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PATIENT INFORMATION SAMPLE REFERRING PHYSICIAN
Patient Id Sample number Name
Sex Male Source Institution
DOB Date received
Reference Date of report Aug 10, 2016
Test results of: SAMPLE REPORT
Reason for the study: Hypertrophic cardiomyopathy
Test(s) requested: Hypertrophic cardiomyopathy - Full panel (90 genes)
RESULT: POSITIVE
A previously described mutation in the MYH7 gene has been identified. This mutation has been extensively described in
association with the development of an overlapping phenotype of hypertrophic cardiomyopathy, dilated
cardiomyopathy, and left ventricular non-compaction that could be different stages of the same disease. Prognosis
seems to be adverse in terms of sudden death occurrence or development of severe ventricular dysfunction, even in
young individuals.
Gene Variant Result Pathogenicity Population frequency
Number of references
MYH7 NP_000248.2:p.Gly716Arg NM_000257.3:c.2146G>A NC_000014.8:g.23895189C>T
Heterozygosis Pathogenic or disease-causing (+++)
Mutation (not found in controls)
48
Clinical interpretation
The presence of a genetic variant does not exclude the existence of additional genetic alterations in other genes potentially
involved in the development of the disease.
Technical aspects of the study
This sample has been studied by a massive parallel sequencing method using a library that included 90 genes related to
hypertrophic cardiomyopathy. Both sensitivity and specificity are above 99% for SNVs and small INDELs (≤ 20 bp).
Signatures
James Dermody, PhD Laboratory Director
ABMG Certified, Clinical Molecular Genetics Admera Health LLC
Doc. Lorenzo Monserrat Iglesias Cardiologist and Scientific Director
Health in Code
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DETAILED RESULTS
Gene: MYH7 (Encoding the protein: Myosin-7)
NP_000248.2:p.Gly716Arg/NC_000014.8:g.23895189C>T
Heterozygous carrier: mutation occurs in only one copy of the gene.
Mutation nomenclature: Nucleotide code: NM_000257.3:c.2146G>A, NC_000014.8:g.23895189C>T. Amino acid code:
NP_000248.2:p.Gly716Arg. dbSNP ID: rs121913638. Alternative names at the DNA level: c2146G>A. Alternative names at
the protein level: Gly716Arg, NP_000248.2:p.G716R. Located in: exon 19.
Pathogenicity: pathogenic or disease-causing (+++).
Population frequency: mutation (not found in controls).
Number of articles/communications that cite it: 48. Number of described families: 23. Number of families with additional
unpublished information: 4.
Major phenotypes Carriers (families)
Non-carriers
Without genetic study
Total
Hypertrophic cardiomyopathy 31 (22) 0 9 40
Hypertrophic cardiomyopathy + Dilated cardiomyopathy 3 (1) 0 0 3
Sudden death 2 (1) 0 13 15
Restrictive cardiomyopathy 2 (1) 0 0 2
No phenotypic study 1 (1) 1 12 14
Hypertrophic cardiomyopathy + Left ventricular non-compaction/hypertrabeculation
1 (1) 0 0 1
Dilated cardiomyopathy 1 (1) 0 1 2
Left ventricular non-compaction/hypertrabeculation 1 (1) 0 0 1
Not affected or healthy 0 (0) 23 7 30
Clinical information
Gly716Arg in MYH7 is a clearly pathogenic mutation which has not been reported in public databases of genotyping in the
general population. It has been described in families from different ethnic backgrounds and is considered one of the
"malignant" mutations in this gene.
Cosegregation with disease was demonstrated in the reported families with complete penetrance (in adults), and the
variant was associated with the development of an overlapping phenotype (also within members of the same family)
consisting of hypertrophic cardiomyopathy, left ventricular non-compaction, and dilated cardiomyopathy that could
represent different stages of the same disease. Some cases also developed restrictive cardiomyopathy. In the majority of
cases, the diagnosis was made below the age of 25 (mean age of diagnosis was 22 years old), including young females.
Moreover, seven of the patients in which the age of diagnosis was available were diagnosed during their childhood and
presented a severe phenotype (see below). Myocardial hypertrophy was asymmetrically distributed (septal), with an
average maximal wall thickness of 22±5 mm (range 15-33 mm). One of the cases who developed a hypertrophy greater
than 30 mm presented a second mutation in the MYH7 gene. Some families deserve a special comment, such as a Korean
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family with a reported high incidence of sudden death, even in individuals younger than 16 years old. In those relatives
who survived, the disease progressed to its end-stage (developed symptomatic dilated cardiomyopathy [DCM], requiring
heart transplantation even below 25 years of age in some cases). The development of left ventricular dysfunction/dilatation
was relatively prevalent. In fact, DCM was the initial diagnosis in some cases. A restrictive behavior was also observed. It
was described in two out of six carriers of a family from the United States, and it was also observed in a proband referred
to our center who developed severe biatrial enlargement and mild impaired ventricular function. Finally, non-compaction
cardiomyopathy was observed in a family referred to our center. The proband and his sister presented severe biventricular
dysfunction, both of them requiring a heart transplant. The proband's daughter, a carrier of the mutation, presented a
phenotype also compatible with non-compaction at 7 years old, which in subsequent echocardiographic evaluation was
manifested as obstructive hypertrophic cardiomyopathy, indicating that both phenotypes could be different stages of the
same disease.
This mutation is located in a crucial functional domain (converter domain) in which more than 50 pathogenic mutations
have been described. In general terms, these mutations showed a worse prognosis than other missense pathogenic
mutations in MYH7. Moreover, there is a specific sub-region of the converter domain (helix motif)—where Gly716Arg is
located—which clusters mutations with the worst prognosis of the converter region (see below: “Information about other
described mutations affecting the same region” and survival curves in Figure 1). These mutations share several features
with Gly716Arg, such as high penetrance, early expression of the disease, high prevalence of sudden death (in some cases),
and progression to ventricular dysfunction. They are also associated with overlapping phenotypes including hypertrophic
cardiomyopathy, left ventricular non-compaction/dysfunction, and restrictive cardiomyopathy. Some well-described
mutations affecting surrounding amino acids (Arg719Trp, Arg719Gln, and Asp717Gly) present practically the same bad
prognosis as Gly716Arg. Survival curves indicate that half of the carriers had presented a serious adverse event (sudden
death, heart failure death, cardiac transplantation, ICD implantation) by the age of 40 years. These events occurred in early
stages of life in several carriers, but their incidence notably increased in the fourth decade of life in carriers of Gly716Arg.
Events
Major events Carriers Non-carriers Without genetic study Total
Sudden death 6 0 13 19
Cardiac transplantation 5 0 0 5
Heart failure death 4 0 1 5
Cerebrovascular accident (without death) 1 0 0 1
Appropriate ICD discharge 1 0 0 1
Almost all families in which several relatives were informed presented more than one member who suffered a serious
event that occurred below the age of 45 in the majority of the reported cases. A high proportion of them were present
during childhood. Sudden death occurred in more than half of those families, affecting a proportion by 12% to 25% of all
members. Ventricular dysfunction, which leads to heart failure or cardiac transplant, was also a frequent event occurring
in the rest of families evaluated in detail (families in which no sudden death cases were reported). Some families presented
both events within their members. Several other probands have been reported to not present events; however, the lack of
family details or familial antecedent descriptions questions whether some bias could exist.
In summary, this mutation seems to be associated with a high prevalence of serious adverse events in terms of an elevated
risk of sudden death or complications such as progression to an end-stage of the disease (heart failure).
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Survival curves
Figure 1. Kaplan-Meier survival curves: Comparative survival estimate (probability) for carriers of Gly716Arg (blue) versus
of mutations located in the specific helix region (orange), the whole converter region (green), and the whole MYH7 gene
(red) over time (years). The analysis included all mutation carriers and all affected relatives with unknown genotype.
Functional study / Animal model
This mutation affects a highly conserved residue (Gly716) and causes a change from a non-polar amino acid to a basic polar
positive one. As a result, there are moderate changes in the physicochemical properties such as mass, polarity, charge, and
hydrophobicity. Fujita et al. performed a functional study of this mutation in the eukaryotic cell model Dictyostelium
discoideum and observed that the actin-myosin interaction was affected. They showed a decreased Vmax of actin-activated
ATPase activity with a weakened affinity for actin, which was among the lowest affinity values observed compared to other
mutations evaluated. Since Gly716Arg is located in the subdomain that amplifies the movements of myosin motor domain
(converter domain), it is possible to infer that mutations similarly located in this subdomain might reduce the affinity to
actin filaments by affecting the swing motion.
Other mutations located in the converter domain were also functionally evaluated. Although their behavior differed from
that observed for Gly716Arg, these mutations remarkably affected the actomyosin cross-bridges, thereby pointing out the
relevance of the converter domain of the myosin head for the vital functions of the motor molecule. Most of the mutations
affecting this important functional domain were associated with a malignant phenotype.
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Mutation effect predictors (These predictors have limited clinical utility and should be used only as supporting evidence)
Predictor Prediction Score Version
SIFT Damaging 0.03 Computed from ENSEMBL 55 (September, 2014)
Polyphen-2 (HumVar) Probably damaging 0.983 v2.2.2 (September, 2014)
Polyphen-2 (HumDiv) Probably damaging 0.999 v2.2.2 (September, 2014)
MutationTaster Disease-causing 1 date of accession: Jul 13, 2016
DANN 0.999306 July, 2015
SIFT: it ranges from 0 to 1. Scores <0.05 are called "Damaging" and all others are called "Tolerated". Polyphen: it ranges from 0 (benign) to 1 (damaging). MutationTaster: it
ranges from 0 to 1. Value close to 1 indicates a high 'security' of the prediction. DANN: the higher score the more potential pathogenicity. Values between 0 and 1.
Conclusions
The Gly716Arg mutation in MYH7 is associated with the development of an overlapping phenotype of hypertrophic
cardiomyopathy, dilated cardiomyopathy, and left ventricular non-compaction that could be different stages of the same
disease. Penetrance is complete (considering young adults), and clinical manifestations have an early onset. Prognosis
seems to be adverse in terms of sudden death occurrence or development of severe ventricular dysfunction, even in
young individuals.
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APPENDIX 1: SUPPLEMENTAL INFORMATION
Detailed description of the families (mutation: p.Gly716Arg, gene: MYH7)
Family 155 [reference: 1]
Country of origin of the family (or of the publication): Italy. Ethnicity: Western Caucasian.
Mutation carriers with available information: 3 (hypertrophic cardiomyopathy: 3). Mutation non-carriers with available
information: 4 (not affected or healthy: 4). Relatives without genetic study: 2 (not affected or healthy: 1, without
phenotypic study: 1).
