Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C) 3

Follow-up

Outcome measures and effect size

Comments

Follow-up for child relatives

Norrish, 2019

Type of study:

Retrospective cohort study

Country: UK

Funding and conflicts of interest:

(Partly) funded by the British Heart Foundatio, Max’s Foundation, Great Ormond Street Hospital Children’s Charity and the National Institute for Health Research Great Ormond Street Hospital

Biomedical Research Centre.

Drs Norrish and Kaski are supported by the British Heart Foundation. The other authors report no conflicts.

Inclusion criteria:

Children ≤18 years referred for family screening (1994-2017) after diagnosis of

HCM in a first-degree relative.

Exclusion criteria: children referred for investigation of symptoms, with a previous diagnosis of HCM, or with a family history of

nonsarcomeric HCM.

N total at baseline:

1198

age ± SD:

7.9 ± 4.7 years

Detailed clinical evaluation at baseline and

during follow-up (12–24 months during preadolescent years

and 6–12 months during adolescent years)

Echocardiographic measurements were made according to current guidelines

No control

Length of follow-up:

until patients were

transitioned to adult services (at 18 years of age) or the end of the study period.

median, 3.5 years; interquartile

range, 1.2–7

Loss-to-follow-up:

-

Genetic testing: 131/1198 (10,9%)

Pathogenic variant identified: 99/131 (75,6%)

Diagnosis of childhood HCM: 57/1198 (4.8%)

Age at diagnosis:

Median: 10 years (IQR 4-13)

<1 year: 6/57 (11%)

1-6 years: 15/57 (26%)

7-12 years: 20/57 (35%)

>12 years: 16/57 (28%)

Diagnosed at baseline:

32/57 (56%)

Diagnosed during follow-up: 25/57 (44%)

> 14/25 (56%) had abnormalities on a resting 12-lead ECG at baseline

> 3/25 (12%) had nondiagnostic

echocardiographic abnormalities (impaired diastolic function, incomplete systolic motion of the mitral

valve) at baseline.

Age at diagnosis

Diagnosed at baseline: median 6 years (IQR, 1–11.5)

Diagnosed during FU: median 12 years (IQR, 9–14)

P=0.02

Interventions

Medication: 18/57 (32%)

ICD: 14/57 (25%) (2 secondary indication)

Myectomy: 2/57 (3,5%)

ECG study: 4/57 (7%)

One patient progressed to end-stage HCM necessitating cardiac transplantation at 15 years of age.

Mortality

1/57 (1,8%)

> cerebrovascular accident at

24 years.

Morbidity

2/57 had resuscitated cardiac arrest (at 14 and 25 years)

1/57 had inappropriate ICD because of lead fracture

1/57 had infective endocarditis with ICD lead vegetations

2/57 had ICD lead replacement as a result of somatic growth.

Patients with a childhood diagnosis were more likely to have a family history of childhood HCM (32/57, 56%) compared to patients with no diagnosis (257/1141, 23%); P<0.001).

Lafreniere-Roula, 2019

Type of study:

Retrospective cohort study

Country:

Canada

Funding and conflicts of interest:

This work was supported by the Ted Rogers Centre for Heart Research

and the Heart and Stroke Foundation Chair funds (to S.M.).

No conflicts of interest were declared.

Inclusion criteria:

children who

underwent echocardiography prior to 18 years of age as part of family screening for primary HCM between 2000 and 2018.

Exclusion criteria:

Hypertrophic cardiomyopathy probands and families with secondary

HCM e.g. syndromic, neuromuscular, metabolic, or mitochondrial disease

N total at baseline:

524

age:

7.7 (3.7–12.0)

Relationship with proband:

First degree: 468 (89.7%)

Second degree: 47 (9.0%)

Third or fourth degree: 7 (1.3%)

Family Screening:

a clinic visit, electrocardiogram (ECG), echocardiogram, and

genetic counselling for the purpose of cascade genetic testing.

