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 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 Newfoundland BRCA1 and BRCA2 mutations in 57 newly recruited probands (phase 2) only resulted in one positive screen; one proband screened positive for the BRCA2 c.6714delACAA mutation. The two BRCA2 c.6714delACAA probands (one from phase 1 and the other from phase 2) appeared to share a 6.02 Mb haplotype on chromosome 13 between markers D13S1242 and D13S220 - suggesting it may be a founder mutation. Furthermore, screening all probands for a low penetrant allele in the CHK2 gene identified three mutation carriers. - Conclusions -- The population of Newfoundland provides opportunity for novel gene discovery particularly in autosomal dominant and X-linked disorders. By studying 15 Newfoundland ARVC families we have identified the cause of ARVD5 as a missense mutation in a novel gene, TMEM43. This discovery, through mutation screening, now aids in disease diagnosis and identifies at-risk individuals, which allows the appropriate life-saving precautions to be taken, including the use of an implantable cardioverter defibrillator. -- A critical region on the X chromosome has been identified that segregates with non-syndromic deafness in a large Newfoundland family. Despite great efforts, the causal gene has not yet been identified and thus there still remains an opportunity for a novel gene discovery. -- The Newfoundland population also provides an opportunity to identify a novel gene(s) in breast cancer. Studying the unsolved families (approximately 84% of the BRCA1 and BRCA2 screened cohort) and determining which ones originate from the same fishing communities may represent clusters of related families that could be used to search for new genes.

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