Objective: Cluster genes, specifically the class 3 semaphorins (SEMA3) including SEMA3C, have been associated with the development of Hirschsprung disease (HSCR) in Caucasian populations. We aimed to screen for rare and common variants in SEMA3C in Indonesian patients with HSCR.
Methods: In this prospective clinical study, we analyzed SEMA3C gene variants in 55 patients with HSCR through DNA sequencing and bioinformatics analyses.
Results: Two variants in SEMA3C were found: p.Val337Met (rs1527482) and p.Val579 = (rs2272351). The rare variant rs1527482 (A) was significantly overrepresented in our HSCR patients (9.1%) compared with South Asian controls in the 1000 Genomes (4.7%) and Exome Aggregation Consortium (ExAC; 3.5%) databases. Our analysis using bioinformatics tools predicted this variant to be evolutionarily conserved and damaging to SEMA3C protein function. Although the frequency of the other variant, rs2272351 (G), also differed significantly in Indonesian patients with HSCR (27.3%) from that in South Asian controls in 1000 Genomes (6.2%) and ExAC (4.6%), it is a synonymous variant and not likely to affect protein function.
Conclusions: This is the first comprehensive report of SEMA3C screening in patients of Asian ancestry with HSCR and identifies rs1527482 as a possible disease risk allele in this population.
Keywords: Damaging effect on protein function; Hirschsprung disease; Indonesia; deleterious conservation score; founder effect; pathogenic variant; semaphorin 3C.