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

Abstract

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.

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

“…8 Additional MLPA probes were used and family MC061 was found to have a 2q37.3 duplication. 8 Twenty-one families of this series were tested for a panel of 13 sarcomeric genes in a second collaborative study, 7 and disease-causing variants were found only in the alpha cardiac heavy chain myosin gene (MYH6), in three families (MC027 p.(Cys539Arg), MC053 p.(Lys543Arg) and MC081 p.(Arg17His)). These 21 families were selected out of the Registry because at least one affected individual had ASD (for details, see Supplementary Table S1).…”

“…Some families of this cohort were screened for other genes or another MLPA test and are reported elsewhere. 7,8 For details on the enrolled families, see Supplementary Table S1. All variants were submitted to LOVD (www.lovd.nl/3.0/home).…”

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

“…[38][39][40][41] To our knowledge, there has been no previous report of cardiomyopathy in patients with CHD who harbor a heterozygous MYH6 mutation. Moreover, there has been no clear correlation between the MYH6 domain in which the mutation resides and cardiac phenotype.…”

“…Heterozygous MYH6 mutations associated with cardiomyopathy trend toward later disease onset, 35,36 consistent with the latent systolic dysfunction observed in carriers of compound heterozygous MYH6 mutations. Dominant MYH6 mutations associated with CHDs have variable penetrance as highlighted by segregation studies of familial atrial septal defect, [38][39][40] which revealed several mutation carriers without structural heart disease. Variable intrafamilial expression was also demonstrated in a family where 4 MYH6 mutation carriers had a range of phenotypes including bicuspid aortic valve, coarctation of the aorta, ventricular septal defect, and subaortic stenosis.…”

CCN1 Mutation is Associated with Atrial Septal Defect

“…Various mutations in transcription factors and sarcomeric genes were described in different studies [3]. We have analyzed different genes involved in the pathogenesis of CHDs and could identify mutations in ASD patients [4,5,6].…”