PMID:17347475

Gene:MYOZ2

HGNC ID:1330

Case: Cecconi_Patient#903, female, 52 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm; the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.488T>C p.(Leu163Ser)

ClinVarID: or CAID: 45784, CA282614

gnomAD: MAF=0.001724 in African/African Americans (43/24948 alleles), total allele frequency=0.0001521. No homozygotes. v2.1.1

AddCaseInfo: Pt has LVWT of 18, LVEF of 59%, and other medical issues (myasthenia gravis, T2DM, HepC, PVC, PACs, PSVT, and SND

PreviouslyPublished: no

VariantEvidence: none

Case: Cecconi_Patient#692, female, 65 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm; the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.36A>C, p.(Lys12Asn)

ClinVarID: or CAID: 1493383, CA104969015

gnomAD: MAF=0.0001635 in (1/6118 alleles), total allele frequency=0.000003986. No homozygotes. v2.1.1

AddCaseInfo: Pt has LVWT of 22, family history of HCM, LVEF% of 65, and history of hypertension. Pt also has a variant in MYBPC3 (c.1624G>C p.Glu542Gln)

PreviouslyPublished: no

VariantEvidence: none

FamilyName: Guo_Family

FamilyPresentingHPOs: HP:0001712

FamilyPresentingHPOFreeText:

FamilyNotHPOs:

FamilyNotHPOFreeText:

CountryOrigin: China

Ethnicity:

Race:

FamilyPreviousTesting: transthoracic echocardiography, LV wall thickness and LV dimensions were measured perpendicular to the long axis of the left ventricle by M-mode imaging and 2-dimensional echocardiography, pulsed-wave, continuous-wave, and color Doppler were used as necessary for accurate definitions of obstruction

FamilyMethod1: WGS

FamilyMethod2: Sanger

FamilyGenotypingMethod: WGS of an immediate family member from each generation

Affected: 25

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: Guo III:15

Variant: c.505A>C in exon 4, L169G

ClinVar or CAID: CA16609625

gnomAD: not in gnomAD

FamilyAddInfo: 12 individuals carried MYH7-A719H, and 16 carried MYOZ2-L169G. Among the 12 subjects who were clinically diagnosed with HCM, 7 carried both MYH7-A719H and MYOZ2-L169G, 4 had only MYH7-A719H, and 1 did not possess either mutation. Those who carried only the MYH7 mutation had mild LV hypertrophy or normal heart function and morphology, and all experienced only chest discomfort or no symptoms at all after activities. Ten of the subjects who carried only the MYOZ2 mutation showed no LV hypertrophy, abnormal ECG or echocardiographic findings, or discomfort. The 7 patients with both MYH7-A719H and MYOZ2-L169G had more serious symptoms, commonly complaining of palpitation and dyspnea. During the follow-up period, 1 of these subjects experienced SCD, and another suffered from myocardial infarction without obvious hyperlipidemia. Compared with subjects with only MYH7-A719H or MYOZ2-L169G mutation, patients with both the MYH7-A719H and MYOZ2-L169G mutations had the largest median left atrial diameter (Kruskal–Wallis test, P = 0.015) and the highest frequency of cardiovascular events (Fisher exact test, P = 0.007). The MYOZ2-L169G mutation alone was not found to be pathogenic, but it did appear to play a modifying role in HCM.

FamilyPMIDs:

CaseIII-15: Male, 47 years report, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: 25 people from 74 family members were positively identified for having HCM, Some of them only carried a single variant while others carried multiple, Many other family members died from sudden cardiac death at various ages

CasePresentingHPOs: HP:0001639, HP:0031352 ( Hypertrophic cardiomyopathy, Chest tightness)

HPOsFreeText: Left atrial diameter at 38 mm, Left ventricular end-diastolic diameter at 52 mm, Interventricular septum thickness maximum at 20 mm, Left ventricular posterior wall thickness maximum at 8 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: All below variants are heterozygous with the wild-type

CaseGenotypingMethod: The above family members, along with IV:14 to serve as a control to compare to, were processed through Whole Exome Sequencing. Any variants found were mapped and filtered for pathogenicity, and any that were detected were confirmed by Sanger sequencing.

Variant: NM_000257.3:c.2155C>T (p.Arg719Trp)

ClinVar: 14104 https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/

gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A

MultipleGeneVariants:

(1) MYOZ2 Mutation

Variant: NM_016599.4:c.505A>C (p.Lys169Gln)

CAID: CA16609625 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_016599.4%3Ac.505A%3EC

gnomAD: Not in gnomAD

(2) DNAJC19 Mutation

Variant: NM_145261.3:c.59G>A (p.Arg20His)

ClinVar: 466328 https://www.ncbi.nlm.nih.gov/clinvar/variation/466328/

gnomAD: South Asian 4.246e-4, Overall 5.304e-5 https://gnomad.broadinstitute.org/variant/3-180705881-C-T

(3) CTNNA3 Mutation

Variant: NM_001127384.2:c.2441T>A (p.Leu814Ter)

CAID: CA377089103 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_013266.3%3Ac.2441T%3EA

gnomAD: Not in gnomAD

Proband III:15, 47 yr old male, Dx = 37 yrs

HP:0001639, HP:0001681

HCM, chest tightness (angina)

Variant: NM_016599.4(MYOZ2):c.505A>C (p.L169G)

Not in ClinVar or EXAC

CaseHCM051: 39 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of hypertrophic cardiomyopathy, Has 2 siblings where the MYH7 and MYOZ2 mutations are solely present in the brother and sister respectively, Brother has LVH and palpitations while sister has no symptoms whatsoever

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 18 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3424G>A (p.Glu1142Lys)

ClinVar: 181222 https://www.ncbi.nlm.nih.gov/clinvar/variation/181222/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) MYOZ2 Variant

Variant: NM_016599.4:c.326C>G (p.Pro109Arg)

CAID: CA104971226 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA104971226

gnomAD: Not in gnomAD

Case 2: male, Dx = n/a, variant identified via direct sequencing

HP:0001712 (left ventricular hypertrophy)

Variant: NM_016599.4(MYOZ2):c.738A>G (p.Ile246Met)

non-LOF

ClinVar ID: 30509, conflicting interpretations of pathogenicity,<br /> https://www.ncbi.nlm.nih.gov/clinvar/variation/30509/

ExAC Score: 0.001897, http://gnomad.broadinstitute.org/variant/4-120107298-A-G

Case: Family 109, female, Dx = 12 yrs, septal thickness 3.2cm

Family had 6 affected individuals sharing MYOZ2 haplotype 4q26-q27

HP:0001635, HP:0001279, HP:0001712, HP:0005110, HP:0004755

heart failure, syncope, left ventricular hypertrophy, atrial fibrillation, supraventricular tachycardia

Variant: NM_016599.4(MYOZ2):c.142T>C (p.Ser48Pro)

Pathogenic, non-LOF

ClinVar ID: 30508 https://www.ncbi.nlm.nih.gov/clinvar/variation/30508/

Not in ExAC or gnomAD