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

Case3: 73 year old man

DiseaseAssertion: He carried the MYL2 p.Ala13Thr variant

FamilyInfo: Yes, his wife, son, and daughter

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0002094, HP:0003388, HP:0012828, HP:0001650, HP:0034313, HP:0030882

CaseHPOFreeText: presented with dyspnea on exertion and easy fatigability. He was found to have severe aortic stenosis with an aortic valve area of 1 cm2 and a peak gradient of 68 mmHg. He had mild LVH with a wall thickness of 13 mm on an echocardiogram and a left ventricular ejection fraction (LVEF) of > 70%. A 12-lead ECG was unremarkable without evidence of LVH. He also had an 80% luminal diameter stenosis of left anterior descending coronary artery on coronary angiography. He underwent aortic valve replacement and a single vessel coronary artery bypass surgery. He has been asymptomatic since surgery

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case4: 43 year old woman.

DiseaseAssertion: diagnosed with HCM and carried variants in TTN, ALPK3, and MYL2 (p.Ala13Thr).

FamilyInfo:Other family members, II-1 is a 72-year old woman with history of intermittent atrial flutter with a normal interventricular septal thickness (8 mm) and a normal LVEF (58%). Likewise, individual II-4 is an asymptomatic 70-year old male, who had normal ECG, echocardiogram, and myocardial stress perfusion tomography. Proband’s children (IV-1 and IV-2) were asymptomatic and had normal ECGs and echocardiograms on the last evaluation. Likewise, individual IV-3 was a 7-year old asymptomatic boy who had a normal ECG and echocardiogram.

ParentalTesting: Yes, mother, brother, and father were tested

CasePresentingHPOs:HP:0031664, HP:0012835, HP:0004972, HP:0001670, HP:0034313, HP:0031656, HP:0012825

CaseHPOFreeText: Her physical exam was notable for the presence of a II/VI mid-systolic ejection murmur at left sternal border that radiated toward base of the heart. She also had a mildly elevated arterial blood pressure. A 12-lead ECG showed evidence of LVH, interventricular conduction delay, and repolarization abnormalities. An echocardiogram showed severe asymmetric septal hypertrophy with a hyperdynamic LV systolic function, systolic anterior motion of the mitral leaflet, and a LVOT gradient of 60 to 70 mmHg at rest (Figure 3B). CMR findings were also notable for asymmetric septal hypertrophy and mild patchy hyperenhancement.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case2: 63 year old woman, diagnosed with HCM

DiseaseAssertion: Individual carried the MYL2 p.Ala13Thr, TTN, and ALPK3 variants.

FamilyInfo: Yes, son and daughter and husband was all diagnosed.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0004383, HP:0005144, HP:0001962, HP:0001279, HP:0001278, HP:0031295, HP:0040284, HP:0011703, HP:0025275

CaseHPOFreeText: Echocardiographic findings of a hyperdynamic left ventricle and an interventricular septal thickness of 19 mm. She had a history of brief episodes of palpitations and one episode of syncope a few years earlier, which was thought to be due to orthostatic hypotension. A 12-lead ECG was notable for possible left atrial enlargement. A 30-day rhythm monitoring showed rare ventricular ectopic beats and episodes of sinus tachycardia. CMR showed a normal LV wall thickness and function and minimal patchy mid myocardial hyperenhancement in the basal inferior and infero-lateral wall.

CaseNotHPOs: HP:0000822, HP:0001639, HP:0032092

CaseNotHPOFreeText: No history of systemic arterial hypertension, valvular disease, or other conditions to explain cardiac hypertrophy. No LVOT obstruction.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case1: A 44-year old male of European (non-Finnish) ancestry.

DiseaseAssertion: Disease, with the MYL2 p.Ala13Thr variant.

FamilyInfo: Mother, father, and sister was diagnosed at different ages; they all had it.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs:HP:0100749, HP:0002094, HP:0031664, HP:0033678, HP:0011703, HP:0001712, HP:0031296,HP:0020034, HP:0031656

CaseHPOFreeText: Presented 3 years ago with persistent but mild chest pain and dyspnea. presence of II/VI mid-systolic murmur that increased with the Valsalva maneuver. Cardiac enzymes were negative for acute coronary syndromes. A 12-lead ECG was notable for sinus tachycardia at the rate of 104 bpm and evidence of left ventricular hypertrophy (LVH) with repolarization abnormalities. Myocardial stress perfusion tomography showed homogeneous distribution of the radiotracer in the myocardium. An echocardiogram showed a hyperdynamic left ventricle with moderate asymmetric septal hypertrophy, a maximum wall thickness of 1.8 cm. There was a resting left ventricular outflow tract (LVOT) gradient of 20 mmHg that increased to 40 mmHg upon Valsalva maneuver. CMR findings were notable for septal hypertrophy and diffuse patchy hyperenhancement, involving multiple myocardial walls. increasing dyspnea with a mild level of physical activity and chest pain. Evidence of LVH with repolarization abnormalities on a 12-lead ECG and a hyperdynamic left ventricle with a septal thickness of 2 cm, systolic anterior motion of mitral leaflets, mild to moderate mitral regurgitation, and an LVOT gradient of 100 mmHg on echocardiography (Figure 3A). Underwent surgical myectomy, which led to resolution of LVOT gradient and symptoms.

