Impact of MYH6 variants in hypoplastic left heart syndrome

Aoy Tomita-Mitchell, Karl D. Stamm, Donna K. Mahnke, Min Su Kim, Pip M. Hidestrand, Huan Ling Liang, Mary A. Goetsch, Mats Hidestrand, Pippa Simpson, Andrew N Pelech, James S. Tweddell, D. Woodrow Benson, John W. Lough, Michael E. Mitchell

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the _-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10-5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10-2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10-3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10-2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

Original languageEnglish (US)
Pages (from-to)912-921
Number of pages10
JournalPhysiological Genomics
Volume48
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Hypoplastic Left Heart Syndrome
Induced Pluripotent Stem Cells
Myosin Heavy Chains
Genes
Heart Diseases
Transcriptome
Case-Control Studies

Keywords

  • Cardiomyocyte-autonomous
  • Genetics
  • Hypoplastic left heart syndrome
  • Transplant-free survival outcome
  • Upregulation of contractility genes

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Tomita-Mitchell, A., Stamm, K. D., Mahnke, D. K., Kim, M. S., Hidestrand, P. M., Liang, H. L., ... Mitchell, M. E. (2016). Impact of MYH6 variants in hypoplastic left heart syndrome. Physiological Genomics, 48(12), 912-921. https://doi.org/10.1152/physiolgenomics.00091.2016

Impact of MYH6 variants in hypoplastic left heart syndrome. / Tomita-Mitchell, Aoy; Stamm, Karl D.; Mahnke, Donna K.; Kim, Min Su; Hidestrand, Pip M.; Liang, Huan Ling; Goetsch, Mary A.; Hidestrand, Mats; Simpson, Pippa; Pelech, Andrew N; Tweddell, James S.; Benson, D. Woodrow; Lough, John W.; Mitchell, Michael E.

In: Physiological Genomics, Vol. 48, No. 12, 01.12.2016, p. 912-921.

Research output: Contribution to journalArticle

Tomita-Mitchell, A, Stamm, KD, Mahnke, DK, Kim, MS, Hidestrand, PM, Liang, HL, Goetsch, MA, Hidestrand, M, Simpson, P, Pelech, AN, Tweddell, JS, Benson, DW, Lough, JW & Mitchell, ME 2016, 'Impact of MYH6 variants in hypoplastic left heart syndrome', Physiological Genomics, vol. 48, no. 12, pp. 912-921. https://doi.org/10.1152/physiolgenomics.00091.2016
Tomita-Mitchell A, Stamm KD, Mahnke DK, Kim MS, Hidestrand PM, Liang HL et al. Impact of MYH6 variants in hypoplastic left heart syndrome. Physiological Genomics. 2016 Dec 1;48(12):912-921. https://doi.org/10.1152/physiolgenomics.00091.2016
Tomita-Mitchell, Aoy ; Stamm, Karl D. ; Mahnke, Donna K. ; Kim, Min Su ; Hidestrand, Pip M. ; Liang, Huan Ling ; Goetsch, Mary A. ; Hidestrand, Mats ; Simpson, Pippa ; Pelech, Andrew N ; Tweddell, James S. ; Benson, D. Woodrow ; Lough, John W. ; Mitchell, Michael E. / Impact of MYH6 variants in hypoplastic left heart syndrome. In: Physiological Genomics. 2016 ; Vol. 48, No. 12. pp. 912-921.
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