Adverse events reported in the family ─ no sudden death has been reported; death of unknown cause: 1 (without genetic
study: 1); transplant: 1 (with the mutation: 1); (see tables).
Family 197 [references: 4, 20]
Country of origin of the family (or of the publication): Korea, Republic of. Ethnicity: Oriental.
Mutation carriers with available information: 10 (hypertrophic cardiomyopathy + dilated cardiomyopathy: 3, hypertrophic
cardiomyopathy: 3, possible left ventricular non-compaction/hypertrabeculation + hypertrophic cardiomyopathy: 1,
sudden deaths of unknown cause: 2, without phenotypic study: 1). Mutation non-carriers with available information: 10
(not affected or healthy: 10). Relatives without genetic study: 10 (sudden deaths of unknown cause: 5, not affected or
healthy: 5).
Adverse events reported in the family ─ sudden death: 8 (with the mutation: 3, without genetic study: 5); heart failure
death: 3 (with the mutation: 3); transplant: 1 (with the mutation: 1); (see tables).
Particularly highly penetrant and with poor prognosis, 13 out of 32 members affected. Four sudden death in patients
younger than 16 years of age (at 9 playing, at 12 in primary school, at 13 running, at 16 immediately after running to catch
a bus). Other SDs: at 40 with no details, at 42 with no details, at 32 after a night of drinking alcohol. Most sudden deaths
apparently had no prior symptoms; the family members were not aware of having any cardiac condition (only one of the
children had a diagnosis, a 9-year-old girl). There is also one heart failure death (age 47), and alive patient (niece of 38
years) had systolic impairment (EF 40%) with enlarged ventricles (LVED 50 mm). None of the five patients with echo details
had obstruction (apparently, reported no SAM in all of them). Most patients (including those with impaired systolic
function) had minor symptoms (NYHA I-II); no syncope recorded in any of the cases. 2/5 had chest pain. Palpitations not
recorded. ECG features: most popular Q wave and ST changes, no conduction or bundle branch blocks. There is no mention
on ECG rhythm, arrhythmias, Holter, exercise, medications, or some other echo parameters such as diastolic dysfunction.
The major phenotypic characteristics of the MYH7 Gly716Arg mutation were HCM with frequent deterioration to DCM or
SCD at a young age. All 15 patients with the mutation exhibited clinical phenotype or clinical events such as SCD or HF with
deterioration to DCM.
- Patient 922: He was diagnosed with HCM with normal LVEF at age 23. Biopsy with hypertrophy, disarray, and fibrosis. He
was a heavy alcohol drinker. At age 38, LVEDD was 60 mm and LVEF was 39%. He continued to drink alcohol despite
aggravation of symptoms. Clinical events of AF, LV thrombus, and renal infarction developed during follow-up. At age 45,
LVEDD was further enlarged to 71 mm and LVEF was reduced to 20%. He died of HF while awaiting cardiac transplantation
at age 46.
- Patient 924: Normal echo at 7 years old and abnormal at 9 years of age.
- Patient 931: Alcohol was a possible precipitating factor at the time of SCD.
- Patient 923: Deterioration to DCM could be aggravated by pregnancy and emotional stress.
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Family 220 [reference: 10]
Country of origin of the family (or of the publication): Canada.
Mutation carriers with available information: 2 (hypertrophic cardiomyopathy: 2).
No adverse events have been reported.
Two carriers diagnosed at 25 and 75 years of age. One of them had a max LV wall thickness of 23, LVEDD of 51, and LA
diameter of 48 (probably the 75-year-old one).
Family 324 [Unpublished]
Country of origin of the family (or of the publication): Spain. Ethnicity: Western Caucasian.
Mutation carriers with available information: 3 (left ventricular non-compaction/hypertrabeculation: 1, hypertrophic
cardiomyopathy: 2). Mutation non-carriers with available information: 1 (not affected or healthy: 1). Relatives without
genetic study: 2 (possible dilated cardiomyopathy: 1, not affected or healthy: 1).
Adverse events reported in the family ─ no sudden death has been reported; heart failure death: 1 (without genetic study:
1); transplant: 2 (with the mutation: 2); (see tables).
Family 477 [Unpublished]
Country of origin of the family (or of the publication): Spain. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (dilated cardiomyopathy: 1). Mutation non-carriers with available
information: 1 (possible arrhythmogenic cardiomyopathy: 1). Relatives without genetic study: 8 (sudden deaths of
unknown cause: 1, without phenotypic study: 7).
Adverse events reported in the family ─ sudden death: 1 (without genetic study: 1); non-cardiovascular death: 1 (with the
mutation: 1); death of unknown cause: 3 (without genetic study: 3); transplant: 1 (with the mutation: 1); (see tables).
Family 939 [reference: 11]
Country of origin of the family (or of the publication): France.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 940 [reference: 11]
Country of origin of the family (or of the publication): France.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 1045 [references: 8, 13]
Country of origin of the family (or of the publication): United States. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1). Relatives without genetic study: 10
(hypertrophic cardiomyopathy: 3, sudden deaths of unknown cause: 3, without phenotypic study: 4).
Adverse events reported in the family ─ sudden death: 3 (without genetic study: 3); (see tables).
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Family 2001 [reference: 14]
Country of origin of the family (or of the publication): United States.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 2670 [reference: 15]
Country of origin of the family (or of the publication): India. Ethnicity: Hindu.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1). Mutation non-carriers with available
information: 3 (not affected or healthy: 3).
Adverse events reported in the family ─ sudden death: 1 (with the mutation: 1); (see tables).
Family 4487 [reference: 16]
Country of origin of the family (or of the publication): Italy. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
Adverse events reported in the family ─ sudden death: 1 (with the mutation: 1); appropriate icd discharge: 1 (with the
mutation: 1); (see tables).
Family 8317 [reference: 17]
Country of origin of the family (or of the publication): United Kingdom.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 8318 [reference: 17]
Country of origin of the family (or of the publication): United Kingdom.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 9948 [reference: 12]
Country of origin of the family (or of the publication): United States.
Mutation carriers with available information: 6 (hypertrophic cardiomyopathy: 4, restrictive cardiomyopathy: 2). Mutation
non-carriers with available information: 5 (not affected or healthy: 5). Relatives without genetic study: 10 (hypertrophic
cardiomyopathy: 1, possible hypertrophic cardiomyopathy: 5, sudden deaths of unknown cause: 4).
Family 10707 [references: 18, 21]
Country of origin of the family (or of the publication): France. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 18867 [reference: 19]
Country of origin of the family (or of the publication): United States. Ethnicity: Spanish American.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
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Adverse events reported in the family ─ no sudden death has been reported; heart failure death: 1 (with the mutation: 1);
stroke without death: 1 (with the mutation: 1); (see tables).
- Patient 51559: He had a syncopal episode at age 35 for which he received an ICD. At age 35, he developed paroxysmal
atrial fibrillation. He subsequently developed dilated cardiomyopathy with progressive congestive heart failure. He had an
ablation for atrial flutter. Because of advanced heart failure, he was considered a candidate for cardiac transplantation.
The patient underwent autologous peripheral blood cell harvest followed by direct myocardial injection of autologous
precursor cells as a means of augmenting heart function. After intra-myocardial injection, he developed ventricular
fibrillation that required defibrillation. He developed acute renal failure for which he received hemodialysis. Due to overall
poor conditioning exacerbated by his post-arrest course, he was not a candidate for heart transplantation. His left
ventricular function remained severely reduced and showed no improvement. He developed an ischemic right lower
extremity due to an embolism for which he was treated with a percutaneous intervention and anticoagulated with
bivalirudin. Shortly after he had a hemorrhagic stroke. Support was withdrawn and he expired. The heart was 660 g (normal,
350 g) at autopsy, with four-chamber dilation and biventricular hypertrophy (left ventricle, 1.5 cm; right ventricle, 0.7 cm).
Histologically, marked diffuse interstitial fibrosis was present and there was myofiber disarray. There were multiple small
areas of necrosis.
Family 22224 [Unpublished]
Country of origin of the family (or of the publication): Greece. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 35780 [reference: 23]
Country of origin of the family (or of the publication): Brazil.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 35845 [reference: 23]
Country of origin of the family (or of the publication): Brazil.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 35846 [reference: 23]
Country of origin of the family (or of the publication): Brazil.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Family 52743 [reference: 22]
Country of origin of the family (or of the publication): Italy.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
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Family 53026 [reference: 22]
Country of origin of the family (or of the publication): Italy.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
Adverse events reported in the family ─ sudden death: 1 (with the mutation: 1); (see tables).
Other mutations in the family: carriers with p.Gln1654His (gene MYH7): 1.
Family 54513 [Unpublished]
Country of origin of the family (or of the publication): Spain. Ethnicity: Western Caucasian.
Mutation carriers with available information: 1 (hypertrophic cardiomyopathy: 1).
No adverse events have been reported.
Total number of controls reported: 860; controls in the reference 1: 2; controls in the reference 10: 106; controls in the
reference 11: 100; controls in the reference 15: 100; controls in the reference 18: 200; controls in other references: 352.
