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Conference Paper: Genetics of congenital megacolon in East Asians
Title | Genetics of congenital megacolon in East Asians |
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Authors | |
Keywords | Genome sequencing Neurogenetics Gastrointestinal system Genetic mapping Rare variants |
Issue Date | 2018 |
Publisher | American Society of Human Genetics. |
Citation | The 67th Annual Meeting of the American Society of Human Genetics, Orlando, FL, 17-21 October 2018 How to Cite? |
Abstract | Hirschsprung disease (HSCR), also known as congenital megacolon, is characterized by the absence of enteric ganglia in the hindgut. HSCR is a multigenic neurocristopathy with a two-fold increase in the incidence among East Asians. The major HSCR gene, RET, has both rare and common variants contribute to the disease risk. In particular, ~80% of Asian HSCR patients carry the high risk common enhancer allele. When in trans with the recently discovered, Asian-specific missense variant, the RET enhancer SNP increases the risk of HSCR by more than 20-fold. Thus far, over 10 HSCR genes were found to have common and/or rare variants attribute to disease susceptibility. To discover novel HSCR-associated gene(s), we performed a whole genome sequencing (WGS) of 443 HSCR cases and 493 controls of East Asian ethnicity. Rare variant association analysis was carried out and, with subsequent follow-up study, we identified a significant excess of rare protein-altering mutations in BACE2 (p=2.9x10-6) in HSCR cases (4%) compared with controls (0.6%). The relevance of BACE2 in HSCR is highlighted by the facts that i) the encoded protein has recently been proposed as a target for drug-based treatment of HSCR; and ii) BACE2 maps to the HSCR-Down Syndrome (DS) critical chromosomal region, with DS being the most frequent chromosomal abnormality associated with HSCR. The BACE2-HSCR association may represent the missing link between these two disorders. Results of the common variant association analysis will also be presented. |
Persistent Identifier | http://hdl.handle.net/10722/259443 |
DC Field | Value | Language |
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dc.contributor.author | Tang, SM | - |
dc.contributor.author | Zhuang, X | - |
dc.contributor.author | Cherny, SS | - |
dc.contributor.author | Sham, PC | - |
dc.contributor.author | Garcia-Barcelo, MM | - |
dc.contributor.author | Tam, PKH | - |
dc.date.accessioned | 2018-09-03T04:07:29Z | - |
dc.date.available | 2018-09-03T04:07:29Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | The 67th Annual Meeting of the American Society of Human Genetics, Orlando, FL, 17-21 October 2018 | - |
dc.identifier.uri | http://hdl.handle.net/10722/259443 | - |
dc.description.abstract | Hirschsprung disease (HSCR), also known as congenital megacolon, is characterized by the absence of enteric ganglia in the hindgut. HSCR is a multigenic neurocristopathy with a two-fold increase in the incidence among East Asians. The major HSCR gene, RET, has both rare and common variants contribute to the disease risk. In particular, ~80% of Asian HSCR patients carry the high risk common enhancer allele. When in trans with the recently discovered, Asian-specific missense variant, the RET enhancer SNP increases the risk of HSCR by more than 20-fold. Thus far, over 10 HSCR genes were found to have common and/or rare variants attribute to disease susceptibility. To discover novel HSCR-associated gene(s), we performed a whole genome sequencing (WGS) of 443 HSCR cases and 493 controls of East Asian ethnicity. Rare variant association analysis was carried out and, with subsequent follow-up study, we identified a significant excess of rare protein-altering mutations in BACE2 (p=2.9x10-6) in HSCR cases (4%) compared with controls (0.6%). The relevance of BACE2 in HSCR is highlighted by the facts that i) the encoded protein has recently been proposed as a target for drug-based treatment of HSCR; and ii) BACE2 maps to the HSCR-Down Syndrome (DS) critical chromosomal region, with DS being the most frequent chromosomal abnormality associated with HSCR. The BACE2-HSCR association may represent the missing link between these two disorders. Results of the common variant association analysis will also be presented. | - |
dc.language | eng | - |
dc.publisher | American Society of Human Genetics. | - |
dc.relation.ispartof | Annual Meeting of the American Society of Human Genetics | - |
dc.subject | Genome sequencing | - |
dc.subject | Neurogenetics | - |
dc.subject | Gastrointestinal system | - |
dc.subject | Genetic mapping | - |
dc.subject | Rare variants | - |
dc.title | Genetics of congenital megacolon in East Asians | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Tang, SM: claratang@hku.hk | - |
dc.identifier.email | Cherny, SS: cherny@hku.hk | - |
dc.identifier.email | Sham, PC: pcsham@hku.hk | - |
dc.identifier.email | Garcia-Barcelo, MM: mmgarcia@hku.hk | - |
dc.identifier.email | Tam, PKH: paultam@hku.hk | - |
dc.identifier.authority | Tang, SM=rp02105 | - |
dc.identifier.authority | Cherny, SS=rp00232 | - |
dc.identifier.authority | Sham, PC=rp00459 | - |
dc.identifier.authority | Garcia-Barcelo, MM=rp00445 | - |
dc.identifier.authority | Tam, PKH=rp00060 | - |
dc.identifier.hkuros | 287960 | - |
dc.publisher.place | Orlando, FL | - |