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Association of A31P and A74T Polymorphisms in the Myosin Binding Protein C3 Gene and Hypertrophic Cardiomyopathy in Maine Coon and Other Breed Cats


Abstract and Figures

Hypertrophic cardiomyopathy (HCM) is an inherited autosomal dominant trait in cats. The A31P single nucleotide polymorphism (SNP) in the myosin binding protein C 3 gene is thought to be the causative mutation in Maine Coon cats. Additionally, the A74T SNP is offered as a genetic test for HCM. To evaluate the genetic association between the above-mentioned SNPs and phenotypes. Eighty-three Maine Coon cats and 68 cats of other breeds. The study was performed prospectively. Cats were phenotyped as healthy or HCM with echocardiography. Taqman genotyping assays were used for genotyping; results were confirmed by sequencing analysis. A31P was found in 18/83 (22%) Maine Coon cats. Fifteen of 18 Maine Coons (83%) with the A31P mutation were healthy on echocardiographic examination (mean age 65 months). A74T was present in 28/79 (35%) of Maine Coons and in 42/68 (62%) of other cat breeds. Twenty-two of 28 (79%) of Maine Coons and 21/42 (62%) of other breed cats with the A74T mutation were healthy at a mean age of 72 months and 91 months, respectively. Of 12 Maine Coons with HCM, 9 (75%) were genotype-negative for A31P and 6 (50%) for A74T. Allele frequencies did not differ significantly (P= .47) between phenotype groups. None of the evaluated genetic tests was able to provide useful predictive information of disease outcome. The value of currently available genetic tests is low in the cats of this study. The mutations analyzed appear to have a low penetrance, and even homozygote cats can remain healthy.
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Association of A31P and A74T Polymorphisms in the Myosin Binding
Protein C3 Gene and Hypertrophic Cardiomyopathy in Maine Coon
and Other Breed Cats
G. Wess, C. Schinner, K. Weber, H. Ku
¨chenhoff, and K. Hartmann
Background: Hypertrophic cardiomyopathy (HCM) is an inherited autosomal dominant trait in cats. The A31P single
nucleotide polymorphism (SNP) in the myosin binding protein C 3 gene is thought to be the causative mutation in Maine Coon
cats. Additionally, the A74T SNP is offered as a genetic test for HCM.
Objectives: To evaluate the genetic association between the above-mentioned SNPs and phenotypes.
Animals: Eighty-three Maine Coon cats and 68 cats of other breeds.
Methods: The study was performed prospectively. Cats were phenotyped as healthy or HCM with echocardiography.
Taqman genotyping assays were used for genotyping; results were confirmed by sequencing analysis.
Results: A31P was found in 18/83 (22%) Maine Coon cats. Fifteen of 18 Maine Coons (83%) with the A31P mutation were
healthy on echocardiographic examination (mean age 65 months). A74T was present in 28/79 (35%) of Maine Coons and in 42/
68 (62%) of other cat breeds. Twenty-two of 28 (79%) of Maine Coons and 21/42 (62%) of other breed cats with the A74T
mutation were healthy at a mean age of 72 months and 91 months, respectively. Of 12 Maine Coons with HCM, 9 (75%) were
genotype-negative for A31P and 6 (50%) for A74T. Allele frequencies did not differ significantly (P5.47) between phenotype
groups. None of the evaluated genetic tests was able to provide useful predictive information of disease outcome.
Conclusions and Clinical Importance: The value of currently available genetic tests is low in the cats of this study. The mu-
tations analyzed appear to have a low penetrance, and even homozygote cats can remain healthy.
Key words: Animals; Carrier proteins/genetics; Genetic tests; HCM.
Hypertrophic cardiomyopathy (HCM) is the most
common familial genetic heart disease in humans,
affecting one in 500 individuals.
In 60% of cases it
is inherited as an autosomal dominant trait, while ex-
hibiting an enormous phenotypic and genotypic hetero-
geneity. De novo mutations are also considered to be a
cause of sporadic HCM.
For many years, HCM in
humans has been suspected of being a genetic disease of
the sarcomere. To date, 4450 different mutations con-
sidered responsible for familial HCM have been
identified within 13 sarcomere- and myofilament-related
HCM is the most common cardiac disease in cats. Au-
tosomal dominant inheritance with a heterogeneous
disease outcome has been documented in a family of
Maine Coon cats.
One point mutations in the cardiac
myosin binding protein C 3 (MYBPC3) gene (A31P)
leading to amino acid changes in the protein occur in
Maine Coon cats with HCM and one point mutation in
the same gene (R820W) is thought to cause the same dis-
ease in Ragdoll cats.
Another single nucleotide
polymorphisms (SNP) (A74T) of the MVBPC3 has been
suspected to cause HCM in Maine Coon cats.
commercial laboratories currently provide genetic tests
for the above-mentioned mutations. The A31P mutation
is present in about 34% of all Maine Coon cats world-
wide, although studies evaluating the relationship
between genotype and clinical outcome are lacking.
The goal of this study, therefore, was to evaluate the ge-
netic association of A31P and A74T SNPs with the
phenotype of HCM in Maine Coon cats in Germany.
Clinical validation (sensitivity, specificity) of both genetic
tests was assessed as well. In addition, the presence of the
2 above-named SNPs was evaluated in other breeds
besides Maine Coon cats.
Materials and Methods
Eighty-three Maine Coon cats and 68 cats of various other
breeds (Norwegian Forest cats, Persian cats, Domestic Shorthair
cats) were included in this prospective study over a period of 2 years
(August 2005–August 2007). All cats were from owners living in
From the Clinic of Small Animal Medicine (Wess, Schinner, Weber,
Hartmann), and the Statistical Consulting Unit (Ku
¨chenhoff), Lud-
wig-Maximilians-University, Munich, Germany. Parts of this study
Corresponding author: Gerhard Wess, DVM, Dipl. ACVIM (Car-
diology), Dipl. ECVIM-CA (Cardiology and Internal Medicine),
Clinic of Small Animal Internal Medicine, Ludwig-Maximilians-
University, Veterinaerstr. 13, 80539 Munich, Germany. e-mail:
Submitted September 5, 2009; Revised February 5, 2010;
Accepted March 1, 2010.
Copyright r2010 by the American College of Veterinary Internal
CV coefficient of variation
HCM hypertrophic cardiomyopathy
IVS interventricular septum
IVSd interventricular septum at end-diastole
LV left ventricular
LVPW left ventricular posterior wall
LVPWd left ventricular posterior wall at end-diastole
MYBPC3 myosin binding protein C 3
PCR polymerase chain reaction
SNPs single nucleotide polymorphisms
TDI tissue Doppler imaging
J Vet Intern Med 2010;24:527–532
Germany, Switzerland, or Austria and patients presented to the
cardiology service of the Clinic of Small Animal Medicine or cats
participating in an HCM screening program. Pedigree sheets and
Internet databases were used to determine the origin of the Maine
Coon cats. The majority of the Maine Coon cats originated from
Germany (n 558) and Austria (n 511), and 8 cats were from the
United States, 3 from Switzerland, and 2 from Canada and Den-
mark each. Looking at the parents level of these cats, 48.2% (n 5
80) were from Germany, 21.1% (n 535) came from United States,
8.4% (n 514) were from Austria, 6.0% (n 520) from Canada,
3.6% (n 56) from Italy, 3.0% (n 55) from Denmark, 3.0% (n 55)
from Switzerland; 3 cats were from United Kingdom, 2 from Po-
land, 2 from France, 2 from the Netherlands, and 1 from Spain.
