A molecular genetics approach to gene discovery of Mendelian diseases on the island of Newfoundland
Background -- Newfoundland is an island off Canada's east coast that has a unique population for gene discovery. Newfoundland out-port communities were founded by English Protestant or Irish Catholic fisherman, and were subject to isolation due to geographical distance between communities and r...
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| Format: | Thesis |
| Language: | English |
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Memorial University of Newfoundland
2011
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| Online Access: | https://research.library.mun.ca/9527/ https://research.library.mun.ca/9527/1/Merner_NancyD.pdf |
| Summary: | Background -- Newfoundland is an island off Canada's east coast that has a unique population for gene discovery. Newfoundland out-port communities were founded by English Protestant or Irish Catholic fisherman, and were subject to isolation due to geographical distance between communities and religious segregation. As such, many genetic isolates formed and have since aided in several gene discoveries. - Objective -- The main objective of this thesis was to identify novel disease-causing genes involved in arrhythmogenic right ventricular cardiomyopathy/dysplasia type 5 (ARVC/D), deafness and breast cancer, by studying Newfoundland families. - Results -- ARVC is an arrhythmic disorder characterized by fat-fibro replacement of the myocardium. The causal gene for one subtype of ARVC, ARVD5, was identified by studying 15 Newfoundland ARVC families. Haplotype analysis initially revealed a 2.36 Mb critical region that all affected individuals shared and after screening positional candidate genes, a missense variant, transmembranre protein 43 (TMEM43) c.1073C>T, was determined to be the causal variant. -- A large, extended Newfoundland family with non-syndromic hearing loss was suspected to have an X-linked mode of inheritance. Haplotypes spanning the entire X chromosome revealed that only a single region was shared among all affected individuals, a 13.3 Mb region on Xp. One key individual, whose parents were both affected and related, had a 0.96 Mb region of homozygosity within the dystrophin (DMD) locus, however, segregation of the affected haplotype on the maternal side was not confirmed. Screening cochlea expressed positional candidate genes in the 13.3 Mb region revealed no deleterious variants. -- Screening a cohort of 96 Newfoundland breast cancer probands, with a family history of breast cancer, for BRCA1 and BRCA2 (breast cancer susceptibility genes 1 and 2) deleterious variants (phase 1) identified 15 truncation mutations solving only 15.6% (15/96) of the cohort. In addition, targeted screening of the 15 ... |
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