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Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

ABSTRACT: The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.

SUBMITTER: Attie T

PROVIDER: S-EPMC1050384 | biostudies-other | 1995 Apr

REPOSITORIES: biostudies-other

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Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

Attié T T Till M M Pelet A A Edery P P Bonnet J P JP Munnich A A Lyonnet S S

Journal of medical genetics 19950401 4

The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible f ...[more]

PMID: 7643365

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Identifying candidate Hirschsprung disease-associated RET variants.

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RET somatic mutations are underrecognized in Hirschsprung disease.

Project description:PurposeWe aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.MethodsTargeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.ResultsWe identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%).ConclusionSomatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.

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| S-EPMC7657479 | biostudies-literature

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AB099. Joint effects of RET and SEMA3 polymorphisms in Hirschsprung disease

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AB097. Combined effects of RET transcriptional enhancer variants in Hirschsprung disease

Project description:Background Hirschsprung disease (HSCR) is a complex genetic disorder, which characterized by absence of ganglion cells along variable lengths of the intestines in neonates, with the RET was identified as a major locus involved in HSCR. In this study, we investigated the joint effects of common variants within the RET transcriptional enhancer, rs2435357 and rs2506030, for development of HSCR in Indonesia. Methods Sixty HSCR patients and 122 non-HSCR controls was involved in this study. Two genetic markers of the RET were examined using TaqMan assay. We analyzed the case-control association tests between two genetic markers and HSCR using the statistic. A P value <0.025 is considered significant given that two tests (markers) were performed in the analysis. Results There was high correlation between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10?8) or transmission disequilibrium test (TDT, P=4.2×10?6), but not RET rs2506030 (OR =1.68, P=0.042 and P=0.034, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with rs2506030 (GG), were associated with the increased disease risks of HSCR (OR =5.42, P=3.9×10?6) compared with a single variant of rs2506030. Conclusions Our study shows that RET rs2435357 variant is a strong genetic risk factors for development of HSCR in Indonesia. In addition, the disease effects of RET rs2506030 genotypes are crucially dependent on the effects of rs2435357 genotypes.

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Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression.

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| S-EPMC1734238 | biostudies-other

Whole Exome Sequencing Identifies a Novel Pathogenic RET Variant in Hirschsprung Disease.

Project description:Hirschsprung disease is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. To uncover genetic variants contributing to HSCR, we performed whole exome sequencing on seven members of an HSCR family. With the minor allele frequency (MAF) calculated by gnomAD, we finally filtered a total of 1,059 rare variants in this family (MAF < 0.1%). With the mode of inheritance and pathogenicity scores by bioinformatics tools, we identified an in-frameshift variant p.Phe147del in RET as the disease-causing variant. Further analysis revealed that the in-frameshift variant may function by disrupting the glycosylation of RET protein. To our knowledge, this is the first study to report the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR.

| S-EPMC6339922 | biostudies-literature

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