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Table 1: Genetic and clinical characteristics of mutant carriers who suffered adverse events (mutation: p.Gly716Arg, gene: MYH7)
Patient Id
Family Id
Mutation Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Event (Age at event)
618 155 + No Hypertrophic cardiomyopathy Male ? 43 + (III) ? ? +(25) ? - ? - + Cardiac transplantation (42)
922 197 + No Hypertrophic cardiomyopathy + Dilated cardiomyopathy
Male 23 46 + (II) ? + +(23) ? - ? - +(16) Heart failure death (46)
923 197 + No Hypertrophic cardiomyopathy + Dilated cardiomyopathy
Female 18 50 + (IV) ? + +(21) ? - ? - +(13) Cardiac transplantation (45)
926 197 + No Hypertrophic cardiomyopathy Male 5 11 - (I) ? + +(25) ? - ? ? - Sudden death (11)
927 197 +(O) No Sudden death of unknown cause
Male ? 35 ? ? ? ? ? ? ? ? ? Sudden death (35)
928 197 +(O) No Sudden death of unknown cause
Female ? 42 - (I) ? + ? ? ? ? ? ? Sudden death (42)
929 197 +(O) No Hypertrophic cardiomyopathy + Dilated cardiomyopathy
Female ? 47 + (IV) ? + +(22) ? ? ? - +(33) Heart failure death (47)
930 197 +(O) No ? Male ? 25 + (?) ? + ? ? ? ? ? ? Heart failure death (25)
2079 324 + No Left ventricular non-compaction/hypertrabeculation
Male 20 42 + (II) + (P)
- +(15) ? - ? - +(34) Cardiac transplantation (42)
2080 324 + No Hypertrophic cardiomyopathy Female 25 43 + (III) + (P)
- +(22) [2] - - - +(44) Cardiac transplantation (43)
3244 477 + No Dilated cardiomyopathy Male 49 74 + (III) ? + +(15) [2] - ? - +(39) Non-cardiovascular death (74) Cardiac transplantation (53)
14489 2670 + No Hypertrophic cardiomyopathy Male 20 21 ? ? ? +(31) ? ? ? ? ? Sudden death (21)
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Patient Id
Family Id
Mutation Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Event (Age at event)
21179 4487 + No Hypertrophic cardiomyopathy Male 7 ? - (I) ? - +(24) ? + - ? ? Sudden death Appropriate ICD discharge
51559 18867 + No Hypertrophic cardiomyopathy Male 9 41 + (?) + (P)
+ + [5] + ? ? +(16) Heart failure death (41) Stroke without death (41)
119003 53026 + Yes Hypertrophic cardiomyopathy Female 10 ? - (I) ? - +(33) ? ? ? - -(66) Sudden death (17)
Mutation: + = yes, +(O) = obligate carrier, +(H) = homozygous carrier; NYHA: New York Heart Association functional class; Atr. fib.: atrial fibrillation ([C] chronic, [P] paroxysmal); FHSD: family history of sudden death; LVH (MLVWT): left ventricular hypertrophy
(maximal ventricular wall thickness in mm); VT-VF-EV: [1] non-sustained ventricular tachycardia, [2] sustained monomorphic ventricular tachycardia, [3] sustained polymorphic ventricular tachycardia, [4] torsade de pointes, [5] ventricular fibrillation, [6] frequent
premature ventricular beats; Abn. BP resp.: abnormal blood pressure response on exercise; Obstr. (grad.): gradient in mmHg; Syst. dysf. (EF): systolic dysfunction (ejection fraction). Non-sustained ventricular tachycardia, previous syncope, family history of
premature sudden death, severe hypertrophy (maximum wall thickness >30 mm) and abnormal blood pressure response on exercise are considered risk factors of sudden death. Shaded rows represent index cases.
Patient119003: mutation p.Gln1654His (gene MYH7).
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Table 2: Genetic and clinical characteristics of mutant carriers without documented adverse events (mutation: p.Gly716Arg, gene: MYH7)
Patient Id
Family Id
Mutation Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Comment
625 155 + No Hypertrophic cardiomyopathy Male ? 22 + (II) ? ? +(17) ? + ? - +
626 155 + No Hypertrophic cardiomyopathy Male ? 16 - (I) ? ? +(20) ? - ? - ?
924 197 + No Hypertrophic cardiomyopathy Female 10 20 - (I) ? + +(15) ? - ? - -
925 197 + No Left ventricular non-compaction/hypertrabeculation? + Hypertrophic cardiomyopathy
Male 9 24 - (I) ? + +(23) ? - ? - -
1204 220 + No Hypertrophic cardiomyopathy ? 25 25 ? ? ? ? ? ? ? ? ?
1205 220 + No Hypertrophic cardiomyopathy ? 75 75 ? ? ? +(23) ? ? ? ? ?
2083 324 + No Hypertrophic cardiomyopathy Female 7 18 - (I) - - +(24) ? + + +(75) -(91)
6988 939 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? + ? ? ? ? ?
6989 940 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? + ? ? ? ? ?
7159 1045 + No Hypertrophic cardiomyopathy Male 24 32 ? ? + +(26) ? - ? +(80) -
12308 2001 + No Hypertrophic cardiomyopathy ? ? <15 ? ? ? + ? ? ? ? ?
31673 8317 + No Hypertrophic cardiomyopathy ? ? <13 ? ? ? + ? ? ? ? ?
31680 8318 + No Hypertrophic cardiomyopathy ? ? <13 ? ? ? + ? ? ? ? ?
35305 9948 + No Hypertrophic cardiomyopathy ? ? ? ? ? + + ? ? ? ? ?
35306 9948 + No Hypertrophic cardiomyopathy ? ? ? ? ? + + ? ? ? ? ?
35307 9948 + No Hypertrophic cardiomyopathy ? ? ? ? ? + + ? ? ? ? ?
35308 9948 + No Hypertrophic cardiomyopathy ? ? ? ? ? + + ? ? ? ? ?
35309 9948 + No Restrictive cardiomyopathy Female ? ? ? ? + ? ? ? ? ? -
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Patient Id
Family Id
Mutation Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Comment
35310 9948 + No Restrictive cardiomyopathy Female ? ? ? ? + ? ? ? ? ? -
36975 10707 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? ? ? ? ? ? ?
38080 197 + No Hypertrophic cardiomyopathy Male 32 43 - (I) ? + +(21) ? ? ? - -
58662 22224 + No Hypertrophic cardiomyopathy Male ? ? ? ? ? + ? ? ? ? ?
86958 35780 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? ? ? ? ? ? ?
87023 35845 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? ? ? ? ? ? ?
87024 35846 + No Hypertrophic cardiomyopathy ? ? ? ? ? ? ? ? ? ? ? ?
118270 52743 + No Hypertrophic cardiomyopathy Female 28 33 - (I) ? ? +(28) ? ? ? - +(68)
122253 54513 + No Hypertrophic cardiomyopathy Female ? ? ? ? ? ? ? ? ? ? ?
Mutation: + = yes, +(O) = obligate carrier, +(H) = homozygous carrier; NYHA: New York Heart Association functional class; Atr. fib.: atrial fibrillation ([C] chronic, [P] paroxysmal); FHSD: family history of sudden death; LVH (MLVWT): left ventricular hypertrophy
(maximal ventricular wall thickness in mm); VT-VF-EV: [1] non-sustained ventricular tachycardia, [2] sustained monomorphic ventricular tachycardia, [3] sustained polymorphic ventricular tachycardia, [4] torsade de pointes, [5] ventricular fibrillation, [6] frequent
premature ventricular beats; Abn. BP resp.: abnormal blood pressure response on exercise; Obstr. (grad.): gradient in mmHg; Syst. dysf. (EF): systolic dysfunction (ejection fraction). Non-sustained ventricular tachycardia, previous syncope, family history of
premature sudden death, severe hypertrophy (maximum wall thickness >30 mm) and abnormal blood pressure response on exercise are considered risk factors of sudden death. Shaded rows represent index cases.
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Table 3: Clinical characteristics of relatives without genetic diagnosis who had adverse cardiovascular events potentially related to the family disease (mutation:
p.Gly716Arg, gene: MYH7)
Patient Id
Family Id
Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Event (Age at event)
931 197 No Sudden death of unknown cause
Male ? 32 - (I) ? + ? ? ? ? ? ? Sudden death (32)
932 197 No Sudden death of unknown cause
Male ? 12 - (I) ? + ? ? ? ? ? ? Sudden death (12)
933 197 No Sudden death of unknown cause
Female ? 13 - (I) ? + ? ? ? ? ? ? Sudden death (13)
950 197 No Sudden death of unknown cause
Female ? 45 ? ? ? ? ? ? ? ? ? Sudden death (45)
951 197 No Sudden death of unknown cause
Male ? 15 ? ? ? ? ? ? ? ? ? Sudden death (15)
2081 324 No Dilated cardiomyopathy?
Male ? ? ? ? ? ? ? ? ? ? ? Heart failure death (47)
3247 477 No ? Male ? 55 ? ? ? ? ? ? ? ? ? Death of unknown cause (55)
3252 477 No Sudden death of unknown cause
Male ? 55 ? ? ? ? ? ? ? ? ? Sudden death (55)
14707 1045 No Sudden death of unknown cause
Female ? 46 ? ? ? ? ? ? ? ? ? Sudden death (46)
14708 1045 No Sudden death of unknown cause
Female ? 16 ? ? + ? ? ? ? ? ? Sudden death (16)
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Patient Id
Family Id
Other mut.
Clinical diagnosis Sex Age at DX
Age last FU
NYHA Atr. fib.
FHSD LVH (MLVWT)
VT-VF-EV
Previous syncope
Abn. BP resp.
Obstr. (grad.)
Syst. dysf. (EF)
Event (Age at event)
14722 1045 No Sudden death of unknown cause
Female ? 42 ? ? + ? ? ? ? ? ? Sudden death (42)
35322 9948 No Sudden death of unknown cause
? ? ? ? ? ? ? ? ? ? ? ? Sudden death
35323 9948 No Sudden death of unknown cause
? ? ? ? ? ? ? ? ? ? ? ? Sudden death
35324 9948 No Sudden death of unknown cause
? ? ? ? ? ? ? ? ? ? ? ? Sudden death
35325 9948 No Sudden death of unknown cause
? ? ? ? ? ? ? ? ? ? ? ? Sudden death
Mutation: + = yes, +(O) = obligate carrier, +(H) = homozygous carrier; NYHA: New York Heart Association functional class; Atr. fib.: atrial fibrillation ([C] chronic, [P] paroxysmal); FHSD: family history of sudden death; LVH (MLVWT): left ventricular hypertrophy
(maximal ventricular wall thickness in mm); VT-VF-EV: [1] non-sustained ventricular tachycardia, [2] sustained monomorphic ventricular tachycardia, [3] sustained polymorphic ventricular tachycardia, [4] torsade de pointes, [5] ventricular fibrillation, [6] frequent
premature ventricular beats; Abn. BP resp.: abnormal blood pressure response on exercise; Obstr. (grad.): gradient in mmHg; Syst. dysf. (EF): systolic dysfunction (ejection fraction). Non-sustained ventricular tachycardia, previous syncope, family history of
premature sudden death, severe hypertrophy (maximum wall thickness >30 mm) and abnormal blood pressure response on exercise are considered risk factors of sudden death. Shaded rows represent index cases.
