European journal of medical genetics · 2019
Novel missense variant in TTN cosegregating with familial atrioventricular block.
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Liu Guohui, Yang Ziying, Chen Weiwei, Xu Junguang, Mao Liangwei, Yu Qinlin, Guo Jian, Xu Hui, Liu Fengxia, Sun Yan, Huang Hui, Peng Zhiyu, Sun Jun, Li Wei, Yang Ping
Аннотация
BACKGROUND: Cardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.
METHODS: Whole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.
RESULTS: Whole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C > A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members but not in the unaffected family members, neither in the large population according to the Genome Aggregation Database (https://gnomad.broadinstitute.org/). The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.
CONCLUSION: Based on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.
METHODS: Whole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.
RESULTS: Whole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C > A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members but not in the unaffected family members, neither in the large population according to the Genome Aggregation Database (https://gnomad.broadinstitute.org/). The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.
CONCLUSION: Based on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.