014]. Na China foi encontrada uma nova mutação, além de outras três já descritas em pacientes com SW4 [Jung et al, 2013].…”

Sequenciamento de nova geração e sua aplicação no estudo genético da síndrome de Waardenburg

“…O gene principal que explica cerca de 50% dos casos de SW4 é o SOX10, com mutações em heterozigose e geralmente de novo (BONDURAND et al, 2007;FERNÁNDEZ et al, 2014;WANG et al, 2017). O fenótipo mais grave, PCWH, é causado por mutações sem sentido e frameshift que acometem o último exon codificador do gene SOX10, o que faz o RNAm mutado escapar do processo de nonsense-mediated mRNA decay (NMD), resultando em efeito dominante negativo (INOUE et al, 2004).…”

“…Duas variantes intrônicas no gene MITF foram relacionadas também à SW2, uma delas tanto em homozigose quanto em heterozigose (HADDAD et al, 2011;RAUSCHENDORF et al, 2019). Na SW4, variantes patogênicas em heterozigose no gene SOX10 representam a causa de 50% dos casos, outros 20 a 30% tem variantes patogênicas em heterozigose e homozigose nos genes EDNRB e EDN3, permanecendo sem detecção de 15 a 35% dos casos de SW4 (BONDURAND et al, 2007(BONDURAND et al, , 2012FERNÁNDEZ et al, 2014;PINGAULT et al, 2010;WANG et al, 2017 (BONDURAND et al, 2007(BONDURAND et al, , 2012FALAH et al, 2017).…”