Low frequency of <i>RET</i> mutations in Hirschsprung disease in Sweden

Svensson, Pär-Johan; Molander, Marie-Louise; Eng, Charis; Anvret, Maria; Nordenskjöld, Agneta

doi:10.1111/j.1399-0004.1998.tb03691.x

Cited by 42 publications

(10 citation statements)

References 30 publications

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“…Our frequencies are therefore concordant with previous studies that report values of up to 50% in familial forms and 3-35% in sporadic cases. 2,9,10,12,22 We have found three missense mutations affecting the extracellular domain of RET, V145L, V282L and A373V, which might act affecting the protein folding, maturation or intracellular transport to the plasma membrane, as it has been previously proposed. Of note, V145 is one of the high conserved residues in the consensus sequence of the cadherin-like domain 1 (CLD1), having a structural role in one of the hydrophobic cores present in the extracellular region of the protein.…”

Section: Discussionmentioning

confidence: 62%

A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes

Ruiz-Ferrer

Fernández

Antiñolo

et al. 2006

Genetics in Medicine

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Purpose: The RET proto-oncogene is considered to be the major susceptibility gene involved in Hirschsprung disease. Traditional RET germline mutations account for a small subset of Hirschsprung disease patients, but several studies have shown that there is a specific haplotype of RET associated with the sporadic forms of Hirschsprung disease. We have investigated for RET germline mutations and analyzed the RET haplotypic distribution in carriers versus noncarriers of RET germline mutations. Methods: We have screened the coding region of RET in 106 Spanish Hirschsprung disease patients using dHPLC technology. Statistical comparisons of the distribution of RET haplotypes between sporadic patients with and without a RET germline mutation were performed. Results: Nine novel germline mutations and one previously described were identified. A significant over-transmission of the "Hirschsprung disease haplotype" was detected when comparing transmitted versus nontransmitted alleles in the group of Hirschsprung disease triads without mutation. However, no distortion of the transmission of alleles was found in the group of mutated families. Conclusions: These results would be concordant with a complex additive model of inheritance. The whole findings seem to suggest that low-penetrance mutations would be necessary but not sufficient and the additional presence of the "Hirschsprung disease haplotype" could contribute to the manifestation of the disease. Genet Med 2006:8(11):704-710.

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Section: Discussionmentioning

confidence: 62%

A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes

Ruiz-Ferrer

Fernández

Antiñolo

et al. 2006

Genetics in Medicine

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“…The RET locus was first identified as a susceptibility locus for HSCR through linkage analyses in multiplex HSCR families (35,36) facilitated by the finding of deletion of the proximal long arm of chromosome 10 in patients with isolated HSCR (37,38) and the co-occurrence of HSCR and multiple endocrine neoplasia type 2 (MEN2) (39,40). This was followed by the identification of numerous RET mutations, including missense, splicing variants, and short insertions and deletions (indels), across the whole spectrum of patients with HSCR occurring both as de novo and inherited events (10)(11)(12)(13)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). Damaging coding mutations in RET are identified in approximately 50% of familial and 15-20% of sporadic HSCR cases (1,(10)(11)(12)(13), and it gradually becomes evident that rare coding variants in RET appear to play a less prominent role in sporadic and S-HSCR compared to the familial and L-HSCR (51,53).…”

Section: Ret Signalingmentioning

confidence: 99%

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

2021

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Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

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“…However, attention must be given to other genes for several reasons: our data and previous studies show that only a small proportion of HSCR cases have known RET coding sequence mutations, 7,8,39 penetrance differs by sex, 4 and the correlation between specific RET mutations and HSCR severity varies. 40 Genes that regulate enteric neural crest cell proliferation, migration, and differentiation, are strong candidates because their disruption in animals leads to phenotypes that resemble HSCR in humans.…”

Section: Discussionmentioning

confidence: 78%

“…5,6 Approximately 50% of familial cases and 7–35% of non-familial cases have loss-of-function germline RET mutations. 7,8 Common variants in the RET promoter (rs10900296; rs10900297), at a SOX10 binding site in intron 1 (rs2435357), and in exon 2 (rs1800858; c.135G>A; p.A45A) have also been associated with HSCR, 9,10 suggesting that common as well as rare variants might influence the occurrence of HSCR.…”

Section: Introductionmentioning

confidence: 99%

Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation

et al. 2012

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Hirschsprung’s disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, HOXB5, L1CAM, PHOX2B, PROK1, PROKR1) chosen because they are involved in ENCC proliferation, migration, and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1 215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM, and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P values between 10−3 and 10−31) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration, and differentiation could be risk factors for HSCR.

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Low frequency of RET mutations in Hirschsprung disease in Sweden

Cited by 42 publications

References 30 publications

A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes

A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation

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