Length of follow-up:

Mean 3.2 year (range 0.0–6.4)

Loss-to-follow-up:

-

Genetic testing: 120/524 (22,9%)

Variant identified:

No: 28/120 (23.3%)

Pathogenic: 86/120 (71.7%)

VUS: 6/120 (5.0%)

Diagnosis of HCM: 80/524 (15,3%)

Age at diagnosis:

Median: 8.9 (4.7–13.4)

<10 yr: 42/80 (52.5%)

Diagnosed at baseline: 52/80 (65%)

Diagnosed during follow-up: 28/80 (35%)

Interventions:

ICD: 7/80 (8,75%) (all primary indication)

Myectomy: 5/80 (6,25%)

Heart transplant: 0

Mortality

3/80 (3,75%)

Morbidity

2/80 aborted sudden cardiac death

On multivariable Cox regression, male gender, family history of SCD/ICD, and P/LP variant in MYH7 or MYBPC3 in the child or family were associated with early onset HCM.

Family history of SCD prior to

25 years of age, symptoms at screening and presence of a P/LP MYH7 or MYBPC3 variant were associated with early occurrence of a Major Cardiac Event.

Vermeer, 2017

Type of study:

Prospective cohort study

Country:

The Netherlands

Funding and conflicts of interest:

NR

A.W. is member of the scientific advisory board of LilaNova. The other authors declare no conflicts of

interest.

Inclusion criteria:

All predictively tested children (<18 years of age at the time DNA diagnostics was performed) referred to our cardiogenetics outpatient clinic from 2001 until January 2016, with a putative pathogenic mutation.

Exclusion criteria:

Children with >1 putative pathogenic mutation (tested because of multiple mutations in the family; n = 3) or an additional (hereditary) cardiovascular disease were excluded.

N total at baseline:

119

age ± SD:

12.1 ± 3.4

Mutation:

MYBPC3: 95/119 (79.8%)

MYH7: 14/119 (11.8%)

TNNT2: 10/119 (8.4%)

After the genetic diagnosis, all children were advised to regularly undergo cardiac

evaluation, including at least an electrocardiogram and

echocardiogram.

-

Length of follow-up:

Mean 6.9 ± 3.8 years

Loss-to-follow-up:

24/119 (20,2%) had only 1 clinical evaluation. There were no differences between these and other children.

Diagnosis of HCM:

8/119 (6,7%)

Diagnosed at baseline: 5/119 (4,5%)

Mean age: 12.1 ± 1.7 years

Diagnosed during follow-up: 3/119 (2,5%)

Age: 16.3, 25.7, and 30.4 yr

Family history:

Positive: 14/119 (11,8%)

Positive in HCM pt: 1/5 (20%)

Interventions:

ICD: 1 (primary indication: extreme LVH)

Myectomy: 0

Heart transplant: 0

Mortality

0

Morbidity

aborted sudden cardiac death: 1

All positively tested children, so not necessarily first degree relatives.?

Jensen, 2013

Type of study:

Prospective cohort study

Country:

Denmark

Funding and conflicts of interest:

This study was supported by the Lundbeck foundation, Dagmar Marshalls Fond, the Heart Center’s Research

Council, and the A.P. Møller Foundation for the Advancement of

Medical Science.

No disclosures.

Inclusion criteria:

Probands and relatives <18 year who were included in the family screening program at the Unit for Inherited Heart Heart Diseases of the Heart Center (National University Hospital, Rigshospitalet, Copenhagen) from 1994 to 2001

Exclusion criteria:

-

N total at baseline:

4 probands and 66 relatives (from 26 families)

age ± SD:

11 ± 5 years (only relatives)

The first step in the screening process was clinical examination,

including ECG recording and echocardiography in probands and relatives.

The second step was genetic testing of the probands.

If a disease-causing gene mutation was identified in the proband, a selective genetic test for the identified mutation was offered to first-degree relatives. Relatives carrying a gene mutation and first-degree relatives from families without an identified gene mutation

were referred for routine follow-up after the initial screening process.

Noncarriers were reassured, and no further clinical follow-up was

offered.

The follow-up assessment included clinical, ECG, and echocardiographic evaluations, as well as questionnaire assessments of the longterm psychological impact of participation in the family screening program

-

Length of follow-up: 12 ± 1 years

Loss-to-follow-up:

-

In 15/26 families (58%), a

disease-causing sarcomere gene mutation was identified in the proband. Genetic testing was performed in 40/45 (89%) of their child relatives. 12/40 (30%) were gene positive. Resulting in 12 G+ and 26 G? being offered routine follow-up.