Cats were classified into 2 breed groups: ‘‘Maine Coon’’ and ‘‘other
breeds.’’ They were then further classified into the groups ‘‘healthy’’
or ‘‘HCM’’ according to echocardiographic phenotype results. In
the control group, female and male cats had to be a minimum age of
36 and 24 months, respectively, based on the fact that HCM can
usually be detected echocardiographically by this age in affected
Cats were considered genotype-positive for A31P or A74T if
at least 1 mutated allele was detected. Cats displaying only the wild-
type allele were considered genotype negative.
Cats were prospectively phenotyped by clinical examination and
echocardiography. Animals with other diseases causing ventricular
concentric hypertrophy were excluded from the study. All echocar-
diographic studies were performed by 1 experienced examiner
(G.W.), with an ultrasound unit equipped with a 5.5–7.5 MHz
phased-array transducer with continuous ECG monitoring and
echocardiographic loops were stored digitally.
Ultrasound exam-
inations were performed without sedation in gently restrained cats
in lateral recumbency. Standard echocardiographic views were ob-
tained in right and left lateral recumbency.
measurements of left ventricular (LV) wall thickness were per-
formed with two-dimensional echocardiography in the right
parasternal short-axis view at the level of the papillary muscles,
and in the right parasternal long-axis view in the basal and mid-
ventricular myocardial segments of the left ventricular posterior
wall at end-diastole (LVPWd) and the interventricular septum at
end-diastole (IVSd). HCM was defined as regional or generalized
hypertrophy with a diastolic wall thickness 6 mm of the LVPWd
or of the IVSd. At least 3 measurements were performed in each of
the myocardial segment described above of the left ventricular pos-
terior wall (LVPW) and interventricular septum (IVS) and the
mean value of at least 3 measurements of the thickest segment was
calculated. Hyperthyroidism and hypertension were excluded as
secondary causes of hypertrophy by measurement of basal serum
T4 concentration and blood pressure by Doppler technique.
pressure was considered normal if systolic blood pressure was
o150 mmHg. Healthy genotype-positive cats were re-examined
after 1 year. In addition, cats with equivocal measurements (only
prominent papillary muscle, or wall thickness between 5.5 and
6.0 mm) were excluded from the study if ultrasound findings
remained equivocal after 1 year. Measurement reliability was
determined for systolic and diastolic LV chamber diameter and
for diastolic wall thickness of the LVPW and IVS. Ten echocardio-
grams were randomly selected to be subjected to 3 repeated
analyses within 1 week by 1 investigator (G.W.) to determine
intraobserver measurement variability. The investigator was un-
aware of the results of the prior echocardiographic analyses.
For genotyping, DNA was extracted from peripheral blood
leucocytes with the QIAamp DNA Mini Kit.
The quantity of
DNA was assessed by photometric measurement. A 250-bp frag-
ment of the feline MYBPC3 gene including both polymorphic sites
was amplified by polymerase chain reaction (PCR) from 4 cats with
known A31P SNP genotype to confirm the feline sequence. Ampli-
fication primers were obtained from a commercial laboratory.
forward primer was 50-AGT CTC AGC CTT CAG CAA GAA
GCC-30, and the reverse primer 5 0-GGT CAA ACT TGA CCT
Standard PCR amplification was carried out with the HotS-
tarTaq PCR Master Mix
according to the manufacturer’s
with 30 cycles on an Eppendorf thermal cycler, using
601C as annealing temperature. The PCR product was visualized by
gel electrophoresis and purified with the MinElute PCR Purification
according to the manufacturer’s instructions.
The PCR prod-
uct was sequenced by a commercial laboratory
performing a single
read of each sample with forward and reverse primers. Using this
sequence as a template, TaqMan Genotyping Assays for the A31P
and A74T SNPs were produced by a commercial Assay-by-Design-
These assays use a primer pair and allele-specific minor
groove binding probes with either VIC or 6-FAM as fluorescent
reporter dye. For allelic discrimination of the A31P SNP, the wild-
type G-allele was labelled with VIC and the mutated C-allele with
6-FAM. For discrimination of the A74T SNP, the wild-type A-allele
was labelled with 6-FAM and the mutated G-allele with VIC.
The allelic discrimination assays were run in 96-well reaction
plates on a 7,500 Real-Time PCR System.
12.5 mLof2TaqMan
Universal Master Mix, no AmpErase UNG
and 1.25 mL20SNP
Assay Mix
were mixed with 11.25 mL DNA, diluted in nuclease-
free water to a final reaction volume of 25 mL. On each plate, no
template controls (reaction mix without DNA) were included as
negative controls. DNA samples from cats with known homo- and
heterozygous genotypes were included as positive controls. Allelic
discrimination analysis was performed by 7,500 SDS software. For
all cases assigned to either the G/C or C/C genotype of the A31P
SNP with the TaqMan assay, standard PCR reactions were per-
formed. PCR products were then sent to a commercial laboratory
for sequencing analysis to confirm specificity of the TaqMan assays.
In silico analysis of A31P and A74T amino acid variations in the
MYBPC3 protein.
The possible impact of the SNPs on the protein was evaluated by
This tool is designed to calculate the likelihood that an
amino acid substitution resulting from a genetic mutation changes
structure and function of a human protein by comparing the allelic
variants with homologous proteins.
The prevalence of HCM in Maine Coon cats was calculated from
randomly screened Maine Coon cats in the HCM screening pro-
gram. Allele frequencies were calculated for all phenotype groups.
Fisher’s exact test was used to compare allele frequencies of the
phenotype groups ‘‘healthy’’ and ‘‘HCM’’ (Po.05). Odds ratios
for having HCM were generated for all genotype-positives and ho-
mozygotes separately. Clinical validity was evaluated for both
genetic tests by calculating sensitivity and specificity.
The intra-
observer coefficients of variations (CV) were calculated by a
variance component analysis. The CV were obtained by dividing
the root of the variance error by the mean of the repeated measure-
ments, times 100.
The prevalence of HCM in cats in the present study
was 15% (95% CI 57–22%). The A31P SNP was found
in 22% (n 518) of the Maine Coon cats, but not in any
of the other breeds. Minor allele frequency was 0.13 for
528 Wess et al
the C-allele. Of the genotype-positive cats, 83% (n 515)
were classified as normal (healthy) on echocardiographic
examination (LVPWd, mean 4.51 mm, range 3.0–
5.5 mm; IVSd mean 4.57 mm, range 3.2–5.4 mm) (Fig 1).
