RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

So, Man-Ting; Leon, Thomas Y.Y.; Cheng, Gregory Yin Ming; Tang, Clara S.; Miao, Xiaoping; Cornes, Belinda K.; Ngo, Diem Ngoc; Cui, Long; Ngan, Elly Sau-Wai; Lui, Vincent Chai-Hang; Wu, Xuan-Zhao; Wang, Bin; Wang, Hualong; Yuan, Zhengwei; Huang, Liuming; Li, Long; Xia, Huimin; Zhu, Deli; Liu, Juncheng; Nguyen, Thanh Phuc; Chan, Iris Hiu-Shuen; Chung, Patrick Ho Yu; Liu, Xuelai; Zhang, Ruizhong; Wong, Kenneth K.; Sham, Pak-Chung; Cherny, Stacey S.; Tam, Paul Kwong‐Hang; García-Barceló, María-Mercé

doi:10.1371/journal.pone.0028986

Cited by 27 publications

(18 citation statements)

References 28 publications

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“…The combination of a de novo appearance and the fact that they are recurrent make it extremely likely that these variants are pathogenic even when no functional effects are found. 27 Common RET variants Several common variants (c.135G4A, c.1296 G4A, c.2307 T4G and c.2712C4G) were identified, for which the frequencies of those polymorphic alleles were similar to those described in other populations. 11,12,26 Garcia-Barcelo et al 28 showed that the haplotype containing three common RET variants (c.135G4A, c.1296G4A and c.2307 T4G) are represented in 66% of HSCR patients and c.1296G4 A is associated with a more severe form of HSCR.…”

Section: De Novo Ret Variantsmentioning

confidence: 64%

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

et al. 2015

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Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p. (Pr270Leu) (Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A4G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.

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Section: De Novo Ret Variantsmentioning

confidence: 64%

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

et al. 2015

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“…For the latter, the RET intron 1 SNP (rs2435357), highly associated with HSCR and known to interact with EDNRB [18] was also amplified and sequenced. Primers and PCR conditions are described elsewhere [22], [23], [24].…”

Section: Methodsmentioning

confidence: 99%

Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia

et al. 2013

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We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and HSCR. None of the members had sensorineural deafness. The family was screened for copy number variations (CNVs) using Illumina-HumanOmni2.5-Beadchip and for coding sequence mutations in WS4 genes (EDN3, EDNRB, or SOX10) and in the main HSCR gene (RET). Confocal microscopy and immunoblotting were used to assess the functional impact of the mutations. A heterozygous A/G transition in EDNRB was identified in 4 affected and 3 unaffected individuals. While in EDNRB isoforms 1 and 2 (cellular receptor) the transition results in the abolishment of translation initiation (M1V), in isoform 3 (only in the cytosol) the replacement occurs at Met91 (M91V) and is predicted benign. Another heterozygous transition (c.-248G/A; -predicted to affect translation efficiency-) in the 5′-untranslated region of EDN3 (EDNRB ligand) was detected in all affected individuals but not in healthy carriers of the EDNRB mutation. Also, a de novo CNVs encompassing DACH1 was identified in the patient with heterochromia iridum and HSCRSince the EDNRB and EDN3 variants only coexist in affected individuals, HSCR could be due to the joint effect of mutations in genes of the same pathway. Iris heterochromia could be due to an independent genetic event and would account for the additional phenotype within the family.

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“…35 The paternally inherited RET variant c.3148C>T p.(Arg1050*) has previously been reported in a patient with Hirschsprung disease. 36 In mice, Slit2-Robo2 signaling is shown to restrict Gdnf-Ret signals to the site of the ureteric bud outgrowth preventing formation of multiple ureteric buds. Robo2 and Slit2 mice mutants show multiplex kidneys due to multiple ureteric bud formation.…”

Section: Variant In Ret (+164761)mentioning

confidence: 99%

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

et al. 2018

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Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

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RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

Cited by 27 publications

References 28 publications

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling

Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

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