PMID: 32453731

Gene: MYL2

HGNC ID: 7583

Case1: Male, Infant, Tunisian

DiseaseAssertion: infantile-onset HCM and mitral valve dysplasia

FamilyInfo: Family with consanguinity in which four children had died before one year of age. The father (37 years old) and mother (27 years old) of the proband are consanguineously related. Two infants (VI:1 and VI:2) died at less than 30 days of age from cardiorespiratory arrest, and two (VI:3 and VI:4, proband) of them displayed abnormal cardiac findings on chest roentgenogram. While all four children displayed hepatomegaly and general hypotonia, VI:3 and VI:4 had a marked increase in heart size and died from refractory cardiogenic shock. The status of the MYL2 allele in siblings is unknown. The proband (fs/fs) was homozygous for the MYL2-fs allele while the parents were found to be heterozygous (fs/wt) carriers. The father (37 years old) and mother (27 years old) of the proband are consanguineously related, were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

ParentalTesting: Homozygous variant in the proband and that the parents are heterozygous carriers using Sanger DNA sequencing of the genomic region. Father (37 years old) and mother (27 years old) were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

CasePresentingHPOs: HP:0200128, HP:0001653, HP:0002092, HP:0001639, HP:0002240

CaseHPOFreeText: Showed a rapid decline in health and was treated for various periods in neonatal intensive care units. The patient also displayed severe mitral valve regurgitation with abnormal thickening of the mitral valve leaflets and pulmonary arterial hypertension. Post-mortem examination of the proband’s heart confirmed severe biatrial dilatation, significant biventricular hypertrophy with small ventricular cavities and severe mitral valve dysplasia

CaseNotHPOs: NR

CaseNotHPOFreeText: no gross developmental defects

CasePreviousTesting: No prior genetic testing reported before exome sequencing

Genotyping Method: Performed exome sequencing on the proband. Exome libraries were constructed using the Agilent SureSelectQXT Target Enrichment System for Illumina Multiplexed Sequencing Protocol (Agilent Technologies, CA). DNA libraries were captured with the Agilent Clinical Research Exome Kit. Paired-end 150 base pair reads were generated for exome-enriched libraries sequenced on the Illumina HiSeq 4000 to a targeted depth of 100× coverage

FunctionalAnalysis: Functional analysis performed. Immunohistochemical analysis of MYL2 expression in the proband’s ventricular myocardium shows a remarkable reduction in the expression of MYL2 as compared to control. Also, MYL2 mRNA was detected in the ventricle of the proband by RT-PCR. This suggests that the frameshift variant adversely affects the levels of MYL2 protein in the proband. Using immunoblot analysis, we observed that overexpression of the MYL2-fs variant was significantly reduced compared to stop-gain variants and the missense variant. When the H9c2 cells were treated with MG-132 after transfection with the MYL2-fs construct, the GFP signal corresponding to MYL2-fs was recovered. The in vitro experiments indicate that the MYL2-fs variant is not stable and that proteasome-mediated degradation of the translated product plays a key role in the instability of the protein. The overexpression of the fs variant identified in our proband or the MYL2-G162R missense variant failed to rescue the phenotype. Results reported in Figures 2, 3, and 4.

Variant: NM_000432.3:c.431_432delCT

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: 4 siblings who died before 1 year of age but MYL2 genotyping was only confirmed in the proband (VI:4)

Case1: Male, 37 years old, Colombian

DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy

FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315

CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation

FunctionalAnalysis: NR

Variant: NM_000432.3:c.260G>C

ClinVar: 43461

CAID: CA009968

gnomAD: NR

AdditionalInfo: NR

PMID: 33139982

Gene: MYL2

HGNC ID: 7583

Case1: Female, 23 years old, ethnicity not stated

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Mother, brother, and sister carry the same MYL2 mutation. Mother has phenotypic HCM without scar or high-risk features for sudden cardiac death. Sister and brother remain phenotypically negative with yearly imaging.

ParentalTesting: Maternal testing confirmed — mother carries the same MYL2 mutation and has phenotypic HCM. Paternal testing not reported.

