CMD1S; CMH1; MPD1; MYHCB; SPMD; SPMM
The MYH7 gene is associated with autosomal dominant hypertrophic cardiomyopathy (HCM) (MedGen UID: 501195), dilated cardiomyopathy (DCM) (MedGen UID: 37831), left ventricular noncompaction (LVNC) (MedGen UID: 349005), and Laing distal myopathy (MPD1) (MedGen UID: 449370). It is also associated with autosomal dominant and recessive myosin storage myopathy (MSMA) (MedGen UID:374868) and autosomal dominant scapuloperoneal myopathy (SPMM) (MedGen UID: 442146).
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Pathogenic MYH7 variants are associated with 13%-20% of clinical cases of LVNC, 16% of cases of HCM, and 4%-5% of DCM cases. MYH7 is the only known causative gene for Laing distal myopathy and myosin storage myopathy.
The gene MYH7 encodes the protein beta myosin heavy chain 7. This protein is part of the sarcomere complex, which is present in both cardiac and skeletal muscle cells. The primary role of the sarcomere complex is muscle contraction. Pathogenic variants in genes that encode sarcomere proteins are a common cause of inherited myopathies.
The MYH7 gene is associated with hypertrophic cardiomyopathy (HCM; MedGen UID: 501195), dilated cardiomyopathy (DCM; MedGen UID: 371831), left ventricular noncompaction (LVNC; MedGen UID: 349005), Laing distal myopathy (MPD1; MedGen UID: 449370), myosin storage myopathy (MSMA; MedGen UID: 374868), and scapuloperoneal myopathy (SPMM; MedGen UID: 442146).
These cardiomyopathies may lead to cardiac dysfunction, heart failure, arrhythmia, blood clots, or stroke (PMID: 22068435, 29567486). Symptoms include palpitations, dizziness, syncope, chest pain, shortness of breath, fatigue, edema, and in some cases, sudden cardiac arrest or death (SCA/D; PMID: 22068435, 22796258, 24998133).
Progression of myopathy symptoms associated with the disorders listed below is variable, and patients may experience muscle weakness in the hands and wrists or facial muscles and may require ambulatory aides or retain a high degree of functionality throughout their life (PMID: 16103042, 24664454).
The MYH7 gene encodes the protein beta-myosin heavy chain 7. This protein is part of the sarcomere complex, which is present in both cardiac and skeletal muscle cells. The primary role of the sarcomere complex is muscle contraction (PMID: 11239412).
Conditions associated with pathogenic variants in MYH7 usually exhibit autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant.
MYH7-associated MSMA can also exhibit autosomal recessive inheritance. This means that affected individuals have two pathogenic variants—one in each copy of their MYH7 genes.
Pathogenic variants in MYH7 are associated with reduced penetrance and variable expressivity, even within families (PMID: 29567486, 20733148).
Individuals with MYH7-related conditions may have cardiomyopathy with myopathy or isolated cardiac or skeletal myopathy, and management decisions should be made based on clinical presentation, symptoms, and family history (PMID: 29097296, 29567486, 22431881).
Cardiomyopathy is recommended to be managed by a combination of lifestyle modification, medication, surgical and device therapy (e.g., pacemaker or implantable cardioverter defibrillator), and heart transplantation (PMID: 29097296, 29567486). Cardiac surveillance through imaging (by echocardiogram and MRI) and electrocardiographic monitoring (by standard and ambulatory methods) are recommended upon diagnosis, at set intervals depending on age and presentation, and whenever symptoms present or worsen (PMID: 22068435, 29567486).
Myopathy management is primarily focused on supportive care and may include pulmonary screening, regular endurance exercise avoiding fatigue and muscle soreness, stretching, orthotics, ambulation and mobility assistance, nutritional monitoring, and speech and language therapy (PMID: 22431881).
Overall, women with cardiomyopathy or myopathy who become pregnant are generally recommended to be considered high-risk and eligible for increased cardiac surveillance both for themselves and their fetus, increased pulmonology monitoring, genetic counseling, and an evaluation of treatment methods to weigh any risks to the pregnancy (PMID: 22068435, 24451172, 22431881).
Genetic testing is recommended for at-risk family members of an individual with a disease-causing pathogenic variant (PMID: 29097296, 29567486).
Review date: May 2018
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|