Familial Hirschsprung Disease

Gene: NRG1

Added 'watchlist' tag to be notified of additional cases.

Created: 18 Oct 2017, 9:02 a.m.

Comment on mode of inheritance: Kept MOI as monoallelic to fit with current literature (e.g. PMID:21706185).

Created: 18 Oct 2017, 8:31 a.m.

Comment on list classification: Updated rating from Red to Amber. Although there is a lot of literature on the role of NRG1 in Hirschsprung's disease, alot report association studies, and point to a role for NRG1 in HSCR susceptibility. PMID:21706185 (2012) provides the most direct data for a role of NRG1 in HSCR, although functional studies were only performed on 2 variants. Therefore rated Amber while awaiting further case studies.

Created: 18 Oct 2017, 8:21 a.m.

PMID:22574178 (Luzon-Toro et al., 2012) performed a mutational screening and analysis of common sequence variants on the NRG1 gene in a Spanish cohort of HSCR patients.

They found no significant difference in common polymorphism frequencies in HSCR patients vs controls. This results differs from previous Chinese studies suggesting population-specific findings.

They go on to report 3 new missense mutations (M111T, M139I and R438H) as probable causing mutations for HSCR. Functional studies showed that mutant proteins resulted in lowered NRG1 protein levels and all 3 variants were absent from controls.

Created: 14 Aug 2017, 10:11 a.m.

PMID:23400839 (Gui et al., 2014) used 254 Chinese sporadic HSCR patients and 143 ethnically matched controls. Their statistical analysis revealed an association between RET and NRG1 variants. In mouse experiments, they show that NRG1 is involved in enteric nervous system development, supporting a role in Hirschsprung's disease.

Created: 14 Aug 2017, 9:53 a.m.

Yang et al., 2017 (28256518) report NRG1 as a HSCR susceptibility locus based on association analysis in the Chinese population.

Created: 14 Aug 2017, 9:45 a.m.

PMID:21706185 (Tang et al 2012) performed GWAS on Chinese HSCR patients to identify the NRG1 gene. They then sequenced NRG1 exons of 358 sporadic HSCR patients from Hong Kong and China, and identified 13 different heterozygous variants including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A), a frameshift (E239fsX10) and a c.503-4insT insertion. Except for T169T (detected in 1 control) and V486M (detected in 2 HSCR patients and 2 controls), all other variants were exclusive to HSCR patients.

Created: 14 Aug 2017, 9:40 a.m.

Comment on publications: Added in PMID (21706185) of publication suggested by M. Garcia-Barcelo.

Created: 14 Aug 2017, 9:27 a.m.

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• CSM Tang, ESW Ngan, WK Tang, MT So, G Cheng, XP Miao, TYY Leon, BMC Leung, KJWS. Hui, VCH Lui, Y Chen, IHY Chan, PHY Chun, XL Liu
• KKY Wong, PC Sham, SS Cherny, PH Tam, MM Garcia-Barcelo. Mutations in the NRG1 gene are associated with Hirschsprung disease. 2012. Hum Genet. 131:67-76.

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

functional test confirming deleterious variants

Created: 8 May 2017, 10:36 a.m.

Variants in this GENE are reported as part of current diagnostic practice