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Conference Paper: RET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients
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TitleRET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients
 
AuthorsCherny, SS
Garcia-Barcelo, MM
Leon, TYY
So, MT
Sham, PC
Tam, PKH
 
KeywordsGenomics
KW139 - Polymorphism
KW117 - Mutation Detection
KW065 - Gastrointestinal System
 
Issue Date2011
 
PublisherAmerican Society of Human Genetics.
 
CitationThe 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011. [How to Cite?]
 
AbstractHirschsprung’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.
 
DescriptionPoster Session - Session Title: Gene Structure and Gene Product Function: Program no. 778F
 
DC FieldValue
dc.contributor.authorCherny, SS
 
dc.contributor.authorGarcia-Barcelo, MM
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorSo, MT
 
dc.contributor.authorSham, PC
 
dc.contributor.authorTam, PKH
 
dc.date.accessioned2012-07-16T09:57:18Z
 
dc.date.available2012-07-16T09:57:18Z
 
dc.date.issued2011
 
dc.description.abstractHirschsprung’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.naturelink_to_OA_fulltext
 
dc.descriptionPoster Session - Session Title: Gene Structure and Gene Product Function: Program no. 778F
 
dc.description.otherThe 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011.
 
dc.identifier.citationThe 12th International Congress of Human Genetics (ICHG 2011), Montreal, Canada, 11-15 October 2011. [How to Cite?]
 
dc.identifier.hkuros200604
 
dc.identifier.urihttp://hdl.handle.net/10722/153113
 
dc.languageeng
 
dc.publisherAmerican Society of Human Genetics.
 
dc.publisher.placeUnited States
 
dc.relation.ispartofInternational Congress of Human Genetics, ICHG 2011
 
dc.subjectGenomics
 
dc.subjectKW139 - Polymorphism
 
dc.subjectKW117 - Mutation Detection
 
dc.subjectKW065 - Gastrointestinal System
 
dc.titleRET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients
 
dc.typeConference_Paper
 
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<contributor.author>Garcia-Barcelo, MM</contributor.author>
<contributor.author>Leon, TYY</contributor.author>
<contributor.author>So, MT</contributor.author>
<contributor.author>Sham, PC</contributor.author>
<contributor.author>Tam, PKH</contributor.author>
<date.accessioned>2012-07-16T09:57:18Z</date.accessioned>
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<description.abstract>Hirschsprung&#8217;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 (&lt;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.abstract>
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<publisher>American Society of Human Genetics.</publisher>
<relation.ispartof>International Congress of Human Genetics, ICHG 2011</relation.ispartof>
<subject>Genomics</subject>
<subject>KW139 - Polymorphism</subject>
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<subject>KW065 - Gastrointestinal System</subject>
<title>RET mutational spectrum in Hirschsprungs disease: evaluation of 601 Chinese patients</title>
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