Diagnosis of HCM at inclusion:

2/38 (5%) (both children were from G+ families, but had not been tested themselves)

Diagnosis of HCM during FU:

 2/36 (6%) (both children were G+), one at age of 26 and one at age of 28.

1/2 (50%) children with HCM at inclusion did not fulfill the

diagnostic criteria for HCM at follow-up

Morbidity and mortality:
0

Psychological burden

G+ and G? relatives and healthy controls did not differ in anxiety, depression, type D

personality, or overall psychological impact of participation in the family screening program

Jensen, 2015

Same study population as Jensen, 2013

Type of study:

Prospective cohort study

Country:

Denmark

Funding and conflicts of interest:

This study was supported by the Lundbeck

foundation, Dagmar Marshalls Fond and The A.P. Møller Foundation for the Advancement of Medical

Science.

No conflicts of interest.

Inclusion criteria:

Children (<18 yr) included tot the family screening program as relatives to HCM patients.

Exclusion criteria:

-

N total at baseline:

66 (26 families)

age ± SD:

11 ± 5 years

The child relatives were

followed with routine clinical and echocardiography evaluation

Length of follow-up:

 12 ± 1 years

Loss-to-follow-up:

-

Gene positive:

12/38 (31,6%)

Diagnosed with HCM:

Gene +: 2/12 (16,7%) (both diagnosed during follow-up)

Gene ?: 1/26 (3,8%) (diagnosed at inclusion)

Relationship to proband not reported.

At inclusion there were no differences in echocardiographic chamber

dimensions, systolic or diastolic function between gen +, gen ? and gen – children.

During follow-up, carriers

(n = 8) developed lower left ventricular end-diastolic

dimension (LVEDd) compared to non-carriers (n = 23) (41 ± 4 versus. 46 ± 4 mm; p = 0.04) and a higher ratio of

early left ventricular filling velocity and early diastolic velocity of lateral mitral annulus (E/e’ 6 ± 1 versus. 5 ± 1;

p = 0.003).

No significant differences in LVEDd or E/e’ were found between relatives with unknown genetic status

and non-carriers.

Follow-up for child and adult relatives

Van Velzen, 2018

Type of study:

Retrospective cohort study

Country:

The Netherlands

Funding and conflicts of interest:

NR. No disclosures

Inclusion criteria:

Relatives (children and adults) from

unrelated probands with HCM who visited the cardiogenetic outpatient clinic of the Erasmus Medical Center for

screening purposes between 1985 and 2016. (results only for G + or G?)

Exclusion criteria:

Relatives who presented symptomatically and families

with HCM caused by Anderson-Fabry disease, Danon disease,

Noonan syndrome, or amyloidosis.

N total at baseline:

777

N undergoing genetic testing: 620 (80%)

N Gen -: 356 (57%)

N Gen ? or + and therefore undergoing cardiac evaluation: 421

age ± SD (of those undergoing follow-up):

 37 ± 18

Relationship te proband:

First degree: 334/421 (79%)

Second/third degree: 87/421 (21%)

Genetic counseling and testing was offered.

Cardiac evaluation included medical history, clinical examination, electrocardiography, and echocardiography.

Length of follow-up:

Follow-up data were obtained in July 2017.

Loss-to-follow-up:

Data were available

in 99% of cases and retrieved from the civil service

register, medical charts and GP.

Diagnosis of HCM at first evaluation: 126/421 (30%)

HCM was diagnosed in 98/264 (37%) of G+ and 28/157 (17%) without GT.

Age at HCM diagnosis

Mean: 44±16 (range, 1–75)

<12: 6/41 (15%)

Tm 18: 7/42 (17%)

Among G+ relatives, the HCM prevalence was higher

in nonfounder MYBPC3 mutation carriers than in Dutch founder MYBPC3 mutation carriers (49% versus 35%; P=0.04)

Predictors of HCM

Multivariate analysis demonstrates that G+

status (adjusted odds ratio, 4.23; 95% CI, 2.88–5.58;

P<0.001), male sex (adjusted odds ratio, 2.13; 95% CI,

1.51–2.76; P=0.02), proband age at diagnosis (adjusted

odds ratio, 0.98; 95% CI, 0.96–0.99; P=0.02), and age

at time of screening (adjusted odds ratio, 1.04; 95%

CI, 1.02–1.06; P<0.001) were independent predictors

of HCM diagnosis.

