Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
BMC Med Genet
; 15: 99, 2014 Sep 16.
Article
en En
| MEDLINE
| ID: mdl-25224718
ABSTRACT
BACKGROUND:
Potentially lethal and heritable cardiomyopathies and cardiac channelopathies are caused by heterogeneous autosomal dominant mutations in over 50 distinct genes, and multiple genes are responsible for a given disease. Clinical genetic tests are available for several of the inherited cardiac diseases and clinical investigations guide which test to order. This study describes a family with cardiac disease in which marked clinical diversity exists. In the absence of a unified clinical diagnosis, we used exome sequencing to identify a causal mutation.METHODS:
Clinical evaluation of family members was performed, including physical examination, electrocardiography, 2D transthoracic echocardiography and review of autopsy records. Exome sequencing was performed on a clinically affected individual and co-segregation studies and haplotype analysis were performed to further confirm pathogenicity.RESULTS:
Clinically affected members showed marked cardiac phenotype heterogeneity. While some individuals were asymptomatic, other presentations included left ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained death. Whole exome sequencing identified an Ala119Thr mutation in the alpha-actinin-2 (ACTN2) gene that segregated with disease. Haplotype analysis showed that this mutation segregated with an identical haplotype in a second, previously described family with clinically diverse cardiac disease, and is likely inherited from a common ancestor.CONCLUSIONS:
Mutations in the ACTN2 gene can be responsible for marked cardiac phenotype heterogeneity in families. The diverse mechanistic roles of ACTN2 in the cardiac Z-disc may explain this heterogeneous clinical presentation. Exome sequencing is a useful adjunct to cardiac genetic testing in families with mixed clinical presentations.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fibrilación Ventricular
/
Actinina
/
Muerte Súbita Cardíaca
/
Cardiopatías Congénitas
Límite:
Adult
/
Female
/
Humans
/
Male
País/Región como asunto:
Oceania
Idioma:
En
Revista:
BMC Med Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Australia