Conference Paper: RET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients

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Title	RET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients
Authors	Cherny, SS Garcia-Barcelo, MM Leon, TYY So, MT Sham, PC Tam, PKH
Keywords	Genomics KW139 - Polymorphism KW117 - Mutation Detection KW065 - Gastrointestinal System
Issue Date	2011
Publisher	American Society of Human Genetics.
Citation	The 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011. [How to Cite?]
Abstract	Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the lower digestive tract. Aganglionosis is attributed to a disorder of the enteric nervous system (ENS) whereby ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. There is significant population variation in the incidence of the disease, and it is most often found among Asians (2.8 per 10,000 live births). HSCR most commonly presents sporadically (80% of the cases), with a recurrence risk of 4%, and more males than females affected (4:1). Both rare (<1% in the population) and common germ line variants of the RET gene, acting either alone or in combination, are the main cause of the disease. Yet, while RET common variants are strongly associated with the commonest manifestation of the disease (male, short segment, and sporadic forms), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females, long or total colonic aganglionosis, and familial). Here we present a rare variant (RV) screening of the CDS and intron/exon boundaries of the RET gene in 607 Chinese sporadic HSCR patients, the largest number of patients ever reported. We have found a total of 61 different heterozygous RVs (50 novel) distributed in 100 patients (16.64%). These include 14 silent, 29 missense, 5 nonsense amino-acid changes, 4 frame-shifts, and one in-frame amino-acid deletion in the exonic region and two splice-site deletions, 4 nucleotide substitutions and a 22 bp deletion in intronic or untranslated regions. The exonic variants were mainly clustered in the sequence encoding the extracellular domain of the RET protein. All RVs were predicted to alter the protein function. The highest frequency of rare variants was found among those patients with the most severe form of the disease (24% in long or total vs 15% in short-segment). Phasing of the RVs with the RET risk-haplotype suggested that RET RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants was found in 250 Chinese controls.
Description	Poster Session - Session Title: Gene Structure and Gene Product Function: Program no. 778F

DC Field	Value
dc.contributor.author	Cherny, SS
dc.contributor.author	Garcia-Barcelo, MM
dc.contributor.author	Leon, TYY
dc.contributor.author	So, MT
dc.contributor.author	Sham, PC
dc.contributor.author	Tam, PKH
dc.date.accessioned	2012-07-16T09:57:18Z
dc.date.available	2012-07-16T09:57:18Z
dc.date.issued	2011
dc.description.abstract	Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the lower digestive tract. Aganglionosis is attributed to a disorder of the enteric nervous system (ENS) whereby ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. There is significant population variation in the incidence of the disease, and it is most often found among Asians (2.8 per 10,000 live births). HSCR most commonly presents sporadically (80% of the cases), with a recurrence risk of 4%, and more males than females affected (4:1). Both rare (<1% in the population) and common germ line variants of the RET gene, acting either alone or in combination, are the main cause of the disease. Yet, while RET common variants are strongly associated with the commonest manifestation of the disease (male, short segment, and sporadic forms), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females, long or total colonic aganglionosis, and familial). Here we present a rare variant (RV) screening of the CDS and intron/exon boundaries of the RET gene in 607 Chinese sporadic HSCR patients, the largest number of patients ever reported. We have found a total of 61 different heterozygous RVs (50 novel) distributed in 100 patients (16.64%). These include 14 silent, 29 missense, 5 nonsense amino-acid changes, 4 frame-shifts, and one in-frame amino-acid deletion in the exonic region and two splice-site deletions, 4 nucleotide substitutions and a 22 bp deletion in intronic or untranslated regions. The exonic variants were mainly clustered in the sequence encoding the extracellular domain of the RET protein. All RVs were predicted to alter the protein function. The highest frequency of rare variants was found among those patients with the most severe form of the disease (24% in long or total vs 15% in short-segment). Phasing of the RVs with the RET risk-haplotype suggested that RET RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants was found in 250 Chinese controls.
dc.description.nature	link_to_OA_fulltext
dc.description	Poster Session - Session Title: Gene Structure and Gene Product Function: Program no. 778F
dc.description.other	The 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011.
dc.identifier.citation	The 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011. [How to Cite?]
dc.identifier.hkuros	200604
dc.identifier.uri	http://hdl.handle.net/10722/153113
dc.language	eng
dc.publisher	American Society of Human Genetics.
dc.publisher.place	United States
dc.relation.ispartof	International Congress of Human Genetics, ICHG 2011
dc.subject	Genomics
dc.subject	KW139 - Polymorphism
dc.subject	KW117 - Mutation Detection
dc.subject	KW065 - Gastrointestinal System
dc.title	RET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients
dc.type	Conference_Paper

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