Abstract
We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and HSCR. None of the members had sensorineural deafness. The family was screened for copy number variations (CNVs) using Illumina-HumanOmni2.5-Beadchip and for coding sequence mutations in WS4 genes (EDN3, EDNRB, or SOX10) and in the main HSCR gene (RET). Confocal microscopy and immunoblotting were used to assess the functional impact of the mutations. A heterozygous A/G transition in EDNRB was identified in 4 affected and 3 unaffected individuals. While in EDNRB isoforms 1 and 2 (cellular receptor) the transition results in the abolishment of translation initiation (M1V), in isoform 3 (only in the cytosol) the replacement occurs at Met91 (M91V) and is predicted benign. Another heterozygous transition (c.-248G/A; -predicted to affect translation efficiency-) in the 5′-untranslated region of EDN3 (EDNRB ligand) was detected in all affected individuals but not in healthy carriers of the EDNRB mutation. Also, a de novo CNVs encompassing DACH1 was identified in the patient with heterochromia iridum and HSCRSince the EDNRB and EDN3 variants only coexist in affected individuals, HSCR could be due to the joint effect of mutations in genes of the same pathway. Iris heterochromia could be due to an independent genetic event and would account for the additional phenotype within the family.
Highlights
Waardenburg-Shah syndrome, Waardenburg-Hirschsprung disease or Type IV Waardenburg syndrome (WS4; MIM #277580) is a congenital developmental disorder characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and aganglionosis of variable portions of the colon (Hirschsprung disease) [1]
WS4 is underlain by homozygous or heterozygous coding sequence (CDS) mutations affecting any of the three following genes, EDN3 (20q13.2–q13.3), encoding the endothelin-3 peptide; EDNRB (13q22), encoding its receptor; and SRY (Sex determining region Y)-box 10 (SOX10) (22q13.1), encoding a transcription factor [8,10]
SOX10 CDS mutations account for about 50% of the WS4 patients and CDS mutations in EDN3 or EDNRB for 20–30% of the WS4 patients [8]
Summary
Waardenburg-Shah syndrome, Waardenburg-Hirschsprung disease or Type IV Waardenburg syndrome (WS4; MIM #277580) is a congenital developmental disorder characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and aganglionosis of variable portions of the colon (Hirschsprung disease) [1]. We observed that while heterozygous mutations in two genes of the same pathway only coexisted in HSCR-affected individuals, a de novo CNV could account for the heterochromia iridum phenotype presented by the only family member displaying WS4 features.
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