Mean age of genotype-positive cats with healthy pheno-
type was 65 months (range 24–146 months). Two of these
cats were homozygous (C/C) for the A31P SNP (58 and
64 months old). On echocardiographic examination, the
phenotype HCM was found in only 3 cats with the A31P-
SNP mutation. One of these cats was homozygous and 2
cats were heterozygous for the A31P SNP. All heterozy-
gous and homozygous cases (G/C and C/C) identified
with the TaqMan assay were confirmed as heterozygous
G/C and homozygous C/C by sequencing analysis.
Sixty-five Maine Coon cats (78%) were genotype-
negative. Of those cats, 68% (n 556) had a normal
phenotype (mean age 71 months); 9 of the cats (14%) in
this group had HCM. In total, 9/12 phenotype-positive
Maine Coon cats were genotype-negative (75%). The
echocardiographic examination of the phenotype-posi-
tive cats included 8 cats with concentric hypertrophy and
4 cats with regional hypertrophy (LVPWd, mean 7.1 mm,
range 6.1–10.0 mm; IVSd mean 7.0 mm, range 6.2–
8.7 mm).
The A74T SNP was found in 28 (35%) of the Maine
Coon cats studied (Fig 2). Minor allele frequency was
0.22 for the A-allele. Of the genotype-positive Maine
Coons cats, 79% had a ‘‘healthy’’ phenotype (n 522) at
a mean age of 72 months. Four of these cats were homo-
zygous (A/A) for the A74T SNP, and 18 cats (82%) were
heterozygous (G/A). The A74T SNP was identified in
21% (n 56) of Maine Coon cats with HCM, 2 of which
were homozygous and 4 of which were heterozygous for
the mutation.
The A74T SNP was present in 42 (62%) cats of other
breeds (Persian, Norwegian Forest cats, and Domestic
Shorthair cats) and in 26 (38%) other breed cats the SNP
was not found (G/G). Of the 21 ‘‘healthy’’ phenotype
Fig 1. Phenotypes and genotypes of Maine Coon cats with the A31P mutation. G/C represents heterozygous state and C/C the homozygous
state. Age is displayed as mean age of the selected group.
Fig 2. Phenotypes and genotypes of Maine Coon cats with the A74T mutation. G/A represents the heterozygous state and A/A the homo-
zygous state. Age is displayed as mean age of the selected group.
529Genetic Basis for HCM in Cats
cats (mean age 91.4 months), 9 cats were heterozygous
(G/A), 4 cats were homozygous (A/A) for the A74T SNP
alleles, and in 8 cats the SNP was not found (G/G). HCM
was diagnosed in 40/68 cats of other breeds (59%). The
echocardiographic examination of the phenotype-
positive cats included 28 cats with concentric hyper-
trophy and 12 cats with regional hypertrophy (LVPWd,
mean 7.2 mm, range 6.1–9.8 mm; IVSd mean 6.8 mm,
range 6.2–8.9 mm).
Of the 40 cats with HCM (mean age 108 months), 35%
(n 514) were heterozygous and 25% (n 510) were ho-
mozygous for the A74T SNP. The SNP was not found in
40% (n 516) of the HCM cats (G/G). Seven cats were
equivocal on the echocardiographic phenotype (2 were
homozygous, and 3 were heterozygous for the A74T
There was no statistically significant difference ob-
served in allele frequencies between cats with HCM and
healthy controls for both SNPs, neither in Maine Coon
cats nor in the other breeds. No statistically significant
association between genotype and HCM was detected
(Table 1).
Sensitivity (25% for A31P; 50% for A74T) was very
low for both genetic tests in the examined population.
None of the genetic tests were able to reliably predict the
echocardiographic phenotype (Tables 2 and 3). Evaluation
of the potential impact of the amino acid substitutions
caused by the A31P and A74T SNPs by PolyPhen did
not suggest damaging effects on the protein. Results of
the echocardiographic repeatability study revealed very
good findings: CV for diastolic LVPW was 3.3%, for
diastolic IVS 2.6%, for diastolic LV diameter 2.0% and
for systolic LV diameter 4.2%.
The current study found that a positive test result in
the AP31 SNP or A74T SNP test does not predict that a
cat has echocardiographic changes or that it will develop
HCM later in life, and that a negative AP31 SNP or
A74T SNP test does not determine whether a cat has or
will develop HCM.
HCM is the most common cardiac disease in cats. It is
considered an autosomal dominant disease in humans as
well as in cats. A penetrance of 100% was reported for a
family of inbred Maine Coon cats, with the stillborns
representing lethal homozygotes that died in utero.
A31P mutation was first detected in this colony of Maine
Coon cats,
most of which had echocardiographic evi-
dence of HCM by an age of 24 months in males and 36
months in females.
Therefore, only males older than 24
months and females older than 36 months were included
into the healthy control group in the current study. HCM
cats were included in the present study at any age. The
possibility that cats in the control group will develop
HCM later in life cannot be excluded, and follow-ups in
this group are desirable. However, as the mean age of the
cats in the control group of the present study was 65
months, it is unlikely that many cats in this group will
develop HCM later in life.
Two cats with a normal phenotype at an age of 58 and
65 months were homozygous for the AP31 SNP. Maine
Coon cats carrying the homozygous mutation were sus-
pected to represent stillborn cats in the Maine Coon
breeding study, but homozygous cats for the A31P mu-
tation were found to be alive not only in the present
study, but also in the UC Davis Maine Coon colony.
Therefore, either the assumption that cats carrying a ho-
mozygous mutation will be stillborn cats is not correct,
or the A31P mutation alone is not the only mutation
causing HCM in Maine Coon cats. At least, the A31P
Table 1. Odds ratios for the A31P and A74T SNPs in
the MYBPC3 gene in Maine Coon cats (MC).
MC Phenotype Genotype 1 Genotype 2 N OR 95% CI
A31P G/G 1G/C C/C 3.14 0.20–5.96
Healthy 69 2 71
HCM 11 1 12
G/G G/C 1C/C 1.24 0.29–5.18
Healthy 56 15 71
HCM 9 3 12
A74T G/G 1G/A A/A 3.15 0.51–9.51
Healthy 63 4 67
HCM 10 2 12
G/G G/A 1A/A 2.04 0.59–7.07
Healthy 45 22 67
HCM 6 6 12
Genotype 1 and Genotype 2 show which combinations of geno-
types were used to calculate the odds ratios. For the A31P SNP G/
C, heterozygous; C/C, homozygous cases and G/G, wildtype; for
A74T G/A, heterozygous; A/A, homozygous cases and G/G, wild-
n, number of animals; OR, odds ratio; CI, confidence interval.
Table 2: Validity of the genetic test for the A31P SNP in
Maine Coon cats.
Scenario 1
G/C 1C/C 5
Genotype Positive
Scenario 2
C/C 5
Genotype Positive
95% CI 95% CI
Sensitivity 0.25 0.08–0.55 0.08 0.01–0.41
Specificity 0.79 0.68–0.87 0.97 0.89–0.99
Scenario 1, heterozygous (G/C) and homozygotes (C/C) are
counted as genotype positives; Scenario 2, only homozygotes are
counted as genotype positives; 95% CI, 95% confidence interval.
Table 3: Validity of the genetic test for the A74T SNP.
Scenario 1
G/A 1A/A 5
Genotype Positive
Scenario 2
A/A 5
Genotype Positive
95% CI 95% CI
Sensitivity 0.50 0.24–0.76 0.17 0.04–0.48
Specificity 0.67 0.55–0.73 0.94 0.85–0.98
Scenario 1, heterozygous (A/C) and homozygotes (A/A) are
counted among genotype positives; Scenario 2, homozygotes
are counted among genotype positives; 95% CI, 95% confidence
530 Wess et al
mutation does not appear to be a prenatal lethal factor,
neither in the present study population nor in the UC
Davis Maine Coon colony and another study evaluating
the A31P mutation in Maine Coon cats.
theless, in the inbred Maine Coon cat colony, the
A31P mutation appears to be associated with cardiac
A recent study demonstrated that the hetero-
zygous manifestation of the MYBPC3 A31P mutation is
not associated with occurrence of LV hypertrophy and
major myocardial dysfunction in Maine Coon cats.
Only inconsistent, minor regional diastolic myocardial
dysfunction were detected in a study using tissue doppler
imaging (TDI) in cats with the A31P mutation. A
reduced diastolic function was identified in only a few
LV wall segments, whereas other segments had normal
TDI values.
A diastolic dysfunction detected using TDI
could be an early marker of HCM, but this remains to be
proven in future studies. In the present study, TDI was
not used and therefore we potentially might have missed
early diastolic dysfunction. However, if diastolic dys-
function is truly an early indicator of HCM, than the
diastolic dysfunction should progress to a more obvious
HCM picture over time. The cats in the present study
were almost twice as old compared with the cats in the
TDI study population, in which the inconsistent regional
diastolic dysfunction was reported.
Therefore, even if
we would have missed diagnosing a diastolic dysfunc-
tion, the disease should have progressed to a more
obvious HCM picture in the cats of the present study.
As this was not the case, the clinical implication of a po-
tentially missed TDI abnormality seems to be low, with
480% of the cats in the present study still being normal
based on echocardiography at an advanced age.
The A31P mutation might be the cause of HCM in the
Maine Coon cats in the UC Davis breeding colony.
However, it could also only be a marker for an unknown
mutation with pathogenic potential. In the Maine Coon
cats tested in this study, the A31P SNP was not associ-
ated with HCM, which could possibly be because of a
varying genetic background. The analysis of the pedi-
grees revealed that Maine Coon cats used in this study
were from catteries throughout the world, with the ma-
jority of the cats originating from Germany, Austria, the
United States, and Canada. As the Maine Coon breed is
a comparatively young breed founded in the 1960s it is
not surprising that there are still many cats imported
from the United States and Canada and that cats in this
breed have a close genetic relationship. A study evaluat-
ing the prevalence of the A31P mutation found that this
mutation exists in about one third of the Maine Coon
cats throughout the world, and that the prevalence of the
mutation (heterozygous or homozygous) was very simi-
lar among countries of submission.
Therefore, the
results of this study could be representative also for other
countries and not only for the selected population. How-
ever, further studies are necessary on this subject.
Basing breeding recommendations for Maine Coon
cats on the A31P or A74T, or both gene tests appears
questionable unless cats that are related to the UC Davis
family are used for breeding. Another reason for the ob-
served variations in field and experimental breeding
conditions could be modifier genes that cause HCM in
combination with the A31P mutation. However, to date
no modifier gene has been identified in cats. In humans,
4400 mutations have been detected in 24 genes encoding
for various forms of HCM.
The other SNP (A74T) suspected to cause HCM in
Maine Coon cats and other breed cats is incompletely
reported, yet the test is already being offered by
commercial laboratories.
Therefore, the A74T SNP was
also investigated in this study. As with the A31P muta-
tion, HCM cats negative for the mutation were
identified. Consequently, it appears highly likely that
other or additional mutations causing HCM exist in
Maine Coon cats. Similar to the A31P mutation, 79%
of the Maine Coon cats with a positive gene test were
normal on echo at a mean age of 72 months. Of these
cats, 4 cats were homozygous for the mutation at a mean
age of 88 months. As with the A31P mutation, no statis-
tical difference in the percentage of affected cats was
found between gene test-positive and -negative cats, nor
was a correlation detected between phenotype and geno-
type. In contrast to the A31P mutation, which was
specific for Maine Coon cats, the A74T mutation was
also detected in other breeds (in which also no correla-
tion was present between genotype and phenotype). The
A74T SNP, therefore, appears to be a mutation that is
neither specific for Maine Coon cats nor causes HCM.
An Internet-based software program (Polyphen) from
Harvard University that tries to predict whether a muta-
tion is likely to affect protein function, classifying the
changes as ‘‘benign’’ or ‘‘malignant,’’ was used in this
study. The feline genome was used in the present study as
a reference to let the software predict if the SNPs are sus-
pected to be benign or malignant changes. For both the
A31P and A74T SNP, the program predicted that the
SNP probably are benign changes, which is in contrast to
a previous study that used the human genome and this
explains the different findings.
Although this might sup-
port the findings of this study, the results are only
calculations by a software and the value of a computa-
tional method should not be overestimated. Only
functional tests of the mutated protein would be able to
prove this assumption. A limitation of this study is that,
as all cats were client-owned cats, no necropsy was per-
formed on the phenotypically healthy, but positively
tested cats, and therefore no necropsy results could be
compared with the genotype. Another limitation is that
some cats may have been too young for the detection of
disease on echocardiography and may develop HCM la-
ter in life. However, as mentioned earlier, the mean age of
the healthy group of cats was 65 months and, thus, quite
old, so that the likelihood of developing the disease later
on is very low. Certainly, long-term follow-up studies
would help answer this question.
This study proves that other mutations or genetic in-
fluences causing HCM must exist as most cats with HCM
were negative for the AP31 SNP.
Therefore, it can be concluded that:
1. A negative AP31 SNP or A74T SNP test does not de-
termine whether a cat has or will develop HCM, as
531Genetic Basis for HCM in Cats
most of the cats with HCM in this study did not have
either SNP;
2. A positive test result does not implicate that a cat has
echocardiographic changes or that it will develop
HCM later in life, at least in the selected population,
as most of the cats with a positive gene test in this
study did not exhibit echocardiographic changes at a
mean age of 65 months;
3. Breeding decisions or recommendations should not
be based solely on A31P or A74T testing.
Nyberg MT, Koch J, Christiansen M. Intra-allelic Genetic Hetero-
genity of Hypertrophic Cardiomyopathy in the Maine Coon Cat.
Hugo Human Genome Meeting HGM2007, Montreal, Canada,
2007; 199 [poster abstract].
Vivid 7, GE, Horten, Norway
Parks 811-BT, Parks Medical Electronics Inc, Aloha, OR
Qiagen, Hilden, Germany
Metabion GmbH, Martinsried, Germany
HotStarTaq PCR Master Mix, Qiagen
MinElute PCR Purification Kit, Qiagen
Applied Biosystems, Foster City, CA
PolyPhen, Harvard University, Cambridge, MA: http://genetics.
1. Maron BJ. Hypertrophic cardiomyopathy: A systematic re-
view. J Am Med Assoc 2002;287:1308–1320.
2. Bos JM, Ommen SR, Ackerman MJ. Genetics of hypertro-
phic cardiomyopathy: One, two, or more diseases? Curr Opin
Cardiol 2007;22:193–199.
3. Nanni L, Pieroni M, Chimenti C, et al. Hypertrophic card-
iomyopathy: Two homozygous cases with ‘‘typical’’ hypertrophic
cardiomyopathy and three new mutations in cases with progression
to dilated cardiomyopathy. Biochem Biophys Res Commun 2003;
4. Olson TM, Doan TP, Kishimoto NY, et al. Inherited and de
novo mutations in the cardiac actin gene cause hypertrophic card-
iomyopathy. J Mol Cell Cardiol 2000;32:1687–1694.
5. Michels M, Hoedemaekers YM, Kofflard MJ, et al. Familial
screening and genetic counselling in hypertrophic cardiomyopathy:
The Rotterdam experience. Neth Heart J 2007;15:184–190.
6. Keren A, Syrris P, McKenna WJ. Hypertrophic card-
iomyopathy: The genetic determinants of clinical disease
expression. Nat Clin Pract Cardiovasc Med 2008;5:158–168.
7. Alcalai R, Seidman JG, Seidman CE. Genetic basis of
hypertrophic cardiomyopathy: From bench to the clinics. J
Cardiovasc Electrophysiol 2008;19:104–110.
8. Kittleson MD, Meurs KM, Munro MJ, et al. Familial
hypertrophic cardiomyopathy in Maine Coon cats: An animal
model of human disease. Circulation 1999;99:3172–3180.
9. Meurs KM, Sanchez X, David RM, et al. A cardiac myosin
binding protein C mutation in the Maine Coon cat with familial hy-
pertrophic cardiomyopathy. Hum Mol Genet 2005;14:3587–3593.
10. Meurs KM, Norgard MM, Ederer MM, et al. A substitution
mutation in the myosin binding protein C gene in Ragdoll hyper-
trophic cardiomyopathy. Genomics 2007;90:261–264.
11. Fries R, Heaney AM, Meurs KM. Prevalence of the myosin-
binding protein C mutation in Maine Coon cats. J Vet Intern Med
12. Kittleson MD Echocardiography. In: Kittleson MD, Kienle
RD, eds. Small Animal Cardiovascular Medicine. St Louis, MO:
Mosby Inc; 1998:95–117.
13. Qiagen. QIAamp DNA Mini Kit and QIAamp DNA Blood
Mini Kit Handbook. Hilden: Qiagen; 2003.
14. Qiagen. Taq PCR Handbook. Hilden: Qiagen; 2002.
15. Qiagen. MinElute Handbook. Hilden: Qiagen; 2006.
16. Ramensky V, Bork P, Sunyaev S. Human non-synonymous
SNPs: Server and survey. Nucleic Acids Res 2002;30:3894–3900.
17. Bickebo
¨ller H, Fischer C. Betrachtungen genetischer Epide-
miologien zu diagnostischen tests mit SNP-Markern. J Lab Med
18. Yang Q, Khoury MJ, Coughlin SS, et al. On the use of pop-
ulation-based registries in the clinical validation of genetic tests for
disease susceptibility. Genet Med 2000;2:186–192.
19. MacDonald KA, Kittleson MD, Kass PH, et al. Tissue
Doppler imaging in Maine Coon cats with a mutation of myosin
binding protein C with or without hypertrophy. J Vet Intern Med
20. Carlos Sampedrano C, Chetboul V, Mary J, et al. Prospec-
tive echocardiographic and tissue doppler imaging screening of a
population of Maine Coon cats tested for the A31P mutation in the
myosin-binding protein C gene: A specific analysis of the heterozy-
gous status. J Vet Intern Med 2009;23:91–99.
21. Fatkin D, Graham RM. Molecular mechanisms of inherited
cardiomyopathies. Physiol Rev 2002;82:945–980.
22. Maron BJ, Towbin JA, Thiene G, et al. Contemporary
definitions and classification of the cardiomyopathies: An
American Heart Association scientific statement from the council
on clinical cardiology, heart failure and transplantation committee;
quality of care and outcomes research and functional Genomics
and translational biology interdisciplinary working groups; and
council on epidemiology and prevention. Circulation 2006;113:
532 Wess et al
... The second variant, MYBPC3 p.R820W, was shown to be associated with HCM in Ragdoll cats [10] These two mutations are widely recognized as HCM-causative mutations, and homozygotes of each mutation have a higher risk of developing HCM [18]. Another study proposed HCM association with the MYBPC3 p.A74T variant; however, this mutation was considered unrelated to cardiomyopathy in recent follow-up studies [19,20]. Next, Myosin heavy chain 7 (MYH7) p. E1883K variant was detected in an HCM-affected Domestic Shorthair cat [21]. ...
... HCM-associated variants have been analyzed occasionally in non-specific breeds that often lead to HCM development. Furthermore, studies in the U.S. have yet to find evidence of variants being universally present among breeds [19,23,25]. Additionally, only a single study of a large European feline population reported the presence of MYBPC3 p.A31P in one of the two British Longhair cats besides Maine Coon; however, the findings appeared insufficient to contradict the conclusion that the mutation is specific to Maine Coon [26]. ...
... The cat may develop HCM in the future since the preferred age for manifestation of HCM symptoms is about two to three years [8]. Moreover, several cats heterozygous for this variant have been reported to be HCM-unaffected [19]. A meta-analysis of numerous Maine Coon cats suggested an increased prevalence risk only in the homozygous condition [18]. ...
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Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats with a suspected genetic origin. Previous studies have identified five HCM-associated variants in three genes (Myosin binding protein C3: MYBPC3 p.A31P, p.A74T, p.R820W; Myosin heavy chain 7: MYH7 p.E1883K; Alstrom syndrome protein 1: ALMS1 p.G3376R). These variants are considered breed-specific, with the exception of MYBPC3 p.A74T, and have rarely been found in other breeds. However, genetic studies on HCM-associated variants across breeds are still insufficient because of population and breed bias caused by differences in genetic background. This study investigates the ubiquitous occurrence of HCM-associated genetic variants among cat breeds, using 57 HCM-affected, 19 HCM-unaffected, and 227 non-examined cats from the Japanese population. Genotyping of the five variants revealed the presence of MYBPC3 p.A31P and ALMS1 p.G3376R in two (Munchkin and Scottish Fold) and five non-specific breeds (American Shorthair, Exotic Shorthair, Minuet, Munchkin and Scottish Fold), respectively, in which the variants had not been identified previously. In addition, our results indicate that the ALMS1 variants identified in the Sphynx breed might not be Sphynx-specific. Overall, our results suggest that these two specific variants may still be found in other cat breeds and should be examined in detail in a population-driven manner. Furthermore, applying genetic testing to Munchkin and Scottish Fold, the breeds with both MYBPC3 and ALMS1 variants, will help prevent the development of new HCM-affected cat colonies.
... It is commonly caused by autosomal dominant gene mutations that encode various cardiac sarcomere proteins. Mutations in cardiac myosin-binding protein C3 (MYBPC3), such as A31P and A74T gene polymorphisms, have been proposed to cause HCM in Maine Coon cats [1][2][3]. Moreover, while the worldwide prevalence of MYBPC3-A31P is approximately 34-42%, the MYBPC3-A74T mutation is 35% in Maine Coon and 62% in other breeds [3][4][5]. ...
... Mutations in cardiac myosin-binding protein C3 (MYBPC3), such as A31P and A74T gene polymorphisms, have been proposed to cause HCM in Maine Coon cats [1][2][3]. Moreover, while the worldwide prevalence of MYBPC3-A31P is approximately 34-42%, the MYBPC3-A74T mutation is 35% in Maine Coon and 62% in other breeds [3][4][5]. A cohort study revealed that 100% of cats with homozygous MYBPC3-A31P mutations developed HCM within 5 years of age [6]. ...
... This study evaluated the prevalence of MYBPC3, A31P, and A74T polymorphisms in Maine Coon cats and investigated risk factors accounting for HCM in cats. The previous studies have revealed that the prevalence of single-nucleotide polymorphisms in MYBPC3 was 34-42% for A31P and 35% for A74T in Maine Coon cats worldwide [3][4][5]. In this study, the prevalence of these single-nucleotide polymorphisms in MYBPC3 was 16.33% for A31P and 22.45% for A74T. ...
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Background and aim: Hypertrophic cardiomyopathy (HCM) is a common heart problem that affects many cats. Although cats with HCM are symptomatic, some die suddenly or develop congestive heart failure. Therefore, this study aimed to estimate the prevalence of myosin-binding protein C3 (MYBPC3), A31P, and A74T polymorphisms in Maine Coon cats to assess risk factors for diagnosing HCM in cats. Materials and methods: Forty-nine Maine Coon cats of at least 10 months of age were enrolled in this study. First, clinical parameters, such as heart rate, systolic blood pressure, and echocardiography, were evaluated. Then, polymerase chain reaction, followed by DNA sequencing, was conducted using specific primers for amino acid substitutions caused by genetic variants of MYBPC3-A31P and -A74T polymorphisms. Results: Investigations showed that the prevalence of MYBPC3-A31P and -A74T mutations in this study was 16.33% and 24.45%, respectively. Moreover, HCM in cats with MYBPC3-A31P and A74T mutations increased with age, body weight, high heart rate, and prolonged isovolumic relaxation time. Conclusion: Therefore, we propose that Maine Coon cats develop HCM due to multiple genetic factors and underlying clinical characteristics in individual cats. Furthermore, relaxation time assessments can be a sensitive technique for HCM screening during its preclinical phase and can help identify the risk of developing HCM. However, further studies are warranted to evaluate the effect of MYBPC3 mutations on the phenotypic expression of HCM.
... In the colony where the variant was first found, HCM developed in all homo-and heterozygotes, though more severe in the homozygotes (Meurs et al., 2005). However, in subsequent studies in clientowned Maine Coons, it has been found that many cats carrying the variant are phenotypically normal, leading to doubts about the clinical significance of this variant or about its proposed mode of inheritance (Wess et al., 2010;Longeri et al., 2013). ...
... To provide more evidence for the mode of inheritance and optimal breeding advice, a meta-analysis of five studies has been performed (Mary et al., 2010;Wess et al., 2010;Godiksen et al., 2011;Longeri et al., 2013;Pellegrino et al., 2017). In this meta-analysis, the penetrance of HCM was found to be 0.04 in homozygous wild type Maine Coon cats. ...
... This variant is not specific for Maine Coons, as it has been found in many other breeds as well as in Domestic Shorthairs (Longeri et al., 2013). However, in subsequent studies, no convincing evidence has been found that this variant causes HCM in cats (Wess et al., 2010;Longeri et al., 2013). ...
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Hypertrophic cardiomyopathy (HCM) is a common and potentially lethal heart disease in cats. To reduce its prevalence, breeding cats are frequently screened on the basis of their phenotype or genotype. Although echocardiography is the most reliable phenotypical method, its efficacy is limited by the incomplete penetrance of HCM and by difficulties in distinguishing primary HCM from other causes of left ventricular hypertrophy. On the other hand, genetic testing is hampered by the genetic heterogeneity of the disease. Genetic tests are currently only available for Maine Coons and Ragdolls. Because of the high prevalence of HCM, stringent selection may have a negative impact on the genetic diversity of a breed. A more optimal selection would therefore be a slow and careful exclusion of phenotypically and/or genetically positive cats.
... The recognition of two sarcomeric genes, myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7), are the most essential variants in felines associated with the HCM phenotype [6,[9][10][11]. Recently, the single nucleotide polymorphism (SNP) at A31P and A74T in the MYBPC3 gene has been shown responsible for HCM in some breeds, especially Maine coon cats [1,12]. However, there are still few reports focusing on the specific gene mutation associated with HCM in Bengal cats. ...
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This study aimed to identify the potential peptide candidates and expected proteins associated with MYBPC3-A74T gene mutations in Bengal cats and determine if peptidome profiles differ between healthy controls and cats with MYBPC3-A74T gene mutations. All animals were evaluated using echocardiography. DNA was isolated and followed by the screening test of MYBPC3 gene mutation. The MALDI-TOF mass spectrometry was conducted for analyzing the targeted peptide and protein patterns. The expected protein candidates were searched for within the NCBI database. Our results demonstrated that the MYBPC3-A74T gene mutation was dominant in Bengal cats but not in domestic shorthair cats. Correlations between baseline characteristics and echocardiographic parameters were discovered in Bengal cats. Mass spectrometry profiles of the candidate proteins were suspected to accompany the cat with the MYBPC3-A74T gene mutation, involving integral protein–membrane, organization of nucleus, DNA replication, and ATP-binding protein. Therefore, MYBPC3-A74T gene mutations occur frequently in Bengal cat populations. The high incidence of homozygotes for the mutation supports the causal nature of the MYBPC3-A74T mutation. In addition, peptidomics analysis was established for the first time under this condition to promise a complementary technique for the future clinical diagnosis of the MYBPC3-A74T mutation associated with physiological variables and cardiac morphology in cats.
... HCM is a myocardial disease caused by dominant mutations in genes encoding cardiac sarcomere protein. Many gene polymorphisms, such as MYBPC3-A31P and A74T, have been detected in Maine Coon cats or cats crossbred with Maine Coon cats (1)(2)(3)(4). HCM can be characterized by an increase in left ventricular myocardial mass. However, other causes of cardiac hypertrophy, such as hyperthyroidism, systemic hypertension, and aortic stenosis, are the primary differential diagnosis for this disease (5)(6)(7). ...
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Background: Hypertrophic cardiomyopathy (HCM) has a complex phenotype that is partly explained by genetic variants related to this disease. The serum peptidome profile is a promising approach to define clinically relevant biomarkers. This study aimed to classify peptide patterns in serum samples between cats with sarcomeric gene mutations and normal cats. Materials and Methods: In the total serum samples from 31 cats, several essential proteins were identified by peptidomics analysis. The 5,946 peptides were differentially expressed in cats with sarcomeric gene mutations compared with cats without mutations. Results: Our results demonstrated characteristic protein expression in control cats, Maine Coon cats, and Maine Coon cats with gene mutations. In cats with gene mutations, peptide expression profiling showed an association with three peptides, Cytochrome 3a132 (CYP3A132), forkhead box O1 (FOXO1), and ArfGAP, with GTPase domains, ankyrin repeats, and PH domain 2 (AGAP2). Discussion: The serum peptidome of cats with mutations might provide supporting evidence for the dysregulation of metabolic and structural proteins. Genetic and peptidomics investigations may help elucidate the phenotypic variability of HCM and treatment targets to reduce morbidity and mortality of HCM in cats.
... Another variant in MYBPC3, A74T, has also been described across multiple cat breeds. However, indepth follow-up studies demonstrated that this polymorphism is unrelated to cardiomyopathy (Wess et al., 2010;Longeri et al., 2013). A third variant in MYBPC3, R820W, has been associated with HCM, most specifically in the Ragdoll (Meurs et al., 2007). ...
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Background: Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart and the most common cause of sudden cardiac death in the young. HCM is considered a disease of the sarcomere owing to the large number of mutations in genes encoding sarcomeric proteins. The riddle lies in discovering how these mutations lead to disease. As a result, treatments to prevent and/or treat HCM are limited to invasive surgical myectomies or ablations. The A31P variant of cardiac myosin binding protein-C, encoded by MYBPC3, was found to be more prevalent in a cohort of Maine Coon cats with HCM. However, other mutations in MYBPC3 and MYH7 have also been associated with HCM in cats of other breeds. In this study, we expand the spectrum of genes associated with HCM in cats. Results: Next Generation Whole Genome sequencing was performed using DNA isolated from peripheral blood of a Maine Coon with cardiomyopathy that tested negative for the MYBPC3 A31P variant. Through risk stratification of variants, we identified a novel, homozygous intronic variant in cardiac troponin T (TNNT2). In silico analysis of the variant suggested that it may affect normal splicing of exon 3 of TNNT2. Both parents tested heterozygous for the mutation, but were unaffected by the disease. Echocardiography analyses revealed that the proband had shown early onset congestive heart failure, which is managed with a treatment regime including ACE and aldosterone inhibitors. Conclusion: In summary, we are the first to demonstrate the association between TNNT2 mutations and HCM in felines, suggesting that this gene should be included in the testing panel of genes when performing genetic testing for HCM in cats.
... Measurements of the diameter of the aortic root (Ao) and the diameter of the left atrium (LA) were performed using the two-dimensional mode, right parasternal window, cross section, in the cardiac base region. An increase in AE was considered when the AE/Ao ratio was greater than 1.5 (WESS et al., 2010). The left atrial-to-aortic root diameter ratio (LA/Ao) was established by echocardiography from the right parasternal short-axis heart base view. ...
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Autosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n=12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.
... However, not all cats with MYBP3 mutation have HCM. Moreover, some cats with MYBPC3 mutation may not develop HCM [27]. Cardiac troponin I is one of the cardiac biomarkers that may be used in test for the diagnosis of HCM with high sensitivity (91.7%) and specificity (95.4%) [28]. ...
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Aim: This study aimed to determine the accuracy of the current methods for diagnosing heart diseases in cats. Materials and Methods: The data of 58 cats were retrospectively retrieved. Cats were classified into two groups: Thirty-eight cats with heart diseases and 20 healthy cats. Echocardiography was the gold standard method for diagnosing heart disease. The results of seven methods were retrieved: (1) Vertebral heart score (VHS) with a cutoff value >8, (2) VHS with a cutoff value >8.5, (3) multiplication of cardiac length (L) and width (W), (4) multiplication of cardiac L and W divided by the L of the fourth sternal thoracic bone, (5) N-terminal Pro-B-type natriuretic peptide (NT-proBNP) point-of-care test, (6) subjective ultrasonographic assessment of the left atrial size, and (7) subjective radiographic assessment of the left atrial size. Cross-tabulation was used to calculate the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for each test. This study found that using the NT-proBNP point-of-care test was optimal in the diagnosis of cats with heart disease. Results: The subjective ultrasonographic assessment of the left atrial size was good for diagnosing hypertrophic cardiomyopathy and congestive heart failure. Conclusion: This study showed that the more tests used, the higher the reliability of the diagnosis.
Heart disease is a common cause of morbidity and mortality in cats. Focused cardiac ultrasonography (FCU) is a useful diagnostic tool for identifying heart disease in symptomatic and asymptomatic cats when performed by trained veterinarians. When used in conjunction with other diagnostics such as physical examination, blood biomarkers, electrocardiography, Global FAST, and other point-of-care ultrasonographic examinations, FCU may improve clinical decision making and help clinicians prioritize which cats would benefit from referral for complete echocardiography and cardiac consultation. This article reviews the definition, advantages, clinical indications, limitations, training recommendations, and a protocol for FCU in cats.
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Zusammenfassung Zum validen Wissenstranfer neuer Erkenntnisse über Krankheiten und ihre genetischen Komponenten spielt insbesondere die Entwicklung und Beurteilung genetischer Tests in der Labormedizin zur Prävention, Diagnostik und Therapie eine Rolle. Die genetische Epidemiologie ist eine wesentliche Komponente der interdisziplinären Forschung in der Humangenetik. Sie integriert Familienstrukturen und biologische Zusammenhänge in ihre Methodik. Die wichtigsten statistischen Verfahren der genetischen Epidemiologie, nämlich Segregationsanalysen, Kopplungsanalysen und Assoziationsanalysen, haben alle Auswirkungen auf die Entwicklung genetischer Tests. Letztlich geht es um eine möglichst genaue Modellierung der Genotyp-Phänotyp-Beziehung. Hieraus lassen sich die Maßzahlen eines diagnostischen Tests entwickeln, d.h. Sensitivität, Spezifität und positiver und negativer Vorhersagewert stehen in direktem Zusammenhang mit der Prävalenz der Erkrankungen und den Penetranzen für die Genotypen. Eine evidenzbasierte Beurteilung diagnostischer Tests verlangt die Untersuchung analytischer Validität, klinischer Validität, klinischer Nützlichkeit und ethischer, legaler und sozialer Grundlagen.
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The cardiac myosin binding protein C gene is mutated in Maine Coon (MC) cats with familial hypertrophic cardiomyopathy. Early diastolic mitral annular velocity is incrementally reduced from normal cats to MC cats with only an abnormal genotype to MC cats with abnormal genotype and hypertrophy. Group 1 consisted of 6 normal domestic shorthair cats, group 2 of 6 MC cats with abnormal genotype but no hypertrophy, and group 3 of 15 MC cats with hypertrophy and abnormal genotype. The genotype and echocardiographic phenotype of cats were determined, and the cats were divided into the 3 groups. Tissue Doppler imaging (TDI) of the lateral mitral annulus from the left apical 4-chamber view was performed. Five nonconsecutive measurements of early diastolic mitral annular velocity (EM) or summated early and late diastolic velocity (EAsum) and heart rate were averaged. There was an ordered reduction in Em-EAsum as group number increased (group 1, range 9.7-14.7 cm/s; group 2, range 7.5-13.2 cm/s; group 3, range 4.5-14.1 cm/s; P = .001). Using the lower prediction limit for normal Em-EAsum, the proportion of cats with normal Em-EAsum decreased as the group number increased (P = .001). However, Em-EAsum was reduced in only 3 of 6 cats in group 2. The incremental reduction of Em-EAsum as group severity increased indicates that diastolic dysfunction is an early abnormality that occurs before hypertrophy development. TDI measurement of Em or EAsum of the lateral mitral annulus is an insensitive screening test for identification of phenotypically normal, genotypically affected cats.
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A mutation in the sarcomeric gene coding for the myosin-binding protein C gene has been identified in a colony of Maine Coon cats with hypertrophic cardiomyopathy (MyBPC3-A31P mutation). However, the close correlation between genotype and phenotype (left ventricular hypertrophy [LVH] and dysfunction) has never been assessed in a large population, particularly in heterozygous (Hetero) cats. To investigate LV morphology and function with echocardiography and tissue Doppler imaging (TDI) in a population of Maine Coon cats tested for the MyBPC3-A31P mutation with focus on Hetero animals. Ninety-six Maine Coon cats. Prospective observational study. Cats were screened for the MyBPC3-A31P mutation and examined with both echocardiography and 2-dimensional color TDI. Fifty-two out of 96 cats did not have the mutation (wild-type genotype, Homo WT), 38/96 and 6/96 were Hetero- and homozygous-mutated (Homo M) cats, respectively. Only 11% of Hetero cats (4/38) had LVH and 29% (10/34) of Hetero cats without LVH were >4 years old (4.1-11.5 years). LVH was also detected in 2 Homo WT cats (4%). A significantly decreased (P < .05) longitudinal E/A (ratio between early and late diastolic myocardial velocities) in the basal segment of the interventricular septum was observed in Hetero cats without LVH (n = 34) compared with Homo WT cats without LVH (n = 50), thus confirming that the Hetero status is associated with regional diastolic dysfunction (P < .05). The heterozygous status is not consistently associated with LVH and major myocardial dysfunction. Moreover, Homo WT cats can also develop LVH, suggesting that other genetic causes might be implicated.
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Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy, is the most common inherited cardiac disorder. This condition is the major cause of sudden death in the young (<30 years of age) and in athletes. The clinical phenotype is heterogeneous, and mutations in a number of sarcomeric contractile-protein genes are responsible for causing the disease in approximately 60% of individuals with HCM. Other inherited syndromes, as well as metabolic and mitochondrial disorders, can present as clinical phenocopies and can be distinguished by their associated cardiac and noncardiac features and on the basis of their unique molecular genetics. The mode of inheritance, natural history and treatment of phenocopies can differ from those of HCM caused by mutations in sarcomere genes. Detailed clinical evaluation and mutation analysis are, therefore, important in providing an accurate diagnosis in order to enable genetic counseling, prognostic evaluation and appropriate clinical management. This Review summarizes current knowledge on the genetics, disease mechanisms, and correlations between phenotype and genotype in patients with HCM, and discusses the implications of genetic testing in routine clinical practice.
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A naturally occurring animal model of familial hypertrophic cardiomyopathy (FHCM) is lacking. We identified a family of Maine coon cats with HCM and developed a colony to determine mode of inheritance, phenotypic expression, and natural history of the disease. A proband was identified, and related cats were bred to produce a colony. Affected and unaffected cats were bred to determine the mode of inheritance. Echocardiography was used to identify affected offspring and determine phenotypic expression. Echocardiograms were repeated serially to determine the natural history of the disease. Of 22 offspring from breeding affected to unaffected cats, 12 (55%) were affected. When affected cats were bred to affected cats, 4 (45%) of the 9 were affected, 2 (22%) unaffected, and 3 (33%) stillborn. Findings were consistent with an autosomal dominant mode of inheritance with 100% penetrance, with the stillborns representing lethal homozygotes that died in utero. Affected cats usually did not have phenotypic evidence of HCM before 6 months of age, developed HCM during adolescence, and developed severe HCM during young adulthood. Papillary muscle hypertrophy that produced midcavitary obstruction and systolic anterior motion of the mitral valve was the most consistent manifestation of HCM. Cats died suddenly (n=5) or of heart failure (n=3). Histopathology of the myocardium revealed myocardial fiber disarray, intramural coronary arteriosclerosis, and interstitial fibrosis. HCM in this family of Maine coon cats closely resembles the human form of FHCM and should prove a valuable tool for studying the gross, cellular, and molecular pathophysiology of the disease.
Hypertrophic cardiomyopathy (HCM) is an unexplained left ventricular hypertrophy (LVH) in the absence of precipitating factors such as hypertension or aortic stenosis. HCM is a disease of enormous phenotypic and genotypic heterogeneity. Affecting 1 in 500 people, it is the most prevalent genetic cardiovascular disease. It can manifest itself with negligible to extreme hypertrophy, minimal to extensive fibrosis and myocyte disarray, absent to severe left ventricular outflow tract obstruction, and distinct patterns of hypertrophy. The clinical presentation of HCM is underscored by extreme variability from an asymptomatic course to that of severe heart failure and arrhythmias. It commonly manifests itself between the second and the fourth decades of life, but can present itself at the extremes of age. Infants and young children may be affected with severe hypertrophy leading to heart failure, and these patients have poor prognosis. The most common symptoms are exertional dyspnea, chest pain, and syncope or presyncope. Approximately 5% of patients with HCM progress to "end-stage" disease characterized by left ventricular dilatation and heart failure. In such cases, cardiac transplantation may be considered. Other serious life-threatening complications include embolic stroke and cardiac arrhythmias. Genetic and clinical screening of family members with HCM plays an important role in its early diagnosis.
Mutations in genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). The sarcomeric protein actin plays a central, dual role in cardiac myocytes, generating contractile force by interacting with myosin and also transmitting force within and between cells. Two missense mutations in the cardiac actin gene (ACTC), postulated to impair force transmission, have been associated with familial dilated cardiomyopathy (DCM). Recently, a missense mutation in ACTC was found to cosegregate with familial HCM. To further test the hypothesis that mutations within functionally distinct domains of ACTC cause either DCM or HCM, we performed mutational analyses in 368 unrelated patients with familial or sporadic HCM. Single strand conformation polymorphism and sequence analyses of genomic DNA were performed. De novo mutations in ACTC were identified in two patients with sporadic HCM who presented with syncope in early childhood. Patients were heterozygous for missense mutations resulting in Pro164Ala and Ala331Pro amino acid substitutions, adjacent to regions of actin-actin and actin-myosin interaction, respectively. A mutation that cosegregated with familial HCM was also found, causing a Glu99Lys substitution in a weak actomyosin binding domain. The cardiac phenotype in many affected patients was characterized by an apical form of HCM. These findings support the hypothesis that a single amino acid substitution in actin causes either congestive heart failure or maladaptive cardiac hypertrophy, depending on its effect on actin structure and function.