CaseNotHPOs: HP:0011675, HP:0011703

CaseNotHPOFreeText: Not show significant cardiac arrhythmias except for periods of sinus tachycardia at rest.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: May affect cardiac contractile function and actin filament velocity, But NR about the MYL2 p.Ala13Thr variant.

Variant: NM_000432.4:c.37G>A

ClinVar:14064

CAID: CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T gmonAD v4 chr12-110919160-C-T

AdditionalInfo: NR

PMID:28223422

Gene:MYL2

HGNC ID:7583

Case#: An El-Salvadoran 22-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with sarcomeric gene variants in MYL3 and MYL2

FamilyInfo: The patient’s mother was the only family member available for evaluation (Fig 2). On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age

ParentalTesting: Patients mother

CasePresentingHPOs: HP:0002099, HP:0012378, HP:0012764, HP:0001962, HP:0034807, HP:0001541, HP:0001410, HP:0031667, HP:0004749,

CaseHPOFreeText: diagnosed with RCM and advanced heart failure requiring heart transplantation. A prior diagnosis of childhood asthma presented with worsening fatigue and dyspnea on exertion over the course of 12 months. She reported having frequent episodes of shortness of breath as a child, also reported orthopnea, paroxysmal nocturnal dyspnea, and palpitations; her heart failure symptoms were classified as NYHA Class III–IV. did have ascites suggestive of congestive hepatopathy. Her cardiovascular examination revealed a nondisplaced, nonsustained point of maximal impulse, with a mild parasternal lift without a pulmonary artery tap.She had a normal S1, but P2>A2. She had an S3, but no S4. She had a soft I/IV holosystolic murmur over the apex; no knock or rub. Her electrocardiogram demonstrated atrial flutter with an atrial rate of 250–300 and a ventricular rate of 85.

CaseNotHPOs: HP:0002321, HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied dizziness, syncope, and lower extremity edema.

CasePreviousTesting: The patient's mother was also tested to assess inheritance.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: MYL2 p.Gly57Glu variant using sequence conservation and computational splice-site prediction

Variant: NM_000432.4:c.170G>A

ClinVar:43458

CAID: CA009910

gnomAD: gnomAD v2 12:111352094 C / T https://gnomad.broadinstitute.org/variant/12-111352094-C-T?dataset=gnomad_r2_1 gnomAD v3 12:110914290 C / T https://gnomad.broadinstitute.org/variant/12-110914290-C-T?dataset=gnomad_r3 , gnomAD v4 chr12-110914290-C-T https://gnomad.broadinstitute.org/variant/chr12-110914290-C-T?dataset=gnomad_r4

PMID: 21823217

Gene: MYL2

HGNC ID: 7583

Case#: a 9-year-old boy

DiseaseAssertion: Hypertrophic obstructive cardiomyopathy (HOCM) during clinical screening, presence of the familial mutation in the MYL2 gene MYL2, c.487G > A [p.(Glu163Lys) as pathogenic.

FamilyInfo: a family history of sarcomeric HCM who was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) during clinical screening. His father suffered from HCM and died 6 years ago in his 3rd decade due to a stroke. The paternal grandfather of the proband and his sister were also diagnosed with HCM. Other affected family members included a paternal uncle and his son as well as a paternal aunt and her son. Genetic testing of the latter family members revealed a mutation in the MYL2 gene.

ParentalTesting: Yes the family members

CasePresentingHPOs: HP:0034313, HP:0031666, HP:0001670

CaseHPOFreeText: He was well and asymptomatic. His weight was 44.6 kg (93rd centile) and height was 150.5 cm (94th centile); heart rate was 60 b.p.m. and right arm blood pressure was 111/67 mmHg with a mean arterial pressure of 83 mmHg. On auscultation, a 2/6 systolic murmur in the 3rd intercostal space at the left sternal edge was audible. N-terminal prohormone of brain natriuretic peptide level was 434 ng/L (normal range <112 ng/L). The echocardiogram showed asymmetric septal hypertrophy (maximal wall thickness 18 mm) of the left ventricle (LV) with mild flow acceleration in the mid-LV cavity (peak systolic velocity 2.6 m/s) consistent with HOCM. Left ventricle systolic function was hyperdynamic with LVEF of 80%. Late gadolinium enhancement (LGE) imaging showed an area of patchy LGE at the level of the maximal LV wall thickness (Figure 4).

CaseNotHPOs: HP:0001635 , HP:0001279, HP:0031656, HP:0001653

CaseNotHPOFreeText: No signs of congestive heart failure and no history of syncope. No systolic anterior movement (SAM) and no mitral regurgitation.

CasePreviousTesting: Clinical screening

Genotyping Method: Genetic testing confirmed

FunctionalAnalysis: NR

Variant: NM_000432.4:c.487G>A

ClinVar: 1051330

CAID: CA386696712

gnomAD: NR

AdditionalInfo: NR

PMID: 36128439

Gene: MYL2

HGNC ID: 7583

PMID: 42074559

Gene: MYL2

HGNC ID: 7583