CasePresentingHPOs: HP:0011675, HP:0001279, HP:0001962, HP:0004756

CaseHPOFreeText: During a sprinting drill, she developed a 42-second episode of polymorphic VT with spontaneous termination. The ambulatory rhythm monitoring showed a ~4% premature ventricular contraction (PVC) burden without sustained or nonsustained VT. CPET 2 demonstrated monomorphic nonsustained VT at peak exertion. Given exercise-induced polymorphic VT, she underwent placement of a subcutaneous implantable cardioverter-defibrillator (ICD) for secondary prevention. In the emergency department, high-sensitivity troponin rose from 105 to 303 ng/L. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis

CaseNotHPOs:HP:0100749, HP:0002094, HP:0031972, HP:0001714

CaseNotHPOFreeText: Normal LV size and function on echocardiography. Normal strain. Repeat cardiac MRI showed complete resolution of LGE. Normal biventricular size, thickness, and function without LGE or scar on third MRI. No sustained VT/VF after ICD placement. Normal complete blood count and basic metabolic panel. Coronary CT angiography unremarkable.

CasePreviousTesting: She underwent coronary computed tomography angiography to rule out ischemia and anomalous coronary origins, which was unremarkable. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis. Follow-up transthoracic echocardiography revealed normal LV size and function with normal strain, and repeat cardiac MRI showed complete resolution of LGE. She underwent maximal cardiopulmonary exercise testing (CPET), exercising for 13 minutes and 15 seconds, achieving 15 METs with a VO2 max of 40.4 mL/kg/min, which demonstrated frequent PVCs without nonsustained ventricular tachycardia (VT). Normal complete blood count and basic metabolic panel, aspartate aminotransferase, 38 U/L, alanine aminotransferase, 38 U/L, magnesium 2.2 mg/dL, thyroid-stimulating hormone, 1.96 μIU/mL, hemoglobin A1c, 5.8%.

Genotyping Method: Comprehensive genetic testing identified a pathogenic MYL2 variant.

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.4:c.173G>A

ClinVar: 14067

CAID: CA009915

gnomAD: 12:111352091 C / T, chr12-110914287-C-T

AdditionalInfo: NR

PMID: 41999369

Gene: MYL2

HGNC ID: 7583

PMID: 31127036

Gene: MYL2

HGNC ID: 7583

Case1: Male, Infant, ethnicity not stated

DiseaseAssertion: congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy

FamilyInfo: The father was a healthy 20-yr old with no particular medical concerns, and there was no family history of neuromuscular or genetic disorders on either side. Both parents confirmed as heterozygous carriers of the MYL2 c.188del variant by Sanger sequencing

ParentalTesting: Both parents were confirmed as heterozygous carriers of MYL2 c.188del p.(Asn63Metfs7) by Sanger sequencing. Father confirmed as heterozygous carrier of NEB c.25435C>T p.(Gln8479)

CasePresentingHPOs: HP:0001290, HP:0001252, HP:0001640, HP:0001638, HP:0001639

CaseHPOFreeText: Newborn exam revealed normal first and second heart sound with gallop rhythm and palpable liver at the right costal margin, as well as generalized hypotonia and diminished reflexes. Echocardiogram was performed at 11 d of age and revealed patent foramen ovale with left to right shunt and right atrial enlargement. At age 5 mo, the proband was admitted to hospital in decompensated heart failure and intubated on inotropic support. Echocardiography revealed left ventricular dilatation, mild to moderate mitral valve regurgitation, and left atrial enlargement, with left ventricular function moderately to severely decreased with shortening fraction of 12% and ejection fraction of 23%. A vastus lateralis biopsy performed at 5 mo of age because of persistent muscle weakness and hypotonia revealed variability in fiber size with checkerboard pattern of 1:1 ratio of type 1 and type 2 fibers exhibiting hypotrophy of type 1 fiber size in comparison to the type 2 fibers. high lactate level (7.8 mmol/L)