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Statistics and summary of the mutant carrier characteristics with available data (mutation:
p.Gly716Arg, gene: MYH7)
Variable Cases with data (n) Positive cases Average (SD) / Range
Demographic variables
Sex 27
Male 16 (59.3%)
Female 11 (40.7%)
Age at diagnosis 18 22.0 (±17.3) / 5-75
Age at time of study or last follow-up 23 36.0 (±16.6) / 11-75
Environmental factors or triggers
Sport 9 0
Symptoms and risk factors
Dyspnea 20 10
NYHA I 10 (50%)
NYHA II 3 (15%)
NYHA III - IV 5 (25%)
NYHA Unknown 2 (10%)
Previous syncope 15 4
Chest pain 13 3 (23.1%)
Ventricular arrhythmias 5 3 (60%)
Abnormal blood pressure response 3 1 (33.3%)
Fibrofatty infiltration 1 1 (100%)
Morphology
LV hypertrophy 31 19 (61.3%)
Asymmetrical septal 13
Maximum LV wall thickness (mm) 20 22.6 (±4.9) / 15-33
LV mass (gr) 4 304 (±79.8) / 205-400
LV dilatation 15 7 (46.7%)
LV end-diastolic diameter (mm) 11 53.1 (±17.3) / 34-90
LV systolic dysfunction 19 10 (52.6%)
Ejection fraction (%) 10 42 (±25.8) / 13-91
LV diastolic dysfunction 6 4 (66.7%)
Abnormal relaxation 1
Restrictive filling 3
Left atrial dilatation 15 10 (66.7%)
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Variable Cases with data (n) Positive cases Average (SD) / Range
Left atrium diameter (mm) 10 51.4 (±8.2) / 36-60
LV obstruction 16 2 (12.5%)
Subaortic gradient (mmHg) 2 77.5 (±3.5) / 75-80
Electrocardiogram
Abnormal ECG 16 16 (100%)
Previous atrial fibrillation 4 3
Rhythm 23 9 (39.1%)
Sinus 5
Atrial fibrillation flutter 4
Abnormal voltage or repolarization 12 10 (83.3%)
Abnormal repolarization 1
Low voltage 2
High voltage 7
Negative T waves 2
Conduction system disease 7 4 (57.1%)
Abnormal Q wave 11 5 (45.5%)
Treatment
Treatment 9 9 (100%)
Medical 8
Surgery 1
Implantable cardioverter defibrillator 4
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Selected references (mutation: p.Gly716Arg, gene: MYH7)
1. Anan R, Greve G, Thierfelder L, Watkins H, McKenna WJ, Solomon S, et al. Prognostic implications of novel beta cardiac
myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994. 93(1):280-285.
http://www.ncbi.nlm.nih.gov/pubmed/8282798
2. Rayment I, Holden HM, Sellers JR, Fananapazir L, Epstein ND. Structural interpretation of the mutations in the beta-
cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A
1995;92(9):3864-8.
http://www.ncbi.nlm.nih.gov/pubmed/7731997?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results
Panel.Pubmed_RVDocSum
3. Fujita H, Sugiura S, Momomura S, Omata M, Sugi H, Sutoh K. Characterization of mutant myosins of Dictyostelium
discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins
may have a prognostic implication. J Clin Invest 1997;99(5):1010-5.
http://www.ncbi.nlm.nih.gov/pubmed/9062359
4. Hwang T,Lee WH, Kimura A, Satoh M, Nakamura T, Kim MK,. Early expression of a malignant phenotype of familial
hypertrophic cardiomyopathy associated with a gly716arg myosin heavy chain mutation in a korean family. Am J Cardiol
1998;82:1509-1513.
http://www.ncbi.nlm.nih.gov/pubmed/9874056
5. Fujita H, Sugiura S, Momomura S, Sugi H, Sutoh K. Functional characterization of Dictyostelium discoideum mutant
myosins equivalent to human familial hypertrophic cardiomyopathy. Adv Exp Med Biol. 1998;453:131-7.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9889823
6. Fananapazir L. Advances in molecular genetics and management of hypertrophic cardiomyopathy. JAMA 1999;281:1746-
1752.
http://www.ncbi.nlm.nih.gov/pubmed/10328076
7. Roopnarine, O. Familial hypertrophic cardiomyopathic myosin mutations that affect the actin-myosin interaction. Results
Probl Cell Differ 2002;36:75-86.
http://www.ncbi.nlm.nih.gov/pubmed/11892286
8. Ackerman MJ, VanDriest SL, Ommen SR, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and age-dependence of
malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a
comprehensive outpatient perspective. J Am Coll Cardiol 2002;39(12):2042-8.
http://www.ncbi.nlm.nih.gov/pubmed/12084606?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results
Panel.Pubmed_RVDocSum
9. Köhler J, Winkler G, Schulte I, Scholz T, McKenna W, Brenner B, Kraft T. Mutation of the myosin converter domain alters
cross-bridge elasticity. Proc Natl Acad Sci U S A. 2002 ;99(6):3557-62.
http://www.ncbi.nlm.nih.gov/pubmed/11904418?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPa
nel.SmartSearch&log$=citationsensor
10. Woo A. Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites
determine prognosis. Heart 2003;89:1179-1185.
http://www.ncbi.nlm.nih.gov/pubmed/12975413
11. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, et al. Hypertrophic cardiomyopathy: distribution of
disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227-2232.
http://www.ncbi.nlm.nih.gov/pubmed/12707239
12. Jedeikin R, Bensley M, Hershberger R, Rice M, Reijo-Pera R, Sehnert A... A beta myosin heavy chain gene mutation
causes restrictive cardiomyopathy. Pediatr Res. 2003 ;53(4):187.
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13. Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, et al. Comprehensive analysis of the beta-myosin
heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004 ;44(3):602-10.
http://www.ncbi.nlm.nih.gov/pubmed/%2015358028
14. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, et al. Shared genetic causes of cardiac
hypertrophy in children and adults. N Engl J Med 2008;358(18):1899-908.
http://www.ncbi.nlm.nih.gov/pubmed/18403758?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results
Panel.Pubmed_RVDocSum
15. Rai TS, Ahmad S, Bahl A, Ahuja M, Ahluwalia TS, Singh B, et al. Genotype phenotype correlations of cardiac beta-myosin
heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy. Mol Cell Biochem. 2009;321(1-
2):189-96.
http://www.ncbi.nlm.nih.gov/pubmed/18953637?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results
Panel.Pubmed_RVDocSum
16. Frisso G, Limongelli G, Pacileo G, Del Giudice A, Forgione L, Calabrò P, Iacomino M, et al. A child cohort study from
southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. Clin Genet. 2009 Jul;76(1):91-101.
http://www.ncbi.nlm.nih.gov/pubmed/19659763
17. Kaski JP, Syrris P, Esteban MT, Jenkins S, Pantazis A, Deanfield JE, McKenna WJ, Elliott PM. Prevalence of sarcomere
protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2009
Oct;2(5):436-41.
http://www.ncbi.nlm.nih.gov/pubmed/20031618
18. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A,. Prevalence and spectrum of mutations in a cohort
of 192 unrelated patients with Hypertrophic Cardiomyopathy. Eur J Med Genet. 2010;53:261-7.
http://www.ncbi.nlm.nih.gov/pubmed/20624503
19. Pytel P, Husain A, Moskowitz I, Raman J, MacLeod H, Anderson AS, et al. Ventricular fibrillation following autologous
intramyocardial cell therapy for inherited cardiomyopathy. Cardiovasc Pathol. 2010r;19(2):e33-6.
http://www.ncbi.nlm.nih.gov/pubmed/19026577
20. Choi JO, Yu CW, Chun Nah J, Rang Park J, Lee BS, Jeong Choi Y, Cho BR, Lee SC, Woo Park S, Kimura A, Euy Park J. Long-
term outcome of 4 korean families with hypertrophic cardiomyopathy caused by 4 different mutations. Clin Cardiol. 2010
Jul;33(7):430-8.
http://www.ncbi.nlm.nih.gov/pubmed/20641121
21. Millat G, Chanavat V, Crehalet H, Rousson R. Development of a high resolution melting method for the detection of
genetic variations in hypertrophic cardiomyopathy. Clin Chim Acta. 2010 Dec 14;411(23-24):1983-91.
http://www.ncbi.nlm.nih.gov/pubmed/20800588
22. Calore C. Genotype-phenotype correlations and genetic family screening in hypertrophic cardiomyopathy. Thesis.
23. Marsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, et al. Screening of MYH7, MYBPC3, and
TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. Am Heart J. 2013;166(4):775-82.
http://www.ncbi.nlm.nih.gov/pubmed/24093860
24. Biagini E, Olivotto I, Iascone M, Parodi MI, Girolami F, Frisso G, et al. Significance of sarcomere gene mutations analysis
in the end-stage phase of hypertrophic cardiomyopathy. Am j cardiol. 2014;114(5):769-76.
http://www.ncbi.nlm.nih.gov/pubmed/25037680
25. Colegrave M, Peckham M. Structural implications of β-cardiac myosin heavy chain mutations in human disease. Anat
Rec (Hoboken). 2014 Sep;297(9):1670-80.
http://www.ncbi.nlm.nih.gov/pubmed/25125180
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Page 21
26. Gomez J, Reguero JR, Coto E. Luces y sombras en el diagnóstico genético de la miocardiopatía hipertrófica. Rev Esp
Cardiol. 2016 Jan;69(1):61-8.
http://https://www.ncbi.nlm.nih.gov/pubmed/26654849
27. Watkins H. Multiple disease genes cause hypertrophic cardiomyopathy. Br Heart J. 1994 ;72(6 Suppl):S4-9.
http://www.ncbi.nlm.nih.gov/pubmed/7873324?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPan
el.SmartSearch&log$=citationsensor
28. Vikstrom KL, Leinwand LA. Contractile protein mutations and heart disease. Curr Opin Cell Biol. 1996;8(1):97-105.
http://www.ncbi.nlm.nih.gov/pubmed/8791411
29. Palmiter, K. A.,Solaro, R. J. Molecular mechanisms regulating the myofilament response to Ca2+: implications of
mutations causal for familial hypertrophic cardiomyopathy. Basic Res Cardiol 1997;92 Suppl 1:63-74.
http://www.ncbi.nlm.nih.gov/pubmed/9202846
30. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to
functional defects. Circ Res. 1998 ;83(6):580-93.
http://www.ncbi.nlm.nih.gov/pubmed/9742053
31. Redwood, C. S.,Moolman-Smook, J. C.,Watkins, H. Properties of mutant contractile proteins that cause hypertrophic
cardiomyopathy. Cardiovasc Res 1999;44(1):20-36.
http://www.ncbi.nlm.nih.gov/pubmed/10615387
32. Kimura A, Ito-Satoh M, Hayashi T, Takahashi M, Arimura T. Molecular etiology of idiopathic cardiomyopathy in Asian
populations. J Cardiol 2001;37 Suppl 1:139-46.
http://www.ncbi.nlm.nih.gov/pubmed/11433818
33. Dalloz F, Osinska H, Robbins J.. Manipulating the contractile apparatus: genetically defined animal models of
cardiovascular disease. J Mol Cell Cardiol. 2001 Jan;33(1):9-25.
http://www.ncbi.nlm.nih.gov/pubmed/11133219
34. Mattos BP. Genetic bases of hypertrophic cardiomyopathy. Arq Bras Cardiol. 2002 Mar;78(3):323-40.
http://www.ncbi.nlm.nih.gov/pubmed/11998826
35. Hengstenberg C, Erdmann J, Charron P. Outcome of clinical versus genetic family screening in hypertrophic
cardiomyopathy with focus on cardiac beta-myosin gene mutations: prediction of clinical status--is molecular genetics a
new tool for the management of hypertrophic cardiomyopathy in clinical practice?. Cardiovasc Res 2003;57(2):298-301.
http://www.ncbi.nlm.nih.gov/pubmed/12566102
36. Ramírez CD, Padrón R. Cardiomiopatia hipertrofica familiar: genes, mutaciones y modelos animales. Invest Clin. 2004
Mar;45(1):69-99.
http://www.ncbi.nlm.nih.gov/pubmed/15058760
37. Ackerman MJ. Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or
fiction. Curr Opin Cardiol. 2005;20(3):175-81.
http://www.ncbi.nlm.nih.gov/pubmed/15861004
38. Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Sarcomeric genotyping in hypertrophic cardiomyopathy.