Outcomes for patient with HCM at baseline:

Relatives with HCM at baseline were followed for a median of 9 (IQR, 6–12) years.

Interventions:

ICD: 18/126 (14%) (12 primary indication)

Appropriate ICD shock: 1 (1%)

Cardiac transplant: 3/126 (2%)

Septal reduction therapy: 8/126 (6%)

Mortality

13/126 (10%) --> 7 by cardiac mortality

Morbidity

2/126 (2%) aborted sudden cardiac death

Outcomes for patient without HCM at baseline:

Relatives with HCM at baseline were followed for a median of 8 (IQR, 3–11) years.

Interventions:

ICD: 5/294 (2%) (all primary indication)

Appropriate ICD shock: 0

Cardiac transplant: 0

Septal reduction therapy: 0

Mortality

4/294 (1%) --> 1 by cardiac mortality

Morbidity

0

0 patients without HCM and without GT had any adverse outcomes

Not all relatives were first-degree

Fragola, 1993

Type of study:

Prospective cohort study

Country:

Italy

Funding and conflicts of interest:

NR

Inclusion criteria:

Relatives of unrelated patient with HCM

Exclusion criteria:

Death or disagree to participate

N total at baseline:

122 (14 second degree)

age ± SD:

34 ± 19 (range 1-77)

Relation to proband

First degree: 106/122 (86,9%)

Second degree: 14/122 (13,1%)

Long-term follow-up evaluation including physical evaluation, 12-lead ECG and M mode and 2-dimensional echocardiogram

Length of follow-up:

Mean 4,3 yr (range 2-7 yr)

Loss-to-follow-up:

6/122 subjects were found to have essential hypertension and were therefore excluded from consideration.

Only 44/122 relatives were re-examined at follow-up

Diagnosis of HCM at baseline:

12/116 HCM (all had ECG abnormalities)

14/116 probable HCM (7 had ECG abnormalities)

90/116 no HCM (20 had ECG abnormalities)

Diagnosis of HCM at follow-up:

2/44 HCM

1/44 probable HCM

All had (minor) abnormalities at ECG at baseline

Gray, 2011

Type of study:

Country:

Australia

Funding and conflicts of interest:

JI is the recipient of a University of Sydney Postgraduate Award,

and CS is the recipient of a National Health and Medical Research

Council (NHMRC) Practitioner Fellowship. The authors of this manuscript have certified that they comply with the Principles of Ethical

Publishing in the International Journal of Cardiology

Inclusion criteria:

Individuals who tested positive for a pathogenic gene mutation and without any evidence of hypertrophy on 2D echocardiography (i.e. G+P−) at their

first visit

Exclusion criteria:

-

N total at baseline:

32

age ± SD:

23±15 years (50% >18 yr)

Mutation

MYBPC3: 20 (63%)

MYH7: 6 (19%)

TNNI3: 4 (13%)

ACTN2: 2 (6%)

Data were recorded at first visit and patients were followed for a minimum of 12 months, either in the HCM Clinic, or by their referring cardiologist.

-

Length of follow-up:

Mean 4.1±2.8 years

Loss-to-follow-up:

-

Diagnosis of HCM:

1/32 (3,1%) (diagnosed during follow-up)

Age at diagnosis: 16 yr

Interventions:

ICD: 1 (primary indication)

Mortality

0

Morbidity

0

Relationship to proband not reported.

McTaggart, 2017

Type of study:

Prospective cohort study

Country:

Australia

Funding and conflicts of interest:

Funded by the Clifford Craig Medical

Research Trust.

No disclosures

Inclusion criteria:

Clinically unaffected mutation carriers (children and adults)

Exclusion criteria:

-

N total at baseline:

15 (3 families)

age (range):

 1-49

all participants underwent clinical examinations, electrocardiography and echocardiography. In addition, magnetic resonance imaging (MRI) studies were performed on 11 participants.

-

Length of follow-up:

Mean 18.4 years (range 10-20 years)

Loss-to-follow-up:

12/15 participated in repeat clinical screening during 2014. 2/15 provided clinical data at 10 years (in 2004) and 13

years (in 2007) after diagnosis, but were not available for

clinical screening in 2014; 1/15 was lost to follow-up

3/14 (21%) developed clinical features of HCM.

