Cardiac Alpha-Myosin (MYH6) Is the Predominant Sarcomeric Disease Gene for Familial Atrial Septal Defects

Maximilian G Posch,Katharina R Schmitt,Stephan Waldmuller,Patrice Bouvagnet,David Fournier,Dany Yousseff,Claire Dauphin,Melanie Müller,Bernard De Geeter,Roland Hetzer,Sophie Guillaumont,Felix Berger,Thomas Scheffold,Andreas Perrot,Cemil Özcelik,Miguel A Andrade-Navarro

doi:10.1371/journal.pone.0028872

Maximilian G Posch, Katharina R Schmitt + Show 14 more

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Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII.

Highlights

Congenital heart defects (CHD) are the most common inborn malformations and are a major cause of perinatal mortality
ASDII was reported to be overrepresented in patients with hypertrophic cardiomyopathy (HCM) or left-ventricular non-compaction cardiomyopathy (LVNC) caused by mutations in ACTC1 and MYH7 encoding the sarcomeric filaments alpha-actin and beta-myosin heavy chain, respectively [8,9]
Array-based resequencing increases the number of genes that can be analyzed simultaneously, more efficient highthroughput DNA sequencing technologies have emerged during the last years commonly referred to as generation sequencing (NGS)

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Introduction

Congenital heart defects (CHD) are the most common inborn malformations and are a major cause of perinatal mortality. Though mutations in cardiac transcription factors are believed to represent a major genetic source for ASDII, mutations in non-regulatory genes were found [3]. In patients with familial ASDII, pedigree based linkage analyses identified mutations in MYH6 and ACTC1, which encode the sarcomeric filament proteins alpha-myosin heavy chain and cardiac alphaactin, respectively [4,5]. ASDII was reported to be overrepresented in patients with hypertrophic cardiomyopathy (HCM) or left-ventricular non-compaction cardiomyopathy (LVNC) caused by mutations in ACTC1 and MYH7 encoding the sarcomeric filaments alpha-actin and beta-myosin heavy chain, respectively [8,9]. Recent studies have reported mutations in MYH6 in patients with various forms of CHD [10] and MYH7 mutations in congenital Ebstein anomaly in combination with LVNC [11]

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