Mayo Clin Proc 2005 ;80(4):463-9.
http://www.ncbi.nlm.nih.gov/pubmed/15819282
39. Landstrom AP, Ackerman MJ. Mutation Type Is Not Clinically Useful in Predicting Prognosis in Hypertrophic
Cardiomyopathy. Circulation. 2010 ;122(23):2441-2450.
http://www.ncbi.nlm.nih.gov/pubmed/21135372
Admera Health, LLC • CLIA ID 31D2038676 126 Corporate Boulevard • South Plainfield, NJ 07080 1-908-222-0533 • [email protected] • http://www.admerahealth.com
Page 22
40. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.
Development and validation of a computational method for assessment of missense variants in hypertrophic
cardiomyopathy. Am J Hum Genet. 2011 Feb 11;88(2):183-92.
http://https://www.ncbi.nlm.nih.gov/pubmed/21310275
41. Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA. Cardiac structural and sarcomere genes
associated with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012 Dec;5(6):602-
10.
http://www.ncbi.nlm.nih.gov/pubmed/23074333
42. Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in
patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart. 2013 Dec;99(24):1800-11.
http://www.ncbi.nlm.nih.gov/pubmed/23674365
43. Zou Y, Wang J, Liu X, Wang Y, Chen Y, Sun K, et al. Multiple gene mutations, not the type of mutation, are the modifier
of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep. 2013 Jun;40(6):3969-76.
http://www.ncbi.nlm.nih.gov/pubmed/23283745
44. Bos JM, Will ML, Gersh BJ, Kruisselbrink TM, Ommen SR, Ackerman MJ. Characterization of a Phenotype-Based Genetic
Test Prediction Score for Unrelated Patients with Hypertrophic Cardiomyopathy. Mayo Clin Proc. 2014 Jun;89(6):727-37.
http://www.ncbi.nlm.nih.gov/pubmed/24793961
45. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships
among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5.
http://www.ncbi.nlm.nih.gov/pubmed/24234437
46. Wang J, Wang Y, Zou Y, Sun K, Wang Z, Ding H, Yuan J, Wei W, Hou Q, Wang H, Liu X, Zhang H, Ji Y, Zhou X, Sharma RK,
Wang D, Ahmad F, Hui R, Song L. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients
with hypertrophic cardiomyopathy. Eur J Heart Fail. 2014 Sep;16(9):950-7.
http://lm.nih.gov/pubmed/25132132
47. Spudich JA. The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic
cardiomyopathy. Biochem Soc Trans. 2015 Feb;43(1):64-72.
http://www.ncbi.nlm.nih.gov/pubmed/25619247
48. García-Giustiniani D, Arad M, Ortíz-Genga M, Barriales-Villa R, Fernández X, Rodríguez-García I, Mazzanti A,, et al.
Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. Heart.
2015 Jul 1;101(13):1047-53.
http://www.ncbi.nlm.nih.gov/pubmed/25935763
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Information about other described mutations affecting the same region (helix-
converter region)
This section describes available data about the following 6 variants: p.Gly716Ala, p.Asp717Gly, p.Arg719Gln, p.Arg719Pro,
p.Arg719Trp, p.Arg721Lys.
Number of families described associated with the selected variants: 80. Carriers with available information: 147 (affected
or possibly affected: 144, not affected or healthy: 3). Non-carriers with available information: 70 (hypertrophic
cardiomyopathy: 1, not affected or healthy: 63, without phenotypic study: 6). Relatives without genetic study: 121
(hypertrophic cardiomyopathy: 39, possible hypertrophic cardiomyopathy: 6, sudden deaths of unknown cause: 11, not
affected or healthy: 27, without phenotypic study: 38).
Major phenotypes Carriers (families)
Non-carriers
Without genetic study
Total
Hypertrophic cardiomyopathy 139 (76) 1 45 185
Not affected or healthy 3 (3) 63 27 93
Restrictive cardiomyopathy 3 (2) 0 0 3
Left ventricular non-compaction/hypertrabeculation 1 (1) 0 0 1
Hypertrophic cardiomyopathy + Left ventricular non-compaction/hypertrabeculation
1 (1) 0 0 1
No phenotypic study 0 (0) 6 38 44
Sudden death 0 (0) 0 11 11
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Variant Phenotypes (patients) Families Affected carriers
Healthy carriers
Events (patients) References
MYH7 p.Gly716Ala
Hypertrophic cardiomyopathy(1) 1 1 0 2
MYH7 p.Asp717Gly
0 0 0 1
MYH7 p.Arg719Gln
Hypertrophic cardiomyopathy(46) Restrictive cardiomyopathy(1)
41 47 1 Sudden death (26) Cardiac transplantation (6) Heart failure death (3)
76
MYH7 p.Arg719Pro
Hypertrophic cardiomyopathy(2) 2 2 0 6
MYH7 p.Arg719Trp
Hypertrophic cardiomyopathy(91) Left ventricular non-compaction/hypertrabeculation(2)
35 92 2 Sudden death (33) Heart failure death (5) Cardiac transplantation (4) Appropriate ICD discharge (1) Stroke-related death (1)
105
MYH7 p.Arg721Lys
Restrictive cardiomyopathy(2) 1 2 0 Heart failure death (1) 4
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Statistics and summary about other described mutations affecting the same region
Variable Cases with data (n) Positive cases Average (SD) / Range
Demographic variables
Sex 74
Male 32 (43.2%)
Female 42 (56.8%)
Age at diagnosis 46 20.9 (±16.2) / 1-68
Age at time of study or last follow-up 52 33.0 (±17.8) / 1-70
Environmental factors or triggers
Sport 3 1 (33.3%)
Non-competitive 1
Symptoms and risk factors
Dyspnea 40 24
NYHA I 16 (40%)
NYHA II 8 (20%)
NYHA III - IV 13 (32.5%)
NYHA Unknown 3 (7.5%)
Previous syncope 35 13
Chest pain 28 10 (35.7%)
RV failure signs 1 0
Ventricular arrhythmias 21 6 (28.6%)
Abnormal blood pressure response 15 5 (33.3%)
Morphology
LV hypertrophy 100 46 (46%)
Apical 1
Asymmetrical septal 26
Atypical 3
Maximum LV wall thickness (mm) 47 20.7 (±7.3) / 5-33
LV mass (gr) 3 240.7 (±130.5) / 90-320
LV dilatation 23 2 (8.7%)
LV end-diastolic diameter (mm) 14 44.8 (±6.1) / 38-60
LV systolic dysfunction 30 9 (30%)
Ejection fraction (%) 20 56.2 (±18.2) / 15-83
LV diastolic dysfunction 11 10 (90.9%)
Abnormal relaxation 3
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Variable Cases with data (n) Positive cases Average (SD) / Range
Pseudonormalization 2
Restrictive filling 4
Left atrial dilatation 23 11 (47.8%)
Left atrium diameter (mm) 18 43.8 (±8.5) / 28-61
LV obstruction 37 10 (27%)
Subaortic gradient (mmHg) 5 70.6 (±22.2) / 40-95
Electrocardiogram
Abnormal ECG 37 32 (86.5%)
Previous atrial fibrillation 9 4
Rhythm 79 24 (30.4%)
Sinus 21
Atrial fibrillation flutter 3
Abnormal voltage or repolarization 24 22 (91.7%)
Abnormal repolarization 4
Long QT 8
High voltage 8
Negative T waves 9
Conduction system disease 19 7 (36.8%)
Abnormal Q wave 19 11 (57.9%)
Corrected QT duration (ms) 8 8 488.3 (±16.8) / 470-520
Electrophysiologic study
Electrophysiologic study done 1
Treatment
Treatment 35 27 (77.1%)
Medical 11
Surgery 7
Pacemaker 2
Implantable cardioverter defibrillator 11
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Page 27
Selected references
p.Gly716Ala
1. Kassem HS, Azer RS, Ayad MS, Moharem-Elgamal S, Magdy G, Elguindy A, et al. Early Results of Sarcomeric Gene
Screening from the Egyptian National BA-HCM. J Cardiovasc Transl Res. 2013 Feb;6(1):65-80.
http://www.ncbi.nlm.nih.gov/pubmed/%2023233322
2. Colegrave M, Peckham M. Structural implications of β-cardiac myosin heavy chain mutations in human disease. Anat Rec
(Hoboken). 2014 Sep;297(9):1670-80.
http://www.ncbi.nlm.nih.gov/pubmed/25125180
p.Asp717Gly
1. García-Giustiniani D, Arad M, Ortíz-Genga M, Barriales-Villa R, Fernández X, Rodríguez-García I, Mazzanti A,, et al.
Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. Heart.
2015 Jul 1;101(13):1047-53.
http://www.ncbi.nlm.nih.gov/pubmed/25935763
p.Arg719Gln
1. Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients
with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart. 2013 Dec;99(24):1800-11.
http://www.ncbi.nlm.nih.gov/pubmed/23674365
2. Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA. Cardiac structural and sarcomere genes associated
with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012 Dec;5(6):602-10.
http://www.ncbi.nlm.nih.gov/pubmed/23074333
3. Ramírez CD, Padrón R. Cardiomiopatia hipertrofica familiar: genes, mutaciones y modelos animales. Invest Clin. 2004
Mar;45(1):69-99.
http://www.ncbi.nlm.nih.gov/pubmed/15058760
4. Bos JM, Will ML, Gersh BJ, Kruisselbrink TM, Ommen SR, Ackerman MJ. Characterization of a Phenotype-Based Genetic
Test Prediction Score for Unrelated Patients with Hypertrophic Cardiomyopathy. Mayo Clin Proc. 2014 Jun;89(6):727-37.
http://www.ncbi.nlm.nih.gov/pubmed/24793961
5. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships
among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5.
http://www.ncbi.nlm.nih.gov/pubmed/24234437
6. Vikstrom KL, Leinwand LA. Contractile protein mutations and heart disease. Curr Opin Cell Biol. 1996;8(1):97-105.
http://www.ncbi.nlm.nih.gov/pubmed/8791411
7. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.
