Dataset Information

Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

ABSTRACT: The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.

SUBMITTER: Emison ES

PROVIDER: S-EPMC2896767 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

Emison Eileen Sproat ES Garcia-Barcelo Merce M Grice Elizabeth A EA Lantieri Francesca F Amiel Jeanne J Burzynski Grzegorz G Fernandez Raquel M RM Hao Li L Kashuk Carl C West Kristen K Miao Xiaoping X Tam Paul K H PK Griseri Paola P Ceccherini Isabella I Pelet Anna A Jannot Anne-Sophie AS de Pontual Loic L Henrion-Caude Alexandra A Lyonnet Stanislas S Verheij Joke B G M JB Hofstra Robert M W RM Antiñolo Guillermo G Borrego Salud S McCallion Andrew S AS Chakravarti Aravinda A

American journal of human genetics 20100701 1

The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site wit ...[more]

PMID: 20598273

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Project description:BackgroundGenetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study.MethodsTo explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers.ResultsBurden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability.LimitationsOnly 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers.ConclusionsLiability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk.

Dataset Information

Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

Publications

Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

Similar Datasets

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