A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

Emison, E; McCallion, Andrew S.; Kashuk, Carl; Bush, Richard T; Grice, Elizabeth A.; Lin, Shin; Portnoy, Matthew E.; Cutler, David J.; Green, Eric D.; Chakravarti, Aravinda

doi:10.1038/nature03467

Cited by 428 publications

(429 citation statements)

References 38 publications

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“…A small subgroup of patients present a rare coding sequence mutation (CDS) of the RET gene with a high and sex-dependent penetrance. 1,2 The remaining group of patients have a risk allele for a noncoding polymorphism in an enhancer element of IVS1, rs2435357, with a low and sex-dependent penetrance [3][4][5][6] (found in 90% of the patient alleles versus 19.4% in the 1000 genomes project). The subgroup with RET CDS mutations represents B45% of familial cases and 7-20% of sporadic cases.…”

Section: Introductionmentioning

confidence: 99%

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

et al. 2012

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Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-oforigin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.

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Section: Introductionmentioning

confidence: 99%

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

et al. 2012

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“…Recent experience bears out the hypothesis that common variants have an important role in disease, with a partial list of validated examples including HLA (autoimmunity and infection) 1 , APOE4 (Alzheimer's disease, lipids) 2 , Factor V Leiden (deep vein thrombosis) 3 , PPARG (encoding PPARg; type 2 diabetes) 4,5 , KCNJ11 (type 2 diabetes) 6 , PTPN22 (rheumatoid arthritis and type 1 diabetes) 7,8 , insulin (type 1 diabetes) 9 , CTLA4 (autoimmune thyroid disease, type 1 diabetes) 10 , NOD2 (inflammatory bowel disease) 11,12 , complement factor H (age-related macular degeneration) [13][14][15] and RET (Hirschsprung disease) 16,17 , among many others.…”

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A haplotype map of the human genome

Belmont¹,

Boudreau²,

Leal³

et al. 2005

Nature

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A haplotype map of the human genomeThe International HapMap Consortium* Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

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“…Recently, it has been shown that a common intronic variant in a RET enhancer is associated with HSCR susceptibility probably by reducing the enhancer activity. 71 This common variant has low penetrance and it explains only 1.1-2.6% of the variance in susceptibility. Thus, a combination of studies in outbred and inbred populations, rare Mendelian transmitted forms of the disease and chromosomal aberrations led to the identification of rare mutations in genes that later were found to be associated with more common forms of the disease.…”

Section: Discussionmentioning

confidence: 99%

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Kohn¹,

Lerer²

2005

Mol Psychiatry

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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations. Keywords: schizophrenia; bipolar disorder; chromosome 6q; molecular genetics; linkageThe last three decades have seen considerable advances in the field of psychiatric genetics. First, family twin and adoption studies conclusively established that genes play a major role in the etiology of many psychiatric disorders. Then, an increasing number of groups embarked on linkage studies aiming at localizing these genes. With ever improving technology, whole genome scans became the standard vehicle for these endeavors. Studies became more and more sophisticated, involving larger samples of carefully characterized affected individuals, using denser maps of markers and employing increasingly powerful statistical tools. Over the years, linkage studies have repeatedly implicated several chromosomal regions as linked to major psychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BPD) (for reviews, see Riley and McGuffin, 1 Berrettini,2 Kohn and Lerer 3 and Mathews and Reus 4 ). Recent meta-analyses of linkage studies have establi...

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A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

Cited by 428 publications

References 38 publications

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

A haplotype map of the human genome

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

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