Distinctive genetic variation of long‐segment Hirschsprung's disease in Taiwan

Abstract

Background Hirschsprung's disease (HSCR) is a congenital disorder with the absence of myenteric and submucosal ganglion cells within distal gut. Due to multigenic inheritance and interactions, we employed next‐generation sequencing (NGS) to investigate genetic backgrounds of long‐segment HSCR (L‐HSCR) in Taiwan. Methods Genomic DNA extracted from peripheral blood of L‐HSCR patients was subjected to capture‐based NGS, based on a 31‐gene panel. The variants with allele frequency <0.05 and predicted by computational methods as deleterious were further validated by Sanger sequencing in patients and their family as well to tell de novo from inherited variants. Results Between 2015/04 and 2018/05, this study enrolled 23 L‐HSCR patients, including 15 (65.2%) sporadic cases and 8 (34.8%) familial patients in 4 different families. Six sporadic and seven familial cases showed possible harmful variants across eight different genes, accounting for an overall detection rate of 56.5%. These variants mainly resided in SEMA3C, followed by RET, NRG1, and NTRK1. Three sporadic and 2 familial cases exhibited strong pathogenic variants as a deletional frameshift or stop codon in RET, L1CAM or NRG1. In a HSCR family, the father passed on a pathogenic RET frameshift to two daughters; however, only one developed HSCR. Conclusion Using NGS, we disclosed deleterious mutations such as a frameshift or stop codon in either familial or sporadic patients. Our cases with isolated L‐HSCR or even total colonic aganglionosis appeared to exhibit complex patterns of inheritance and incomplete penetrance even in families with the same genetic variants, reflecting the possible effects of environmental factors and genetic modifiers.

Hirschsprung disease: Insights on genes, penetrance, and prenatal diagnosis

“…In a recent article which accompanies this mini‐review, Yang et al present new potential gene variants involved in long‐segment Hirschsprung disease as identified by genomic DNA extracted from peripheral blood and validated by Sanger sequencing. Twenty‐three patients with long‐segment Hirschsprung disease, 14 of these with total colonic aganglionosis, were enrolled over three years and included both sporadic and familial cases from four different families.…”

A Novel Method for Identifying the Transition Zone in Long-Segment Hirschsprung Disease: Investigating the Muscle Unit to Ganglion Ratio

“…This could be due to clinicopathological differences between the two phenotypes. Variation in genetic profiles have been noted, with mutations in SEMA3C , important for axonal guidance and neural crest cell migration, being more common in long-segment compared to short-segment disease [ 9 , 41 , 42 , 43 ]. In contrast to short-segment disease, submucosal nerve hypertrophy may be limited or absent in rectal biopsies of long-segment HSCR, contributing to longer time to diagnosis of 11–14 days compared to 2–3 days for short-segment disease [ 8 , 9 , 23 ].…”