All were adults at time of inclusion.

All were identified by MRI (2 positive, 1 borderline) and only 1 also by echocardiography.

Relationship to proband not reported.

Maron, 2001

Type of study:

Prospective cohort study

Country:

VS

Funding and conflicts of interest:

This study was supported by

grants from the National Institutes of Health and Howard Hughes Medical

Foundation (to Drs. J.G. Seidman and Christine E. Seidman) and from the Paul G.

Allen Foundation (to Dr. Maron).

Inclusion criteria:

Closely related relatives (children and adults) of each proband from the Minneapolis Heart Institute genotyped to have

mutations in the MyBPC gene.

Exclusion criteria:

Died before investigation (n=28, 14 (50%) because of HCM

N total at baseline:

119 (7 families)

Cardiovascular examination before genotyping, including 12-lead electrocardiography and two-dimensional

echocardiography with Doppler imaging.

Serial echocardiograms in genetically affected family members with normal LV wall thicksness at initial cardiogram.

-

Length of follow-up:

3-6 yrs

Loss-to-follow-up:

7/12 who met agree for FU did not agree to have serial echocardiograms

MyBPC mutations positive:

61/119 (51%)

HCM at initial echocardiogram:

40/61 (66%)

Adults: 36/48 (75%)

Children: 4/13 (31%)

Identification of the

HCM phenotype increased with age and ranged from 31% (<20 yr) to 83% (>50 yr)

Outcomes of G+/F- relatives

In 5/12 (42%) G+/F- adults one or more ECG alterations were evident at baseline.

In 3/5 (60%) G+/F- adults with serial echocardiograms available, substantial increases in wall thickness of 6 to 7 mm were found

Closely related relatives not further specified

Tomasov, 2014

Type of study:

Country:

Czech Republic

Funding and conflicts of interest:

Supported by the project for conceptual development of research

organization (Ministry of Health, Czech Republic),

grants from the Internal Grant Agency,

Ministry of Health, Czech Republic and

from the Third Faculty of Medicine, Charles University in Prague,

Czech Republic.

COI NR

Inclusion criteria:

unrelated HCM patients of Caucasian origin examined

at our institutions between the dates September 2006 –

December 2007.

Exclusion criteria:

N total at baseline:

Relatives of 99 HCM patients

Genetic testing was performed in 52 relatives and cardial examination in 20 relatives.

age ± SD:

Not reported (children and adults)

In families with positive results of genetic testing, we suggested all the first-degree relatives to undergo genetic testing (apart from the usual clinical examination) as well.

Cardial examination included ECG and echocardiography

Length of follow-up:

No follow-up

Loss-to-follow-up:

-

Positive gene result of first-degree relatives of G+ probands:

18/52 (35%)

Phenotypic features of HCM on echocardiographic examination: 3/20 (15%) (all were G+. = 30% of G+ relatives)

Clinical parameters during follow-up were not significantly different between G+ and G- relatives (those with phenotypic features of HCM were excluded!), with the exception of the combined echocardiographic score proposed by Gandjbakhch et al.(2015): genotype positive versus. genotype negative 3.316 versus.

‑0.489, P = 0.01

Genetic testing of

one HCM proband allowed us to omit 2.45 (2 yr FU) – 5.15(5 yr FU) future cardiologic examinations of the relatives.

Valente, 2013

Type of study:

Retrospective cohort study

Country:

VS

Funding and conflicts of interest:

This work was supported by the National Heart, Lung, and Blood Institute at the National

Institutes of Health

No disclosures

Inclusion criteria:

subjects participating in ongoing research studies and

from patients receiving clinical care at Brigham and Women's Hospital and Boston Children's Hospital between 2006 and 2011. Inclusion criteria:

(1) confirmed to carry their family's pathogenic or likely pathogenic HCM-associated sarcomere

(2) did not have echocardiographic evidence of hypertrophy;

(3) had a CMR performed within 6 months of echo.

Exclusion criteria:

N total at baseline:

40 (27 families)

age ± SD:

21.7 ± 11.1 (range 5-40)

Echo, CMR, and

standard 12-lead ECGs were available on all participants. These studies were performed

either during participation in research studies or in the course of clinical family screening of

at-risk relatives.

