RGD Reference Report - Impact of MYH6 variants in hypoplastic left heart syndrome. - Rat Genome Database

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Impact of MYH6 variants in hypoplastic left heart syndrome.

Authors: 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 
Citation: Tomita-Mitchell A, etal., Physiol Genomics. 2016 Dec 1;48(12):912-921. doi: 10.1152/physiolgenomics.00091.2016. Epub 2016 Oct 27.
RGD ID: 12798513
Pubmed: PMID:27789736   (View Abstract at PubMed)
PMCID: PMC5206387   (View Article at PubMed Central)
DOI: DOI:10.1152/physiolgenomics.00091.2016   (Journal Full-text)

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 α-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 ß-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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MYH7Humanhypoplastic left heart syndrome  IGIMYH6 (Homo sapiens) RGD 
Myh7Rathypoplastic left heart syndrome  ISOMYH7 (Homo sapiens) RGD 
Myh7Mousehypoplastic left heart syndrome  ISOMYH7 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Myh7  (myosin heavy chain 7)

Genes (Mus musculus)
Myh7  (myosin, heavy polypeptide 7, cardiac muscle, beta)

Genes (Homo sapiens)
MYH7  (myosin heavy chain 7)


Additional Information