CaseNotHPOs: NR

CaseNotHPOFreeText: Gomori trichrome–stained light micrographs and electron microscopy (EM) showed no evidence of ragged red fiber or nemaline rods, and oxidative stains revealed no evidence of cores, targetoid, or target fibers. Normal serum creatine kinase level. Normal birth weight, length, and head circumference. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Genetic testing for POLG and Noonan syndrome genes normal

CasePreviousTesting: Genetic testing was performed for DNA polymerase γ, catalytic subunit (POLG) and Noonan syndrome genes (PTPN11, SOS1, KRAS, RAF1, BRAF, MAP2K1, MAP2K2, and HRAS), all of which were normal. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Muscular dystrophy was considered unlikely given the histopathologic findings and normal serum creatine kinase level.

Genotyping Method: Next-generation sequencing was performed by the Laboratory for Molecular Medicine (LMM) of Partners Healthcare Personalized Medicine using the Agilent SureSelect Design process. The gene panel utilized an all exon approach for 43 genes of interest for neuromuscular and cardiac conditions by targeting coding exons with bait out to coding sequence (CDS) ±65 bases. The complete coding regions of all genes were sequenced to average depth of 316 reads

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.3:c.188del

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: This case also has a heterozygous pathogenic NEB variant c.25435C>T p.(Gln8479*) inherited from the father, classified as pathogenic but considered unlikely to be a significant contributor to disease as no second NEB allele was identified.

Case1: Male, Infant,

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Healthy, reportedly non-consanguineous, and had no known history of cardiomyopathy, heart failure, arrhythmia, sudden unexplained death, neuromuscular disease, or inherited metabolic disorder

ParentalTesting: Both parents were confirmed as heterozygous carriers by trio-based whole-exome sequencing.

CasePresentingHPOs: HP:0012378, HP:0030831, HP:0030864, HP:0033113, HP:0001712,

CaseHPOFreeText: “On arrival, he appeared pale, tachypneic, and fatigued, with subcostal retractions and scattered rhonchi and crepitations on chest auscultation. Cardiac examination revealed a gallop rhythm. Electrocardiography demonstrated biatrial enlargement, left ventricular hypertrophy, and borderline QT prolongation.”

CaseNotHPOs: NR

CaseNotHPOFreeText: No dysmorphic features recognized clinically, normal social interaction and visual tracking for age, normal brain MRI (normal cerebral structure and myelination, no malformation or demyelination), normal skeletal survey, creatine kinase within normal range, broad metabolic screening unrevealing, no pericardial effusion on echocardiography, no overt skeletal myopathy clinically recognized, negative SMA molecular testing, negative Prader–Willi syndrome methylation analysis

CasePreviousTesting: Broad metabolic screening was unrevealing. Creatine kinase was within the normal range. Molecular testing for spinal muscular atrophy and methylation analysis for Prader–Willi syndrome was negative. Brain magnetic resonance imaging performed at 9 months of age demonstrated normal cerebral structure and myelination, without malformation or evidence of demyelination. A skeletal survey was also normal. Additional investigations for muscular dystrophy and primary myopathic disorders had been initiated but were still incomplete at the time of his acute deterioration.

Genotyping Method: Trio-based whole-exome sequencing. Genomic DNA extracted from peripheral blood. Exome enrichment targeting coding exons and flanking splice junctions of >20,000 protein-coding genes. Illumina platform, mean on-target coverage >100×, ≥98% of targeted bases covered at ≥20× depth. Alignment to GRCh37/hg19, GATK-based variant calling pipeline.

FunctionalAnalysis: No functional analysis was performed.

Variant: NM_000432.4:c.413T>A

ClinVar: 840366

CAID: CA042802

gnomAD: 12:111348969 A / T, chr12-110911165-A-T

PMID:28223422

Gene:MYL2

HGNC ID:7583

PMID: 42074559

Gene: MYL2

HGNC ID: 7583

PMID: 36128439

Gene: MYL2

HGNC ID: 7583

PMID: 21823217

Gene: MYL2

HGNC ID: 7583