In 85% echo and CMR were on the same day. Of 6 subjects who did not have both studies performed on the same day, the interval between studies

ranged from 1 to 174 days (median interval, 24.5 days), with the echo occurring first.

-

Length of follow-up:

Median 35 months (range 24,5 – 61,5)

Loss-to-follow-up:

10/40 (25%).

> 7 subjects completed baseline studies within the final year of the study period, and longitudinal evaluation is planned;

> 3 subjects declined further study.

ECHO

Diagnosis of HCM

No subjects had clinical features of HCM on echo

Quality

median overall echo

image quality score was 2 (good), and 4/40 (10%) had an overall image quality score of poor).

CMR

Diagnosis of HCM

3/40 (7.5%) mild, focal hypertrophy (measuring 13.1–13.9 mm)

1/40 (1,5%) borderline

LVH (MWT=12.6 mm).

Quality

The median overall CMR image quality score was 1 (excellent), and only 1/40 (2%) had

poor overall CMR image quality.

Diagnostic agreement

90%

Echo and CMR were performed on the same day for the 4 subjects with discordant echo and CMR findings. Mean difference of maximal LV wall thickness was 1.9±1.2 mm (range, 0.7–3.5 mm).

For 3/4 subjects with discordant findings, longitudinal FU was available. 1 showed clear progression to overt HCM. The other 2 did not demonstrate substantial change in LV wall thickness during 5 and 4 years of follow-up, respectively.

1/27 subjects with no clinical features of HCM at baseline eveloped overt HCM during a 2-year period.

Relationship to proband not reported.

Nannenberg, 2011

Type of study:

Retrospective cohort study

Country:

The Netherlands

Funding and conflicts of interest:

This study was supported by grants from the Interuniversity Cardiological Institute of the Netherlands, Zorg Onderzoek

Nederland Medische Wetenschappen (ZON-MW), and the Dutch Heart

Foundation.

Dr. Wilde is a member of the advisory board of PGxHealth LLC. All other authors have reported that they have no relationships

relevant to the contents of this paper to disclose

Inclusion criteria:

1) multigenerational pedigrees: Unrelated consecutive HCM patients (probands) with a truncating MYBPC3 mutation who were evaluated in the cardiogenetics/cardiovascular outpatient clinics in the University Hospitals in Amsterdam and Rotterdam between 1996 and 2009.

> Maternal and paternal ancestors of the

probands were traced throughout as many generations as possible and all first-degree relatives (50% carriers) of these persons were traced and data was collected.

2) small pedigrees: all first-degree relatives of 140 probands

referred to our University Hospitals.

Exclusion criteria:

Multigenerational pedigrees: probands, first-degree relatives of these probands, persons because of missing date of birth or

death, and persons who died before the age of 1 year

Small pedigrees: probands and relatives who died in

the first year

N total at baseline:

160 persons (92 males, 68 females) of 6 large

Pedigrees

958 (508

males, 450 females) persons of 140 small pedigrees

-

-

Length of follow-up:

-

Loss-to-follow-up:

-

Overall mortality (SMR (95% CI)):

Large pedigrees:

0.86 (0.72 - 1.03)

> 10 - 19 yr: 2.7 (1.2 - 5.2) (between the periods 1804 to 1904 and 1904 to 2002, the SMR for 10 – 19 yr was similar)

Small pedigree:

1.5 (95% CI 1.3 - 1.6)

10 - 19 years 2.5 (95% CI: 1.002 to 5.1))

20 - 29 years (2.9 (95% CI: 1.5 to 5.1))

30 - 39 years (3.8 (95% CI: 2.4 to 5.6))

50 - 59 years (1.9 (95% CI: 1.4 to 2.5))

Prognostic factors of mortality

Type of mutation

probability of carrying the c.2373dup mutation in the small families did not show differences in survival from carriers of other truncating MYBPC3 mutations

Gender

Females at risk of a MYBPC3 mutation had a better survival than males (log-rank test, p =0.001) (HR: 2.0 (95% CI: 1.5 to 2.6; p

Cause of death

cause of death in a subsample of small pedigrees <40 yr:

13/22 (59%) died because of SCD

1/22 died of an unknown cause.

