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Novel missense variant in TTN cosegregating with familial atrioventricular block.

Authors
  • Liu, Guohui1
  • Yang, Ziying2
  • Chen, Weiwei1
  • Xu, Junguang3
  • Mao, Liangwei3
  • Yu, Qinlin4
  • Guo, Jian3
  • Xu, Hui3
  • Liu, Fengxia5
  • Sun, Yan3
  • Huang, Hui3
  • Peng, Zhiyu3
  • Sun, Jun2
  • Li, Wei6
  • Yang, Ping7
  • 1 Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, 100029, Jilin Province, China; Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, USA. , (China)
  • 2 Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China; Binhai Genomics Institute, BGI-Tianjin, BGI Shenzhen, Tianjin, 300308, China; James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China. , (China)
  • 3 BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China. , (China)
  • 4 BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China; Department of Molecular Cell Biology, UC Berkeley, Berkeley, CA, 94704, USA. , (China)
  • 5 Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China; Binhai Genomics Institute, BGI-Tianjin, BGI Shenzhen, Tianjin, 300308, China. , (China)
  • 6 BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China. Electronic address: [email protected] , (China)
  • 7 Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, 100029, Jilin Province, China; Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, USA. Electronic address: [email protected] , (China)
Type
Published Article
Journal
European journal of medical genetics
Publication Date
Mar 01, 2020
Volume
63
Issue
3
Pages
103752–103752
Identifiers
DOI: 10.1016/j.ejmg.2019.103752
PMID: 31470098
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. Copyright © 2019 Elsevier Masson SAS. All rights reserved.

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