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Novel missense variant in TTN cosegregating with familial atrioventricular block
Guohui Liu1, Ziying Yang2, Weiwei Chen1
1Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, 100029, Jilin Province, China; Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, USA.
Insights
A novel mutation in the titin (TTN) gene was identified as a cause of severe autosomal dominant atrioventricular block (AVB) in a Chinese family. This finding expands the known genetic causes of AVB.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Cardiovascular diseases are a leading global cause of death.
- Atrioventricular block (AVB) is a common cardiac disorder with genetic underpinnings.
- The genetic basis of many AVB cases remains unidentified.
Observation:
- A three-generation Chinese family presented with severe autosomal dominant cardiac AVB.
- Known causative genes for AVB were excluded in this family.
- Whole-exome sequencing was performed on affected and unaffected family members.
Findings:
- A novel heterozygous missense mutation (c.49287C>A, p.N16429K) in the titin (TTN) gene was identified in all affected individuals.
- This TTN mutation was absent in unaffected family members and the general population (gnomAD).
- In-silico analysis and cross-species comparison predicted the mutation to be functionally deleterious.
Implications:
- The titin (TTN) gene is implicated as a novel candidate gene for autosomal dominant AVB.
- This study expands the known mutation spectrum of the TTN gene.
- The findings are the first to link TTN mutations to AVB in a Chinese pedigree.
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.
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