Development and validation of a computational method for assessment of missense variants in hypertrophic
cardiomyopathy. Am J Hum Genet. 2011 Feb 11;88(2):183-92.
http://https://www.ncbi.nlm.nih.gov/pubmed/21310275
8. Kapplinger JD, Landstrom AP, Bos JM, Salisbury BA, Callis TE, Ackerman MJ. Distinguishing Hypertrophic Cardiomyopathy-
Associated Mutations from Background Genetic Noise. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61.
http://www.ncbi.nlm.nih.gov/pubmed/24510615
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Page 28
9. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to functional
defects. Circ Res. 1998 ;83(6):580-93.
http://www.ncbi.nlm.nih.gov/pubmed/9742053
10. Jelusic M, Gall-Troselj K, Jurak I, Pavelic K, Kniewald H, Putarek NR, et al. Genetic analysis of hypertrophic
cardiomyopathy in 12 Croatian families. Eur J Hum Genet. 2002;10:255-.
http://www.distrofiamuscular.net/resumos11.htm
p.Arg719Pro
1. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships
among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5.
http://www.ncbi.nlm.nih.gov/pubmed/24234437
2. Xu Q, Dewey S, Nguyen S, Gomes AV. Malignant and benign mutations in familial cardiomyopathies: Insights into
mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol. 2010 May;48(5):899-909.
http://www.ncbi.nlm.nih.gov/pubmed/20298698
3. García-Giustiniani D, Arad M, Ortíz-Genga M, Barriales-Villa R, Fernández X, Rodríguez-García I, Mazzanti A,, et al.
Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. Heart.
2015 Jul 1;101(13):1047-53.
http://www.ncbi.nlm.nih.gov/pubmed/25935763
4. Marsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, et al. Screening of MYH7, MYBPC3, and
TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. Am Heart J. 2013;166(4):775-82.
http://www.ncbi.nlm.nih.gov/pubmed/24093860
5. Colegrave M, Peckham M. Structural implications of β-cardiac myosin heavy chain mutations in human disease. Anat Rec
(Hoboken). 2014 Sep;297(9):1670-80.
http://www.ncbi.nlm.nih.gov/pubmed/25125180
p.Arg719Trp
1. Green, E. M.,Wakimoto, H.,Anderson, R. L.,Evanchik, M. J.,Gorham, J. M.,Harrison, B. C.,Henze, M.,Kawas, R.,Oslob, J.
D.,Rodriguez, H. M.,Song, Y.,Wan, W.,Leinwand, L. A.,Spudich, J. A.,McDowell, R. S.,Seidman, J. G.,Seidman, C. E. A small-
molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science
2016;351(6273):617-21.
http://www.ncbi.nlm.nih.gov/pubmed/%2026912705
2. Ramírez CD, Padrón R. Cardiomiopatia hipertrofica familiar: genes, mutaciones y modelos animales. Invest Clin. 2004
Mar;45(1):69-99.
http://www.ncbi.nlm.nih.gov/pubmed/15058760
3. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships
among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5.
http://www.ncbi.nlm.nih.gov/pubmed/24234437
4. Vikstrom KL, Leinwand LA. Contractile protein mutations and heart disease. Curr Opin Cell Biol. 1996;8(1):97-105.
http://www.ncbi.nlm.nih.gov/pubmed/8791411
5. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.
Development and validation of a computational method for assessment of missense variants in hypertrophic
cardiomyopathy. Am J Hum Genet. 2011 Feb 11;88(2):183-92.
http://https://www.ncbi.nlm.nih.gov/pubmed/21310275
Admera Health, LLC • CLIA ID 31D2038676 126 Corporate Boulevard • South Plainfield, NJ 07080 1-908-222-0533 • [email protected] • http://www.admerahealth.com
Page 29
6. Kapplinger JD, Landstrom AP, Bos JM, Salisbury BA, Callis TE, Ackerman MJ. Distinguishing Hypertrophic Cardiomyopathy-
Associated Mutations from Background Genetic Noise. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61.
http://www.ncbi.nlm.nih.gov/pubmed/24510615
7. Emory University. EmVClass: Variant Classification Database. 2013.
http://geneticslab.emory.edu/emvclass/emvclass.php
8. Piano MR. Familial hypertrophic cardiomyopathy. J Cardiovasc Nurs. 1999;13(4):46-58.
http://www.ncbi.nlm.nih.gov/pubmed/10386271
9. Marian AJ, Roberts R. Familial hypertrophic cardiomyopathy: a paradigm of the cardiac hypertrophic response to injury.
Ann Med. 1998;30 Suppl 1:24-32.
http://www.ncbi.nlm.nih.gov/pubmed/9800880
10. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to
functional defects. Circ Res. 1998 ;83(6):580-93.
http://www.ncbi.nlm.nih.gov/pubmed/9742053
p.Arg721Lys
1. Xu Q, Dewey S, Nguyen S, Gomes AV. Malignant and benign mutations in familial cardiomyopathies: Insights into
mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol. 2010 May;48(5):899-909.
http://www.ncbi.nlm.nih.gov/pubmed/20298698
2. García-Giustiniani D, Arad M, Ortíz-Genga M, Barriales-Villa R, Fernández X, Rodríguez-García I, Mazzanti A,, et al.
Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. Heart.
2015 Jul 1;101(13):1047-53.
http://www.ncbi.nlm.nih.gov/pubmed/25935763
3. Rai TS, Ahmad S, Ahluwalia TS, Ahuja M, Bahl A, Saikia UN, et al. Genetic and clinical profile of Indian patients of idiopathic
restrictive cardiomyopathy with and without hypertrophy. Mol Cell Biochem. 2009 Nov;331(1-2):187-92.
http://www.ncbi.nlm.nih.gov/pubmed/19449150?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results
Panel.Pubmed_RVDocSum
4. Colegrave M, Peckham M. Structural implications of β-cardiac myosin heavy chain mutations in human disease. Anat Rec
(Hoboken). 2014 Sep;297(9):1670-80.
http://www.ncbi.nlm.nih.gov/pubmed/25125180
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Page 30
APPENDIX 2
AVAILABLE INFORMATION ON OTHER IDENTIFIED VARIANTS
We have identified genetic variants that we consider not to be associated with disease development either because they
have been reported in healthy controls or because they do not affect protein structure nor function.
Region Variants found
Exonic 106
Synonymous 69
Nonsynonymous 37
Intronic 158
Intronic splicing 20
UTR 16
Total 280
Only good quality variants were included (QUAL ≥170)
106
1620
138
Exon
UTR
Intron splicing
Intron non-splicing
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List of probably non-disease causing exonic genetic variants (excluding synonymous)
Gene Variant Function Exonic function
dbSNP dbSNP freq.
1000G MAF
5000G MAF
HiC freq.
AF1 DP Qual
Qual Freq. alt.
AARS2 NP_065796.1:p.Ile339Val; NM_020745.3:c.1015A>G; NC_000006.11:g.44275011T>C
Exon Nonsynonymous rs324136 88.9 11.34 99.74 Hom. 682 255 100
AGL NP_000633.2:p.Pro1067Ser; NM_000642.2:c.3199C>T; NC_000001.10:g.100358103C>T
Exon Nonsynonymous rs3753494 13.1 11.06 13.95 27.03 Het. 1696 255 49
BSCL2 NP_001124174.2:p.Lys268Arg; NM_001130702.2:c.803A>G; NC_000011.9:g.62458275T>C
Exon Nonsynonymous rs6856 17.47 13.5 18.33 36.03 Hom. 627 255 100
COQ2 NP_056512.5:p.Val66Leu; NM_015697.7:c.196G>T; NC_000004.11:g.84205872C>A
Exon Nonsynonymous rs6818847 67.59 64.98 31.48 91.21 Hom. 501 255 99.8
COX15 NP_004367.2:p.Phe374Leu; NM_004376.5:c.1120T>C; NC_000010.10:g.101473218A>G
Exon Nonsynonymous rs2231687 82.71 16.52 97.63 Hom. 1320 255 100
FHOD3 NP_001268669.1:p.Ser455Leu; NM_001281740.1:c.1364C>T; NC_000018.9:g.34232610C>T
Exon Nonsynonymous rs2848901 28.39 31.95 42.33 Het. 858 255 47.7
FHOD3 NP_001268669.1:p.Val1326Ile; NM_001281740.1:c.3976G>A; NC_000018.9:g.34324091G>A
Exon Nonsynonymous rs2303510 37.62 35.55 55.64 Het. 1091 255 47.4
GAA NP_000143.2:p.His199Arg; NM_000152.3:c.596A>G; NC_000017.10:g.78079597A>G
Exon Nonsynonymous rs1042393 65.72 60.08 32.75 93.29 Het. 922 170 43.4
GAA NP_000143.2:p.Arg223His; NM_000152.3:c.668G>A; NC_000017.10:g.78079669G>A
Exon Nonsynonymous rs1042395 64.56 60.24 32.76 93.2 Het. 727 255 45.1
GAA NP_000143.2:p.Val780Ile; NM_000152.3:c.2338G>A; NC_000017.10:g.78091405G>A
Exon splicing
Nonsynonymous rs1126690 72.27 71.19 26.68 94.2 Het. 1119 255 53.5
GFM1 NP_079272.4:p.Val215Ile; NM_024996.5:c.643G>A; NC_000003.11:g.158366900G>A
Exon Nonsynonymous rs2303909 58.33 40.16 79.01 Het. 1201 255 46.4
GLB1 NP_000395.2:p.Ser532Gly; NM_000404.2:c.1594A>G; NC_000003.11:g.33055688T>C
Exon Nonsynonymous rs73826339 5.57 3.49 5.17 15.06 Het. 772 255 49.1
GLB1 NP_000395.2:p.Cys521Arg; NM_000404.2:c.1561T>C; NC_000003.11:g.33055721A>G
Exon Nonsynonymous rs4302331 93.63 92.71 6.74 99.95 Hom. 643 255 100
GLB1 NP_000395.2:p.Pro10Leu; NM_000404.2:c.29C>T; NC_000003.11:g.33138549G>A
Exon Nonsynonymous rs7637099 47.24 43.19 47.4 88.24 Het. 1850 255 49
JPH2 NP_065166.2:p.Ala396Thr; NM_020433.4:c.1186G>A; NC_000020.10:g.42747247C>T
Exon Nonsynonymous rs3810510 22.82 27.04 19.71 31.18 Het. 547 255 51.2
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Gene Variant Function Exonic function
dbSNP dbSNP freq.
1000G MAF
5000G MAF
HiC freq.
AF1 DP Qual
Qual Freq. alt.
