Familial Hirschsprung Disease

Gene: NRG3

Comment on list classification: Updated rating from Red to Amber: Although NRG3 is on original expert submitted list, NRG3 has one red external review, plus most evidence for role in Hirschsprung's disease comes from association studies. Only 2 variants (3 individuals) reported in PMID:23315268. Therefore Amber while awaiting further evidence.

Created: 14 Aug 2017, 2:35 p.m.

Added 'cnv' tag based on notes in Expert list submitted by Sumitra Chhabra and colleagues (Alder Hey - Erasmus MC): supported by PMID:22589734.

Created: 14 Aug 2017, 2:25 p.m.

Comment on mode of inheritance: Updated MOI to 'NOT imprinted' to match suggestion by Erwin Brosens.

Created: 14 Aug 2017, 2:25 p.m.

PMID:27889765 (Wang et al., 2016) evaluated polymorphisms in NRG3 (and GABRG2 and RELN) in 104 HSCR cases and 151 controls of Han Chinese origin. They observed significant associations between Hirschsprung disease and 2 NRG3 SNPs (rs6584471 and rs7074694).

Created: 14 Aug 2017, 2:22 p.m.

PMID:23315268 (Yang et al., 2013) performed exome sequencing of 2 HSCR patients from a Han Chinese family (mother and son). Filtering identified the E285K variant in NRG3. An additional P455P variant was found in the validation phase by sequencing NRG3 in >200 additional HSCR cases. The authors conclude that NRG3 may be a susceptibility gene for HSCR in a Chinese population.

Created: 14 Aug 2017, 1:59 p.m.

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted