Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.
ABSTRACT To report the frequency of single and multiple gene mutations in an Australian cohort of patients with hypertrophic cardiomyopathy (HCM).
Genetic screening of seven HCM genes (beta-MHC, MyBP-C, cTnT, cTnI, ACTC, MYL2, and MYL3) was undertaken in 80 unrelated probands. Screening was by denaturing high performance liquid chromatography and direct DNA sequencing. Clinical data were collected on all patients and on genotyped family members.
26 mutations were identified in 23 families (29%). Nineteen probands (24%) had single mutations (11 beta-MHC, 4 MyBP-C, 3 cTnI, 1 cTnT). Multiple gene mutations were identified in four probands (5%): one had a double mutation and the others had compound mutations. Six of 14 affected individuals from multiple mutation families (43%) experienced a sudden cardiac death event, compared with 10 of 55 affected members (18%) from single mutation families (p = 0.05). There was an increase in septal wall thickness in patients with compound mutations (mean (SD): 30.7 (3.1) v 24.4 (7.4) mm; p<0.05).
Multiple gene mutations occurring in HCM families may result in a more severe clinical phenotype because of a "double dose" effect. This highlights the importance of screening the entire panel of HCM genes even after a single mutation has been identified.
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ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a global disease with cases reported in all continents, affecting people of both genders and of various racial and ethnic origins. Widely accepted as a monogenic disease caused by a mutation in 1 of 13 or more sarcomeric genes, HCM can present catastrophically with sudden cardiac death (SCD) or ventricular arrhythmias or insidiously with symptoms of heart failure. Given the velocity of progress in both the fields of heart failure and HCM, we present a review of the approach to patients with HCM, with particular attention to those with HCM and the clinical syndrome of heart failure.Clinical Medicine Insights. Cardiology. 01/2014; 8(Suppl 1):53-65.
- Circulation Journal 01/2012; 76(2):303-304. · 3.69 Impact Factor
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ABSTRACT: Contribuyente adicional: Constantinos O’Mahony (Reino Unido) Comité de la ESC para las Guías de Práctica Clínica (GPC): Jose Luis Zamorano (presidente) (España), Stephan Achenbach (Alemania), Helmut Baumgartner (Alemania), Jeroen J. Bax (Países Bajos), Héctor Bueno (España), Veronica Dean (Francia), Christi Deaton (Reino Unido), Çetin Erol (Turquía), Robert Fagard (Bélgica), Roberto Ferrari (Italia), David Hasdai (Israel), Arno W. Hoes (Países Bajos), Paulus Kirchhof (Alemania/Reino Unido), Juhani Knuuti (Finlandia), Philippe Kolh (Bélgica), Patrizio Lancellotti (Bélgica), Ales Linhart (República Checa), Petros Nihoyannopoulos (Reino Unido), Massimo F. Piepoli (Italia), Piotr Ponikowski (Polonia), Per Anton Sirnes (Noruega), Juan Luis Tamargo (España), Michal Tendera (Polonia), Adam Torbicki (Polonia), William Wijns (Bélgica) y Stephan Windecker (Suiza).Revista Espa de Cardiologia 01/2015; · 3.34 Impact Factor
Compound and double mutations in patients with
hypertrophic cardiomyopathy: implications for genetic
testing and counselling
J Ingles, A Doolan, C Chiu, J Seidman, C Seidman, C Semsarian
J Med Genet 2005;42:e59 (http://www.jmedgenet.com/cgi/content/full/42/10/e59). doi: 10.1136/jmg.2005.033886
Objective: To report the frequency of single and multiple
gene mutations in an Australian cohort of patients with
hypertrophic cardiomyopathy (HCM).
Methods: Genetic screening of seven HCM genes (b-MHC,
MyBP-C, cTnT, cTnI, ACTC, MYL2, and MYL3) was under-
taken in 80 unrelated probands. Screening was by denatur-
ing high performance liquid chromatography and direct
DNA sequencing. Clinical data were collected on all patients
and on genotyped family members.
Results: 26 mutations were identified in 23 families (29%).
Nineteen probands (24%) had single mutations (11 b-MHC,
4 MyBP-C, 3 cTnI, 1 cTnT). Multiple gene mutations were
identified in four probands (5%): one had a double mutation
and the others had compound mutations. Six of 14 affected
individuals from multiple mutation families (43%) experi-
enced a sudden cardiac death event, compared with 10 of
55 affected members (18%) from single mutation families
(p=0.05). There was an increase in septal wall thickness in
patients with compound mutations (mean (SD): 30.7 (3.1) v
24.4 (7.4) mm; p,0.05).
Conclusions: Multiple gene mutations occurring in HCM
families may result in a more severe clinical phenotype
because of a ‘‘double dose’’ effect. This highlights the
importance of screening the entire panel of HCM genes even
after a single mutation has been identified.
loading conditions such as hypertension.1 2The prevalence of
HCM in the general population is thought to be 0.2% (or 1/
500),3making it the commonest known cardiovascular
genetic disorder. HCM shows considerable clinical hetero-
geneity, both between and within families. Variability in
clinical presentation ranges from minimal or no symptoms to
the most serious complications including heart failure and
sudden cardiac death.4This heterogeneity could be explained
by environmental influences such as exercise, modifier genes,
or the presence of compound or double disease causing
mutations in affected individuals.5–12
Over 200 different mutations in at least 11 genes have been
identified in HCM. In most cases, HCM is caused by single
heterozygote mutations in genes encoding sarcomeric pro-
teins. These include the b-myosin heavy chain (b-MHC),
myosin binding protein C (MyBP-C), cardiac troponin T
(cTnT), cardiac troponin I (cTnI), a-tropomyosin, essential
and regulatory light chain (MYL2 and MYL3), titin and actin
(ACTC) genes.1 5Most recently, it has been reported that
approximately 5% of HCM patients carry more than one
ypertrophic cardiomyopathy (HCM) is a primary
cardiac disorder characterised by myocardial hypertro-
phy, usually of the left ventricle, in the absence of
disease causing gene mutation, leading to a double or
compound heterozygote genotype.9 10It appears that these
patients may develop a more severe clinical phenotype
because of a ‘‘double dose’’ gene mutation effect.9–11
In this study we report the frequency of single and multiple
gene mutations in an Australian cohort of HCM patients. We
discuss the implications of the findings for clinical risk
stratification and for genetic counselling of families with
regard to genetic testing, inheritance risk, and the accuracy of
predictive genetic testing for family members.
Patients referred to the HCM clinic, a tertiary referral centre
at Royal Prince Alfred Hospital in Sydney, Australia, were
included in this study. Clinical evaluation was undertaken as
described previously13and included a full clinical history and
physical examination, electrocardiography (ECG), and cross
section and M mode echocardiography. A sudden cardiac
death event was defined as death occurring within one hour
of symptoms in an individual with HCM, or a resuscitated
cardiac arrest related to HCM. The primary diagnostic
criterion for HCM in adults was a maximum left ventricular
wall thickness of >13 mm on echocardiography in the
absence of loading conditions such as hypertension. Within
the context of a family history, the diagnosis of HCM was
made by the above echocardiographic findings and/or at least
one of the following major abnormalities on ECG: abnormal
Q waves (.0.04 s or depth .25% of R wave), left ventricular
hypertrophy (voltage criteria), or marked repolarisation
changes (for example, T wave inversion in at least two leads).
Following informed consent, a 20 ml blood sample was
taken from the proband in each family for genetic analysis.
All studies were undertaken in strict accordance with the
Central Sydney Area Health Service human ethics standards.
Analysis of the entire coding sequence of seven genes known
to cause HCM (b-MHC, MyBP-C, cTnI, cTnI, ACTC, MYL2,
and MYL3) was carried out as a collaborative effort between
the Department of Genetics at Harvard Medical School,
Boston, and the Agnes Ginges Centre for Molecular
Cardiology, Sydney. Genetic screening of these genes was
undertaken as previously described.14 15In brief, the entire
coding sequence of each of the seven genes was system-
atically analysed for the proband in each family. Exons were
amplified by polymerase chain reaction (PCR) from genomic
DNA and sequenced using an ABI Prism 377 DNA analyser.
Sequencher v3.1. A sequence variant (polymorphism) was
Abbreviations: AICD, automatic implantable cardioverter-defibrillator;
HCM, hypertrophic cardiomyopathy
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considered to be a disease causing mutation on the basis of
the following three criteria: co-segregation with affected
members in the family; absence of the mutation in 300
unrelated chromosomes from healthy adult controls; and the
conservation of the mutated residue among species and
isoforms. Once a mutation was confirmed in the proband by
restriction enzyme digestion, other family members were
offered genetic testing and evaluated.
We used x2analysis and Student’s t test to determine
significant differences for variables. For all comparisons, a
Disease causing gene mutations identified in Australian hypertrophic
AF , AS
O , AI
*Indicates those mutations found in the compound and double heterozygotes.
b-MHC, b-myosin heavy chain; cTnI, cardiac troponin I; cTnT, cardiac troponin T; MyBP-C, myosin binding
coded by family: family C, blue; family D, red; family G, green; family O, mauve. Binding domains are highlighted below the gene. MyBP-C has titin
and myosin heavy chain (MHC) binding sites. The phosphorylation site is also shown. Actin, myosin light chain (MLC), and ATP binding sites are
represented on the b-MHC gene. Exon 19 of b-MHC contains two ‘‘active thiols’’, SH1 and SH2.
Diagram of compound and double mutations identified in MyBP-C and b-MHC. Family mutations are shown above the gene and are colour
2 of 6 Electronic letter
probability (p) value of ,0.05 was considered significant. All
values are given as mean (SD).
In all, 80 unrelated probands underwent genetic screening of
the seven HCM disease genes. Twenty six gene mutations
were identified in 23 probands (29%) (table 1). In these
families, where at least one mutation was identified, 52% had
a family history of HCM before genetic testing. The same
gene defect was found in three families; thus 24 separate
mutations were identified. Eleven of the 24 mutations were
novel (46%). Of these 23 probands, 19 (24% of all tested)
were found to have single mutations (heterozygotes), of
which 11 were identified in b-MHC, four in MyBP-C, three in
cTnI, and one in cTnT (table 1). Two of the four MyBP-C
mutations were identified in intronic regions and were
thought to be responsible for alternate splicing. All were
missense mutations apart from one nonsense mutation
which resulted in truncation of the affected protein (family
Four families (5%) were found to carry more than one
disease causing gene mutation. The proband from family C
was identified as a double heterozygote, with an Arg719Gln
mutation in exon 19 of b-MHC and an Arg273His mutation
in exon 8 of MyBP-C. The remaining three probands were
found to carry compound mutations in MyBP-C. Family D
had an Asp745Gly and a Pro873His mutation, while family G
had a Glu542Gln and an Ala851Val mutation. Family O had a
nonsense Gln1233Ter mutation and a missense Arg326Gln
mutation. The positions of these mutations are shown in fig 1.
The pedigrees of the four multiple mutation families are
shown in fig 2. Identification of a mutation in a proband
allowed further investigation of other family members. In
family C, V:1 was identified as having inherited both the b-
MHC and the MyBP-C mutations from his mother (IV:4,
proband). This individual is aged 15 years and is clinically
affected. Individual V:2 is aged 13 years and is clinically
normal but has inherited one of the two genes and is
therefore heterozygous for the MyBP-C mutation (genotype
positive–phenotype negative). Tissue was not available for
genetic analysis in any of the deceased family members,
although available clinical and necropsy information allowed
accurate diagnosis of HCM and the nature of death in the
deceased individuals. All died suddenly except for individual
III:4, who had severe biventricular heart failure and died at
age 42 years. In family D, only the proband (II:1) had
II:3II:2 II:4II:6II:7 II:8II:9
III:2 III:1III:7III:6 III:3III:5III:4III:9
below the individual, where ‘‘+’’ means that the individual has a mutation in the indicated gene and ‘‘2’’ indicates the individual does not have the
mutation. N, clinically unaffected.
Multiple mutation family pedigrees. Arrow indicates proband; black symbols represent clinically affected individuals. The genotype is shown
Electronic letter3 of 6
undergone genetic testing, although his brother (II:2) has
clinical evidence of HCM and had a resuscitated cardiac
arrest, during which he sustained hypoxic brain damage. The
proband from family G (II:1) has severe left ventricular
hypertrophy (34 mm) and has a 13 year old son (III:1) who
also has severe hypertrophy requiring myectomy on two
occasions and implantation of an automatic implantable
cardioverter-defibrillator (AICD). Genetic analysis of family
members of family O has not identified any other affected
individuals to date.
The clinical features of the compound and double hetero-
zygote patients are summarised in table 2. Probands with
wall thickness than the single mutation patients (30.7 (3.1) v
24.4 (7.4) mm, p,0.05). No significant difference between
other echocardiographic variables was found (including frac-
tional shortening and left ventricular outflow tract obstruc-
tion). Fourteen members of the multiple mutation families
were found to be clinically affected. Six (43%) of these
individuals suffered a sudden cardiac death event (age range
16 to 66 years). In contrast, 55 members of the single mutation
families were found to be clinically affected, of whom 10 (18%)
suffered a sudden cardiac death event (p=0.05 v sudden death
events in multiple mutation families). Six of eight (75%)
clinically affected living family members from the multiple
mutation families were managed with AICD implantation
because of a family history of sudden cardiac death, massive
left ventricular hypertrophy (>30 mm), non-sustained ven-
tricular tachycardia, or syncope.
In this report we describe the frequency of single and
multiple gene mutations in an Australian cohort of 80
unrelated HCM families. A gene mutation was identified in
23 probands (29%), with four probands being compound or
double heterozygote genotypes (5%). Probands carrying
multiple gene mutations were shown to express a more
severe clinical phenotype than single heterozygote HCM
patients, as demonstrated by an increase in left ventricular
hypertrophy and an increased incidence of sudden cardiac
death events. Implications for genetic counselling of patients
harbouring multiple mutations include limitations to the
accuracy of predictive gene testing in HCM, alterations of
inheritance risk in children, and the implications of multiple
mutations and clinical severity of disease on decision making
processes relating to pregnancy.
Multiple mutations may account for some of the clinical
heterogeneity observed in patients with HCM. Most recently,
a subgroup of patients has been identified as carrying more
than one gene mutation, leading to a compound or double
heterozygote genotype. As in the current study, recent reports
indicate that this subgroup comprises approximately 5% of
HCM patients.9 10Descriptions of large cohorts of HCM
patients who have undergone genetic testing have included
individuals carrying compound MyBP-C and b-MHC muta-
tions, double MyBP-C/b-MHC, MyBP-C/cTnT, MyBP-C/cTnI,
MyBP-C/TPM, b-MHC/cTnT mutations, and homozygous
MyBP-C, b-MHC, and cTnT mutations.9–11 16It is thought
that these genotypes have a double dose effect, leading to a
clinically more severe phenotype.9This may relate to direct
effects of these mutations on protein function, affecting
actin–myosin interactions within the sarcomere, the overall
stability of the sarcomere structure, and alterations in
calcium handling within myocyte.
The relatively high incidence of multiple mutations in
HCM suggests that the reported prevalence of this disease of
around 1/5003may be an underestimate. This is not
surprising as such prevalence studies have been based largely
on echocardiographic diagnosis, and we now know that some
individuals may have either low or late penetrance—that is,
they carry the gene defect but do not show clinical evidence
of disease such as symptoms or echocardiographic evidence
of left ventricular hypertrophy. Interestingly, the overall rate
for mutations in the current study of 29% was significantly
lower than in previous studies, and may reflect both a
clinically orgenetically different
Patients with multiple mutations have been reported to
develop more significant left ventricular hypertrophy, are
diagnosed at an earlier age, and require more advanced and
invasive treatments such as surgical myotomy/myectomy and
AICD implantation.9 10In the current study, a consistent
finding in a geographically distinct population was observed,
whereby patients with multiple mutations had a greater left
ventricular wall thickness and a 2.4-fold higher incidence of
sudden cardiac death events among family members.
Limitations regarding the availability of necropsy tissues
did not allow us to confirm the presence of two mutations in
all clinically affected individuals who had a sudden death
event. Nevertheless, the overall trend towards more sudden
death events in this cohort of families compared with
Further elucidation of the phenotype of compound and
HCM population in
Clinical and genetic characteristics of compound and double heterozygote families
Family CaseAge (y)
AICD, automatic implantable cardioverter defibrillator; CH, compound heterozygote; DH, double heterozygote; HZ, heterozygote; LVWT, left ventricular wall
thickness; N/A, not available; NT, not tested; SCD, sudden cardiac death; y, years.
4 of 6Electronic letter
double heterozygotes could lead to alterations in their
clinical management. Given the important clinical issue of
risk stratification for determining which HCM patients are
at highest risk of heart failure and sudden cardiac death,
the presence of two mutations in an individual may be a
major factor in this cardiac event risk algorithm. The
available clinical data in those who had sudden death
events and carried multiple mutations showed that they
had clinical risk factors for sudden death, such as a positive
family history of sudden death and severe cardiac hyper-
trophy (>30 mm). Identification of multiple mutations in an
individual may prompt more aggressive treatment including
implantation of an AICD to prevent sudden death and
management of symptomatic left ventricular outflow tract
The role of genetic counselling and testing is an important
component of the evaluation, diagnosis, and management of
individuals and families with HCM.17–19The occurrence of
multiple mutations in a subgroup of this HCM population
has raised new questions about what we tell families in the
context of genetic testing. For example, based on the current
findings, genetic screening should not cease after a single
mutation has been identified. As HCM genetic testing moves
out from the research phase and in to the clinical arena, it
will become more difficult to ensure that families receive the
correct information about the limitations of this test. It is
important that commercial HCM genetic testing is offered as
screening of a panel of common genes, rather than on a
single gene basis, which may seem more cost-effective to a
patient. This testing panel would ideally be made up of the
three most common HCM disease genes as a minimum, as
most reports of multiple mutations involve b-MHC, MyBP-C,
and cTnT.10The implications for a family of not identifying a
second gene mutation could be devastating, as currently an
individual who receives a negative predictive gene test is
released from clinical screening and believes their children
are no longer at risk of developing HCM.
An integral part of the genetic counselling process is the
explanation of the inheritance of the disease and the risk to
children. HCM is an autosomal dominant disorder, whereby
most affected individuals have a single heterozygote geno-
type. However, double and compound mutations significantly
alter the chances of inheriting the gene defect in families. If a
patient was found to be a double heterozygote carrying a
gene mutation on two different genes inherited indepen-
dently (as in family C), the risk that a child will receive at
least one disease causing gene mutation becomes 75%. In
addition, there is a 25% chance that the child will inherit both
gene mutations and potentially show the more severe
phenotype so commonly reported. Similarly, if a patient
was identified as being a compound heterozygote (for
example, families D, G, and O), the chance of passing on
the gene defect depends on whether the two mutations are in
cis (both mutations on the same allele) or trans form
(mutations on different alleles). In the former situation, the
chance of passing on the gene defect is 50%, while in the
latter the risk of passing on one of the two mutations is 100%.
These clinical scenarios could have an effect on the uptake of
prenatal genetic testing for HCM, which is currently reported
to be very low20owing to the extreme clinical variability seen.
Further elucidation of the clinical consequences of multiple
mutations may eventually assist some couples in making a
more informed decision about prenatal genetic testing and
termination of pregnancy. These are important considera-
tions for a family and highlight the value of accurate genetic
testing of the proband. It is of equal importance to ensure
that cardiologists dealing with HCM families are equipped
with the skills to offer appropriate genetic counselling.
Ideally, all families with HCM should be referred to a cardiac
clinic where genetic counselling support is available to
discuss these issues at length.
Multiple gene mutations within a HCM family are being
increasingly reported and raise many issues for genetic
counselling. Integral to these issues is the need for accurate
HCM genetic testing, which will allow an individual’s
genotype to be clearly established and understood by
clinicians and their patients. Further clarification of the
proportion of HCM patients with multiple mutations and
how this correlates with an individual’s phenotype are
important aspects in accounting for the marked clinical
heterogeneity characteristic of HCM.
CS is the recipient of a National Health and Medical Research Council
Practitioner Fellowship. AD is the recipient of an Australian
Postgraduate Award. The research is supported by project grants
from the National Heart Foundation and the National Health and
Medical Research Council of Australia.
J Ingles, A Doolan, C Chiu, Agnes Ginges Centre for Molecular
Cardiology, Centenary Institute, Sydney, Australia
C Semsarian, Department of Cardiology, Royal Prince Alfred Hospital,
J Seidman, C Seidman, Department of Genetics, Harvard Medical
School, Boston, Massachusetts, USA
Competing interests: none declared
Correspondence to: Associate Professor Christopher Semsarian, Agnes
Ginges Centre for Molecular Cardiology, Centenary Institute, Locked
Bag 6, Newtown, NSW 2042, Australia; email@example.com.
Received 11 April 2005
Revised version received 11 May 2005
Accepted for publication 13 May 2005
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