MYH6 NP_002462.2:p.Val1101Ala; NM_002471.3:c.3302T>C; NC_000014.8:g.23861811A>G
Exon Nonsynonymous rs365990 42.34 37.48 45.56 62.44 Het. 801 255 52.6
MYL3 NP_000249.1:p.Val156Leu; NM_000258.2:c.466G>T; NC_000003.11:g.46900980C>A
Exon Nonsynonymous rs199474707 0 Het. 1303 255 48.4
OBSL1 NP_056126.1:p.Arg1767Gln; NM_015311.2:c.5300G>A; NC_000002.11:g.220417266C>T
Exon splicing
Nonsynonymous rs59332477 41.86 42 65.65 Het. 890 255 48.7
OBSL1 NP_056126.1:p.Gln1578Arg; NM_015311.2:c.4733A>G; NC_000002.11:g.220419339T>C
Exon Nonsynonymous rs10932814 97.02 3.86 100 Hom. 998 255 100
OBSL1 NP_056126.1:p.Glu1365Asp; NM_015311.2:c.4095G>C; NC_000002.11:g.220421417C>G
Exon Nonsynonymous rs1983210 71.05 29.88 92.25 Het. 1480 255 48.7
OBSL1 NP_056126.1:p.Arg723Lys; NM_015311.2:c.2168G>A; NC_000002.11:g.220430203C>T
Exon Nonsynonymous rs1039898 37.87 17.18 98.42 Hom. 1479 255 99.9
TTN NP_003310.4:p.Gln24857His; NM_003319.4:c.74571G>C; NC_000002.11:g.179399576C>G
Exon Nonsynonymous rs55886356 0.61 0.46 0.78 3.75 Het. 2169 255 45
TTN NP_003310.4:p.Ile17160Thr; NM_003319.4:c.51479T>C; NC_000002.11:g.179432185A>G
Exon Nonsynonymous rs12463674 15.35 13 22.59 42.89 Het. 2478 255 46.3
TTN NP_003310.4:p.Ala13351Pro; NM_003319.4:c.40051G>C; NC_000002.11:g.179444768C>G
Exon Nonsynonymous rs4145333 99.47 99.46 0.44 99.55 Hom. 2189 255 99.9
TTN NP_001254479.2:p.Arg11096His; NM_001267550.2:c.33287G>A; NC_000002.11:g.179545859C>T
Exon Nonsynonymous rs36051007 17.9 12.6 22.64 43.08 Het. 1694 255 43.9
TTN NP_001254479.2:p.Gly10622Arg; NM_001267550.2:c.31864G>A; NC_000002.11:g.179554305C>T
Exon Nonsynonymous rs2244492 41.33 43.35 56.13 Het. 1849 255 47.9
TTN NP_003310.4:p.Ile3716Val; NM_003319.4:c.11146A>G; NC_000002.11:g.179605725T>C
Exon Nonsynonymous rs34070843 1.11 1.62 1.44 7.35 Het. 1946 255 43.8
TTN NP_596870.2:p.Arg4915His; NM_133379.4:c.14744G>A; NC_000002.11:g.179612383C>T
Exon Nonsynonymous rs72648907 1.46 4.24 10.04 Het. 2021 255 50.8
TTN NP_596870.2:p.Asp3747Gly; NM_133379.4:c.11240A>G; NC_000002.11:g.179615887T>C
Exon Nonsynonymous rs922984 80.17 73.3 18.19 97.65 Hom. 1923 255 99.8
TTN NP_596870.2:p.Leu3732Phe; NM_133379.4:c.11196G>C; NC_000002.11:g.179615931C>G
Exon Nonsynonymous rs922985 97.5 97.5 2.75 99.38 Hom. 2043 255 99.8
TTN NP_001254479.2:p.Gly3751Asp; NM_001267550.2:c.11252G>A; NC_000002.11:g.179620951C>T
Exon splicing
Nonsynonymous rs7585334 83.2 80.45 9.72 98.93 Hom. 1503 255 100
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Gene Variant Function Exonic function
dbSNP dbSNP freq.
1000G MAF
5000G MAF
HiC freq.
AF1 DP Qual
Qual Freq. alt.
TTN NP_001254479.2:p.Ala3576Thr; NM_001267550.2:c.10726G>A; NC_000002.11:g.179621477C>T
Exon Nonsynonymous rs6433728 99.97 99.9 0.08 99.95 Hom. 1302 255 100
TTN NP_003310.4:p.Ser3373Asn; NM_003319.4:c.10118G>A; NC_000002.11:g.179623758C>T
Exon Nonsynonymous rs2291310 87.38 80.89 9.76 98.65 Hom. 1766 255 100
TTN NP_003310.4:p.Val3215Met; NM_003319.4:c.9643G>A; NC_000002.11:g.179629461C>T
Exon Nonsynonymous rs2291311 86.72 80.49 10.35 98.91 Hom. 998 255 100
TTN NP_003310.4:p.Ser1249Leu; NM_003319.4:c.3746C>T; NC_000002.11:g.179644035G>A
Exon Nonsynonymous rs1552280 92.01 4.91 99.5 Hom. 1940 255 100
TTN NP_003310.4:p.Lys1155Glu; NM_003319.4:c.3463A>G; NC_000002.11:g.179644855T>C
Exon Nonsynonymous rs10497520 55.49 50.02 26.51 96.11 Hom. 1876 255 100
TTN NP_003310.4:p.Thr765Ile; NM_003319.4:c.2294C>T; NC_000002.11:g.179650408G>A
Exon Nonsynonymous rs35813871 10.04 18.97 43.58 Het. 1612 255 48.6
Function: location of the variant according to RefSeq annotation database: exonic, intronic, splicing, UTR. dbSNP: identification of the Single Nucleotide Polymorphism Database. dbSNP freq.: variant frequency taken from dbSNP (%). 1000G MAF: minor allele
frequency taken from the 1000 Genomes Project (%). 5000G MAF: minor allele frequency taken from the 5000 Genomes Project (%). HiC freq.: variant frequency taken from our HiC database (%). AF1: heterozygous, hemizygous or homozygous. DP Qual: depth of
coverage after filtering low quality bases or low quality alignments. Qual: quality of the variant reported by SAMtools (maximum value is 255 and means that the variant has a high probability of being different from homozygous wild type. Low values indicate that
it has a high probability of being homozygous for wild type and thus having a low probability of being a true variant). Freq. alt.: the frequency of alternative allele in high quality fragments (%). Only good quality variants were included (QUAL ≥170).
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List of probably non-disease causing intronic genetic variants in splicing zones
Gene Variant dbSNP dbSNP freq. 1000G MAF 5000G MAF HiC freq. AF1 DP Qual Qual Freq. alt.
AARS2 NM_020745.3:c.243+6G>A; NC_000006.11:g.44280812C>T rs167772 47.37 45.33 49.74 80.51 Het. 299 255 55.2
ACADVL NM_000018.3:c.1605+6T>C; NC_000017.10:g.7127718T>C rs17671352 52.88 51.98 43.83 87 Hom. 424 255 100
AGL NM_000642.2:c.2001+8T>C; NC_000001.10:g.100346741T>C rs3736296 54.22 55.85 49.58 75.89 Het. 1200 255 45.2
CALR3 NM_145046.4:c.397+10C>T; NC_000019.9:g.16601168G>A rs3810197 11.68 11.4 12.96 25.21 Het. 1256 170 52.2
CASQ2 NM_001232.3:c.420+6T>C; NC_000001.10:g.116283343A>G rs9428083 67.55 64.36 29.16 96.11 Hom. 1027 255 100
DLD NM_000108.4:c.439-7T>C; NC_000007.13:g.107545799T>C rs10263341 70.61 71.61 35.15 83.81 Het. 1173 255 46.8
GAA NM_000152.3:c.547-4C>G; NC_000017.10:g.78079544C>G rs3816256 44.95 60.28 32.73 93.29 Het. 809 255 41.3
GAA NM_000152.3:c.858+7_858+8insAGCGGGC; NC_000017.10:g.78081528_78081529insAGCGGGC rs3071247 59.29 92.36 Het. 785 255 47.6
GLB1 NM_000404.2:c.1233+8T>C; NC_000003.11:g.33063050A>G rs13093698 18.2 16.35 21.25 36.41 Het. 716 255 44.5
MAP2K1 NM_002755.3:c.1023-8C>T; NC_000015.9:g.66782048C>T rs41306345 8.2 8.93 9.18 18.56 Het. 1589 255 48.5
MTO1 NM_133645.2:c.938+7G>A; NC_000006.11:g.74189574G>A rs7766570 99.96 100 99.95 Hom. 1481 255 99.9
OBSL1 NM_015311.2:c.5309-4C>G; NC_000002.11:g.220416942G>C rs34490902 42.92 43.53 66.08 Het. 1146 255 46.2
RYR2 NM_001035.2:c.3599-9delT; NC_000001.10:g.237753084delT rs371111802 28.51 50.18 Het. 1094 223 50.9
RYR2 NM_001035.2:c.13783-6A>G; NC_000001.10:g.237957161A>G rs790901 71.93 75.76 34.86 86.62 Hom. 1155 255 100
RYR2 NM_001035.2:c.14091-11_14091-10insT; NC_000001.10:g.237965145_237965146insT rs35563566 50 37.8 39.05 Hom. 594 233 82.7
SLC22A5 NM_003060.3:c.652+6A>G; NC_000005.9:g.131719999A>G rs4551059 100 100 99.95 Hom. 1076 255 100
TNNI3 NM_000363.4:c.373-10T>G; NC_000019.9:g.55665584A>C rs7252610 100 100 99.95 Hom. 367 255 99.5
TNNI3 NM_000363.4:c.25-8T>A; NC_000019.9:g.55668509A>T rs3729836 42.6 45.81 31.62 43.51 Het. 768 255 46.3
TNNT2 NM_001001430.2:c.53-11_53-7delCTTCT; NC_000001.10:g.201341181_201341185delAGAAG rs45533739 53.11 52.04 81.66 Hom. 1062 255 100
TTN NM_003319.4:c.4342+6C>T; NC_000002.11:g.179642425G>A rs719201 91.59 91.15 5.35 99.69 Hom. 1499 255 99.9 dbSNP: identification of the Single Nucleotide Polymorphism Database. dbSNP freq.: variant frequency taken from dbSNP (%). 1000G MAF: minor allele frequency taken from the 1000 Genomes Project (%). 5000G MAF: minor allele frequency taken from the 5000
Genomes Project (%). HiC freq.: variant frequency taken from our HiC database (%). AF1: heterozygous, hemizygous or homozygous. DP Qual: depth of coverage after filtering low quality bases or low quality alignments. Qual: quality of the variant reported by
SAMtools (maximum value is 255 and means that the variant has a high probability of being different from homozygous wild type. Low values indicate that it has a high probability of being homozygous for wild type and thus having a low probability of being a
true variant). Freq. alt.: the frequency of alternative allele in high quality fragments (%). Only good quality variants were included (QUAL ≥170
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APPENDIX 3
Detailed technical aspects
CardioGxOne was performed using a multiple approach based on targeted Next Generation Sequencing (NGS) combined
with the gold standard Sanger technique. Patient specimens (blood, saliva, tissue) were subjected to automated genomic
DNA purification (QIAsymphony SP®, Qiagen), and sample preparation was carried out using the Agilent SureSelectXT
Target Enrichment technology for Illumina paired-end multiplexed sequencing method. Enrichment was performed using
a custom SureSelect library (Agilent) for the coding regions and adjacent intronic areas for the selected genes. After cluster
generation on a cBot (Illumina), captured DNA was sequenced on either Illumina HiSeq 1500, MiSeq, or the NextSeq
platform. Clinically relevant variants and low-coverage regions were tested in parallel by standard Sanger sequencing. The
analytical sensitivity and accuracy of this assay are greater than 99% for single nucleotide variants (SNVs) and small
insertions/deletions (INDELs).
