Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events

Núñez-Torres, Rocío; Fernández, Raquel M.; Acosta, Manuel J.; Enguix-Riego, María del Valle; Marbà, Martina; Agustín, Juan Carlos de; Castaño, Luís; Antiñolo, Guillermo; Borrego, Salud

doi:10.1186/1471-2350-12-138

Cited by 14 publications

(16 citation statements)

References 20 publications

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“…However, in our cohort, the higher frequency of variant alleles in S-HSCR was likely caused by a higher representation of male patients in S-HSCR (78%) than in the L-HSCR cohort (71%). A gender effect was previously described in rs2435357 where the variant allele was present in 65% of males vs. 56% of females [19]. Our data documented this trend not only in SNPs of the haploblock (76% of males vs. 60% of females) but also in risk variant alleles of rs1800861 and rs2565200.…”

Section: Discussionsupporting

confidence: 87%

RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease

Václavíková

Dvořáková²,

Škába³

et al. 2014

PLoS ONE

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Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of RET proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic RET variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire RET proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR.

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Section: Discussionsupporting

confidence: 87%

RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease

Václavíková

Dvořáková²,

Škába³

et al. 2014

PLoS ONE

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“…More recently, copy number variations in various neurodevelopmental genes ( MAPK10 , ZFHX1B , SOX2 and NRG2 ) have been shown to modify the penetrance of Hirschsprung disease (Jiang et al 2011; Tang et al 2012b). Taken together, these findings are consistent with an impact of both common and rare variants on the inheritance (and hence penetrance) of this highly complex disorder (Sánchez-Mejías et al 2009; Núñez-Torres et al 2011; Alves et al 2013). …”

Section: Influence Of Modifier Genes On Disease Penetrancesupporting

confidence: 72%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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“…Subsequently, follow‐up replication study of these loci reveals the consistent genetic associations in different cohorts . Similar with the findings in RET , the congregation of both common and rare variants in NRG1 underlies the predisposition to HSCR . Recently, Jiang et al .…”

Section: Introductionsupporting

confidence: 57%

Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population

Zhang

Xie

Zeng

et al. 2018

J Cellular Molecular Medi

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Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of enteric ganglia. There are more than 15 genes identified as contributed to HSCR by family‐based or population‐based approaches. However, these findings were not fulfilled to explain the heritability of most sporadic cases. In this study, using 1470 HSCR and 1473 control subjects in South Chinese population, we replicated two variants in NRG1 (rs16879552, P = 1.05E‐04 and rs7835688, P = 1.19E‐07), and further clarified the two replicated SNPs were more essential for patients with short‐segment aganglionosis (SHSCR) (P = 2.37E‐05). We also tried to replicate the most prominent signal (rs7785360) in AUTS2, which was a potential susceptibility gene with HSCR. In our results, in terms of individual association, marginal effect was observed to affect the HSCR patients following recessive model (P = 0.089). Noteworthy, significant intergenic synergistic effect between rs16879552 (NRG1) and rs7785360 (AUTS2) was identified through cross‐validation by logistic regression (P = 2.45E‐03, OR = 1.53) and multifactor dimensionality reduction (MDR, P < 0.0001, OR = 1.77). Significant correlation was observed between expression of these two genes in the normal segments of the colons (P = 0.018), together with differential expression of these genes between aganglionic colonic segments and normal colonic segments of the HSCR patients (P value for AUTS2 <0.0001, P value for NRG1 = 0.0243). Although functional evaluation is required, we supply new evidence for the NRG1 to HSCR and raised up a new susceptibility gene AUTS2 to a specific symptom for the disease.

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Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events

Cited by 14 publications

References 20 publications

RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease

RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population

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