Abstract
BackgroundMyosin VI, encoded by MYH6, is expressed dominantly in human cardiac atria and plays consequential roles in cardiac muscle contraction and comprising the cardiac muscle thick filament. It has been reported that the mutations in the MYH6 gene associated with sinus venosus atrial septal defect (ASD type III), hypertrophic (HCM) and dilated (DCM) cardiomyopathies.MethodsTwo patients in an Iranian family have been identified who affected to Congenital Heart Disease (CHD). The male patient, besides CHD, shows that the thyroglossal sinus, refractive errors of the eye and mitral stenosis. The first symptoms emerged at the birth and diagnosis based on clinical features was made at about 5 years. The family had a history of ASD. For recognizing mutated gene (s), whole exome sequencing (WES) was performed for the male patient and variants were analyzed by autosomal dominant inheritance mode.ResultsEventually, by several filtering processes, a mutation in MYH6 gene (NM_002471.3), c.3835C > T; R1279X, was identified as the most likely disease-susceptibility variant and then confirmed by Sanger sequencing in the family. The mutation frequency was checked out in the local databases. This mutation results in the elimination of the 660 amino acids in the C-terminal of Myosin VI protein, including the vital parts of the coiled-coil structure of the tail domain.ConclusionsOur study represents the first case of Sinus venosus defect caused directly by MYH6 stop codon mutation. Our data indicate that by increase haploinsufficiency of myosin VI, c.3835C > T mutation with reduced penetrance could be associated with CHD.
Highlights
Myosin VI, encoded by MYH6, is expressed dominantly in human cardiac atria and plays consequential roles in cardiac muscle contraction and comprising the cardiac muscle thick filament
We identified a novel nonsense mutation in MYH6, NM_002471.3 c.3835C > T; R1279X, by whole exome sequencing (WES) of the patient in SH1190831 family and this mutation was confirmed by Sanger sequencing
To find the main cause of congenital heart disease (CHD) in the proband by known genetic mutation (s), based on proband phenotype, we especially focused on the 42 genes that have critical roles in CHD etiology and revised our strategies with a filter of pertinent variants in these genes (Additional file 1: Table S1)
Summary
Myosin VI, encoded by MYH6, is expressed dominantly in human cardiac atria and plays consequential roles in cardiac muscle contraction and comprising the cardiac muscle thick filament. Congenital Heart Defects (CHDs) are one of the major causes of death due to congenital malformations and show some of the more preponderant malformations among live births. It has been revealed that both familial and sporadic forms of CHDs result from mutations in several genes based on human cases and animal models [1, 2]. Based on targeted deletions studies in mice, it has been suggested that there are more than five hundred genes involved in heart disorders (Mouse Genome Informatics (http://www.informatics.jax.org)) [3]. CHDs treat greatly as a complex trait and to date, the number. Both inherited and non-inherited factors account for congenital heart disease (CHD). With development of whole exome/genome sequencing more CHD causing genes possibly will be clarified which will increase our insight into the genetic causes of CHD
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