CardioGxOne was developed and assessed for accuracy and precision by Admera Health. The design of the custom capture
library is property of Health in Code and includes the following 90 genes related to hypertrophic cardiomyopathy:
AARS2, ACAD9, ACADVL, ACTA1, ACTC1, ACTN2, AGK, AGL, AGPAT2, ANK2, ANKRD1, ATPAF2, BAG3, BRAF, BSCL2, CALR3,
CASQ2, CAV3, COQ2, COX15, COX6B1, CRYAB, CSRP3, CTF1, DES, DLD, FAH, FHL1, FHL2, FHOD3, FLNC, GAA, GFM1, GLA,
GLB1, GNPTAB, GUSB, HRAS, JPH2, KCNJ8, KLF10, KRAS, LAMP2, LDB3, LIAS, LMNA, MAP2K1, MAP2K2, MLYCD, MRPL3,
MRPS22, MTO1, MURC, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEXN, NRAS, OBSL1, PDHA1, PDLIM3,
PHKA1, PLN, PMM2, PRKAG2, PTPN11, RAF1, RYR2, SHOC2, SLC22A5, SLC25A4, SOS1, SURF1, TAZ, TCAP, TMEM70, TNNC1,
TNNI3, TNNT2, TPM1, TRIM63, TSFM, TTN, TTR, VCL.
The genes included in this test have been selected on a clinical basis according to their relation with a particular phenotype
and classified taking in consideration the level of evidence of this relation (priority genes, secondary genes, candidate
genes).
Probes were designed to cover all coding exons and 30 bp at intronic or UTR flanking regions. Those regions with suboptimal
quality coverage were sequenced by dideoxy Sanger technique. This test is not able to identify genetic variants located at
deep intronic/UTR regions.
CardioGxOne is aimed at identifying single nucleotide variants (SNVs) and small insertions/deletions (INDELs) up to 20 bp.
Genetic variants are described following the Human Genome Variation Society (HGVS) recommendations (www.hgvs.org).
Those selected genetic variants that were considered potentially associated with the patient’s phenotype or constitute
relevant incidental findings are reported in the main table of the report on the first page. Please note that clinical
interpretation of variants could be subject to changes as new scientific evidence appears.
Confirmation by dideoxy Sanger sequencing will be performed in those selected variants included in the main table that
meet the following conditions:
▪ Point mutations identified with suboptimal quality parameters: coverage \<30x, alternative allele frequency
different from 40%-60% / 80%-100%, or quality score \<170
▪ Point mutations affecting regions/genes with high homology with other genomic regions (i.e., pseudogenes)
▪ Insertions or deletions
We have also developed an alternative bioinformatics pipeline that is able to identify gross deletions/insertions affecting
one or more exons of a gene/s included in the panel (CNVs: Copy Number Variations). This complementary analysis is
possible when bioinformatics data is adequate and might not be available in some cases. An alternative method is used to
confirm this kind of variants.
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Page 36
Frequently, our test is not able to identify the phase (same/different alleles) of more than one variant affecting the same
gene. This limitation should be considered in cases of recessive disorders that need both alleles of the gene to be mutated.
Although CardioGxOne has an analytical sensitivity and specificity of over 99%, some genotyping errors could occur in
specific situations:
▪ Pre-arrival contamination of samples
▪ Mosaic mutations
▪ Monosomies and trisomies
▪ Genetic paternity problems
▪ Genetic variants producing allelic drop-outs
▪ Studies performed on paraffin-embedded tissues
▪ Presence of pseudogenes
▪ Incorrect identification of variants in homo-polymers or high GC-content zones
▪ Errors in the reference sequence
We have developed an efficient method that ensures tracking of samples after arrival, guaranteeing their proper
identification once they arrive at our laboratory. However, we cannot take responsibility for labeling errors in samples prior
to their arrival.
The clinical report: Admera, powered by Health in Code, provides a detailed report with all relevant existing clinical data
on the detected mutations. This information has been evaluated by experts on the disease and includes a description of all
families with reported cases of each mutation along with information from our own research and existing information on
in vitro and in vivo (animal models) studies for the different mutations. To handle all this information, Health in Code has
developed a computerized database that includes records of more than 106,500 individuals from the existing literature on
inherited cardiovascular diseases and from our own research.
Comments, recommendations and disclaimers
It is highly recommended that the interpretation of this genetic report is done with the help/counseling from a physician
with enough expertise in genetic conditions. Our test is not designed in a direct-to-consumer fashion. The results of this
test must be interpreted in the clinical context of each patient. This test does not replace clinical assessment of patients
and must not to be used as the only tool to decide on treatment, diagnosis, and/or pre-implantation/pre-natal studies.
When the genetic study identifies one or more genetic variants potentially associated with the development of pathology,
family screening is recommended. All first-degree relatives (parents, siblings, children; whether or not clinically affected)
should be considered for inclusion in this screening due to variable penetrance and age of onset associated with the
majority of these genetic alterations. Genetic diagnosis can identify those family members who are at risk of disease
development and need periodical clinical assessment. Moreover, testing in family members can be useful in determining
the cosegregation of the identified variants with the phenotype and the associated prognosis in carriers.
This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA), but the FDA has determined
that such clearance or approval is not necessary. The CardioGxOne test is used for clinical purposes. It should not be
regarded as investigational or for research. This laboratory is certified under the Clinical Laboratory Improvement
Amendments (CLIA) as qualified to perform high complexity clinical laboratory testing. Health in Code provided the
professional component of clinical interpretation of the CardioGxOne results.
For additional information or comments, please contact us at [email protected].
Admera Health, LLC • CLIA ID 31D2038676 126 Corporate Boulevard • South Plainfield, NJ 07080 1-908-222-0533 • [email protected] • http://www.admerahealth.com
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Resource references
Population databases:
▪ Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [version 0.3.1].
▪ Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL:
http://evs.gs.washington.edu/EVS/) [ESP6500SI-V2-SSA137].
▪ 1000 Genomes Project, An integrated map of genetic variation from 1,092 human genomes, McVean et al., Nature
491, 56–65 (01 November 2012) doi:10.1038/nature11632 (www.1000genomes.org/).
▪ Database of Single Nucleotide Polymorphisms (dbSNP) [Internet]. Bethesda (MD): National Center for
Biotechnology Information, National Library of Medicine (dbSNP Build ID:135) Available from:
www.ncbi.nlm.nih.gov/SNP.
▪ HGMD® [Internet]: Stenson PD et al. Genome Med. 2009;1(1):13 www.hgmd.cf.ac.uk.
▪ ClinVar: Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of
relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan 1;42(1):D980-5. doi:
10.1093/nar/gkt1113. PubMed PMID: 24234437.
▪ Health in Code proprietary database.
Functional studies:
▪ POLYPHEN: A method and server for predicting damaging missense mutations. Adzhubei IA, Schmidt S, Peshkin L,
Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. Nat Methods. 2010 Apr;7(4):248-9.
▪ SIFT: Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Kumar
P, Henikoff S, Ng PC. Nat Protoc. 2009;4(7):1073-81.
▪ MUTATION TASTER: MutationTaster2: mutation prediction for the deep-sequencing age. Schwarz JM, Cooper DN,
Schuelke M, Seelow D. Nat Methods. 2014 Apr;11(4):361-2.
▪ NNSplice: Eeckman, FH, Kulp, D, Haussler, D, 1997. Improved Splice Site Detection in Genie. J Comp Biol 4(3), 311-
23.
▪ HSFHuman Splicing Finder: FO Desmet, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human
Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acid Research, 2009.
▪ MaxEntScan: Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA
splicing signals. J Comput Biol. 2004;11(2-3):377-94.
Admera Health, LLC • CLIA ID 31D2038676 126 Corporate Boulevard • South Plainfield, NJ 07080 1-908-222-0533 • [email protected] • http://www.admerahealth.com
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0
500
1000
1500
AA
RS2
AC
AD
9
AC
AD
VL
AC
TA1
AC
TC1
AC
TN2
AG
K
AG
L
AG
PA
T2
AN
K2
AN
KR
D1
ATP
AF2
BA
G3
BR
AF
BSC
L2
CA
LR3
CA
SQ2
CA
V3
CO
Q2
CO
X1
5
CO
X6
B1
CR
YAB
CSR
P3
CTF
1
DES
DLD
FAH
FHL1
FHL2
FHO
D3
FLN
C
GA
A
GFM
1
GLA
GLB
1
GN
PTA
B
GU
SB
HR
AS
JPH
2
KC
NJ8
KLF
10
KR
AS
LAM
P2
LDB
3
LIA
S
Average coverage per gene
Coverage 15 x
0
500
1000
1500
LMN
A
MA
P2
K1
MA
P2
K2
MLY
CD
MR
PL3
MR
PS2
2
MTO
1
MU
RC
MYB
PC
3
MYH
6
MYH
7
MYL
2
MYL
3
MYL
K2
MYO
Z2
MYP
N
NEX
N
NR
AS
OB
SL1
PD
HA
1
PD
LIM
3
PH
KA
1
PLN
PM
M2
PR
KA
G2
PTP
N1
1
RA
F1
RYR
2
SHO
C2
SLC
22
A5
SLC
25
A4
SOS1
SUR
F1
TAZ
TCA
P
TMEM
70
TNN
C1
TNN
I3
TNN
T2
TPM
1
TRIM
63
TSFM TT
N
TTR
VC
L
Coverage 15 x
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Page 39
Coverage stats
Stats Studied genes Priority genes
Average coverage 1526 x 1158 x
Bases sequenced 327540 36293
% Bp with coverage ≥15 100% 100%
% Bp with coverage ≥30 100% 100%