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A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

ABSTRACT: Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10?²?. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

SUBMITTER: Holm H

PROVIDER: S-EPMC3066272 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

Holm Hilma H Gudbjartsson Daniel F DF Sulem Patrick P Masson Gisli G Helgadottir Hafdis Th HT Zanon Carlo C Magnusson Olafur Th OT Helgason Agnar A Saemundsdottir Jona J Gylfason Arnaldur A Stefansdottir Hrafnhildur H Gretarsdottir Solveig S Matthiasson Stefan E SE Thorgeirsson Gu Mundur GM Jonasdottir Aslaug A Sigurdsson Asgeir A Stefansson Hreinn H Werge Thomas T Rafnar Thorunn T Kiemeney Lambertus A LA Parvez Babar B Muhammad Raafia R Roden Dan M DM Darbar Dawood D Thorleifsson Gudmar G Walters G Bragi GB Kong Augustine A Thorsteinsdottir Unnur U Arnar David O DO Stefansson Kari K

Nature genetics 20110306 4

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × ...[more]

PMID: 21378987

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Project description:Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease; however, its etiology remains largely unknown. We previously demonstrated that genetic variants in the MYH6 gene are significantly associated with HLHS. Additionally, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from an HLHS-affected family trio (affected parent, unaffected parent, affected proband) carrying an MYH6-R443P head domain variant demonstrated dysmorphic sarcomere structure and increased compensatory MYH7 expression. Analysis of iPSC-CMs derived from the HLHS trio revealed that only beta myosin heavy chain expression was observed in CMs carrying the MYH6-R443P variant after differentiation day 15 (D15). Functional assessments performed between D20-D23 revealed that MYH6-R443P variant CMs contracted more slowly (40 ± 2 vs. 47 ± 2 contractions/min, P < 0.05), shortened less (5.6 ± 0.5 vs. 8.1 ± 0.7% of cell length, P < 0.05), and exhibited slower shortening rates (19.9 ± 1.7 vs. 28.1 ± 2.5 ?m/s, P < 0.05) and relaxation rates (11.0 ± 0.9 vs. 19.7 ± 2.0 ?m/s, P < 0.05). Treatment with isoproterenol had no effect on iPSC-CM mechanics. Using CRISPR/Cas9 gene editing technology, introduction of the R443P variant into the unaffected parent's iPSCs recapitulated the phenotype of the proband's iPSC-CMs, and conversely, correction of the R443P variant in the proband's iPSCs rescued the cardiomyogenic differentiation, sarcomere organization, slower contraction (P < 0.05) and decreased velocity phenotypes (P < 0.0001). This is the first report to identify that cardiac tissues from HLHS patients with MYH6 variants can exhibit sarcomere disorganization in atrial but not ventricular tissues. This new discovery was not unexpected, since MYH6 is expressed predominantly in the postnatal atria in humans. These findings demonstrate the feasibility of employing patient-derived iPSC-CMs, in combination with patient cardiac tissues, to gain mechanistic insight into how genetic variants can lead to HLHS. Results from this study suggest that decreased contractility of CMs due to sarcomere disorganization in the atria may effect hemodynamic changes preventing development of a normal left ventricle.

Dataset Information

A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

Publications

A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

Similar Datasets

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