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Whole exome sequencing identified a pathogenic nonsense mutation in LMNA in a family with a progressive cardiac conduction defect: A case report.

Abstract：

:Progressive cardiac conduction defect (PCCD) is an inherited autosomal dominant cardiac disorder characterized by an age‑dependent cardiac electrical conduction block. Several genes have been associated with the genetic pathogenesis of PCCD. The present study aimed to identify the causal mutation of PCCD and to investigate the association between genotype and phenotype in a Chinese family with PCCD. A total of 39 family members were included in the present study. All subjects participated in physical, biochemical, electrocardiography and echocardiography examinations. Whole‑exome sequencing was performed for four individuals from the same generation, including three patients with PCCD and one normal control with no cardiovascular disease. Sanger sequencing and in silico analysis were used to identify the causal mutation. Whole‑exome sequencing and variant identification revealed a candidate nonsense mutation (c.1443C>A, p.Tyr481*) in lamin A/C (LMNA). The mutation was identified in seven patients (including the proband) and two asymptomatic mutation carriers, but it was not detected in 100 control subjects of matched ancestry. Clinical examinations identified typical symptoms in patients with PCCD, including bradycardia and various types of conduction defect, and excluded other phenotypes related to the LMNA mutation. The genotype and phenotype were co‑associated among all participants. In the present study, the c.1443C>A mutation in the LMNA gene was identified as a potential cause of PCCD. In silico analysis predicted that the identified mutation was damaging through its effect on the lamin tail domain of LMNA. From the present study, it could be suggested that genetic screening and family counseling, early pacemaker implantation or a sudden death in the family may be essential for risk stratification and treatment of patients with PCCD.

journal_name

Mol Med Rep

journal_title

Molecular medicine reports

authors

Fan P,Zhang D,Yang KQ,Tian T,Luo F,Liu YX,Wang LP,Zhou XL

doi

10.3892/mmr.2020.11048

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

2459-2465

issue

eissn

1791-2997

issn

1791-3004

journal_volume

pub_type

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Whole exome sequencing identified a pathogenic nonsense mutation in LMNA in a family with a progressive cardiac conduction defect: A case report.