Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

Show full item record



Permalink

http://hdl.handle.net/10138/314531

Citation

Virtanen , V B , Salo , P P , Gao , J , Löf-Granström , A , Milani , L , Metspalu , A , Rintala , R J , Saarenpää-Heikkilä , O , Paunio , T , Wester , T , Nordenskjöld , A , Perola , M & Pakarinen , M P 2019 , ' Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant ' , European Journal of Medical Genetics , vol. 62 , no. 4 , pp. 229-234 . https://doi.org/10.1016/j.ejmg.2018.07.019

Title: Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant
Author: Virtanen, Valtter B.; Salo, Perttu P.; Gao, Jia; Löf-Granström, Anna; Milani, Lill; Metspalu, Andres; Rintala, Risto J.; Saarenpää-Heikkilä, Outi; Paunio, Tiina; Wester, Tomas; Nordenskjöld, Agneta; Perola, Markus; Pakarinen, Mikko P.
Contributor: University of Helsinki, Children's Hospital
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Lastenkirurgian yksikkö
University of Helsinki, Department of Psychiatry
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Lastenkirurgian yksikkö
Date: 2019-04
Language: eng
Number of pages: 6
Belongs to series: European Journal of Medical Genetics
ISSN: 1769-7212
URI: http://hdl.handle.net/10138/314531
Abstract: The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls. As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T > C; genotype TT, OR = 17.31, P = 1.462 x 10(-21)). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A > C; allele C, OR = 2.268, P = 0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A > G; allele G, OR = 1.567, P = 0.015; rs7835688, NC_000008.10:g.32411499G > C; allele C, OR = 1.567, P = 0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease. Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.
Subject: Hirschsprung disease
RET
Genetics
GWAS
NERVOUS-SYSTEM DEVELOPMENT
MUTATIONS
GENE
EXPRESSION
1184 Genetics, developmental biology, physiology
3111 Biomedicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
1_s2.0_S1769721218300764_main.pdf 472.1Kb PDF View/Open
Noncoding_RET_v ... oding_sequence_variant.pdf 309.2Kb PDF View/Open

This item appears in the following Collection(s)

Show full item record