NRG1 variant effects in patients with Hirschsprung disease.
Gunadi, Budi NYP, Sethi R, Fauzi AR, Kalim AS, Indrawan T, Iskandar K, Makhmudi A, Adrianto I, and San LP. NRG1 variant effects in patients with Hirschsprung disease. BMC Pediatr 2018; 18(1):292.
BACKGROUND: Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population.
METHODS: We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients.
RESULTS: All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case-control analysis (p = 0.037).
CONCLUSIONS: This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.
Medical Subject Headings
Adult; Asian Continental Ancestry Group; Case-Control Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Hirschsprung Disease; Humans; Indonesia; Male; Neuregulin-1; Polymerase Chain Reaction; Protein Binding; Sequence Analysis, DNA; Transcription Factors