SMR= ratio of observerd to expected nr of deaths

Expected nr of deaths was calculated by multiplying the total number of years lived

by the study population with the age- and sex-specific

mortality rates of the Dutch population for each calendar

period available at ‘Statistics Netherlands’

Follow-up for adult relatives

Michels, 2009

Type of study:

Prospective cohort study

Country:

The Netherlands

Funding and conflicts of interest:

NR

No conflict of interest declared

Inclusion criteria:

Asymptomatic family members (adult first-degree relatives of an index patient with a sarcomeric mutation) in whom a pathogenic HCM mutation was identified in 2007 and 2008.

Exclusion criteria:

-

N total at baseline:

76 (32 families)

age ± SD:

40 + 14 (range 16-79)

Gender

33M (43%) / 43 F (57%)

All HCM mutation carriers were referred for cardiac evaluation including medical history, clinical examination, electrocardiography (ECG), Doppler echocardiography, exercise testing, and 24 h Holter monitoring.

-

Length of follow-up:

-

Loss-to-follow-up:

-

Diagnosis of HCM:

31/76 (41%)

MYBPC3 carriers: 23/64 (35%)

MYH7 carriers: 6/10 (60%)

The mean age of those with HCM was not significantly

different from those without HCM. Men had a significantly higher risk for HCM than women (P=0.04).

Mutations in MYH7 were associated with an earlier age at onset of HCM than mutations in MYBPC3 in this

study (P=0.01).

echo versus ECG

HCM diagnosis based on echo & ECG: 16/31 (52%)

Only ECG: 12/31 (39%)

only echo: 3/31 (9%)

Risk of SCD

Syncope: 0

Non-sustained ventricular tachycardia: 3/76 (4%) (2 with HCM, 1 without)

Abnormal blood pressure response: 4/76 (5%) (3 with HCM, 1 without)

Family history

≥2 first-degree relatives who experienced SCD <40 yr: 0

1 first-degree relative that

experienced SCD <40 years: 4/76 (5%). (2 with HCM, 2 without)

Relative who died suddenly: 56/76 (74%)

Christiaans, 2009

Type of study:

Cross-sectional study

Country:

The Netherlands

Funding and conflicts of interest:

Grant sponsors: ZorgOnderzoek Nederland (ZonMw); The Netherlands Heart Foundation (NHS);

Inclusion criteria:

Asymptomatic relatives from HCM patients with a single pathogenic mutation undergoing DNA testing and being identified as HCM mutation carriers

Ng. Disclosure of their DNA test result had occurred at least 18 months ago.

Participants had to be Dutch

speaking and at least 16 years of age.

Exclusion criteria:

-

N total at baseline:

143

age ± SD:

46.8 16.1

DNA testing

Received cardiogenetic care was evaluated by questionnaires. Each counselee was sent a questionnaire, an explanatory letter, and a reply paid envelope. After 2 weeks a reminder was sent.

Length of follow-up:

-

Loss-to-follow-up:

-

Response rate: 123/143 (86%)

In 34/123 (27,6%) of mutation carriers a

clinical diagnosis of HCM could be made after DNA testing.

Experiences with DNA testing

Genetic counseling was valued positively and only 5/119 (4%) would rather not have known that they were a mutation carrier.

A majority received their DNA test result by mail (35%) or telephone(36%), and almost all were satisfied (102/107 (95%)).

Experiences with cardiac FU

Only 91/123 (74%) of carriers received regular cardiac follow-up. Reasons for not having regular follow-up most often mentioned were: ‘‘not having symptoms of the disease’’, ‘‘not necessary according to the cardiologist’’, and ‘‘cardiac tests showed no abnormalities’’. Mutation carriers receiving no follow-up were older (P < 0.001)

and more often female (P ¼ 0.035)

76/89 (85%) of mutation carriers having

regular follow-up were content with the frequency of these visits, on average once every 16 months.

In general communication with the cardiologists was valued as positive, patients obtain a sense of reassurance from their visists, disadvantages of visits were valued as low (especially by older

carriers, men and carriers with manifest HCM) and they do not experience much nervous anticipation.

Relationship to proband not reported.

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Jensen, 2013

likely

unlikely

unlikely

likely