2009 Vienna - European Society of Human Genetics

Molecular and biochemical basis of disease
in common analysis) and in MYBPC3(novel). The patient group consisted
of 16 individuals with a clinical diagnostic of HCM. DNA extraction
was extracted from peripheral blood. All samples from the patient
group were genotyped by MSG using a MassARRAY MALDI-TOF. The
samples with no mutation found were scanned for novel mutations by
HRM. All variants found were confirmed by automatic sequencing. The
CSRP3 c.128delC mutation was found in heterozygoty in a 50-year
old patient with diffused left ventricle hypertrophy. A novel mutation
of the MYBPC3 was discovered in another HCM patient: c.C>T817/
p.Arg273Cys. Although still uncharacterized as disease-causing,
affects a codon known to harbor a known HCM-causing mutation -
p.Arg253His. This coupling of innovative techniques allowed the detection
both of a known mutation on a seldom analyzed gene and a
probably HCM-causing novel mutation.
P16.28
Familial noncompaction cardiomyopathy: genetic and
cardiologic features in adults and children
Y. M. Hoedemaekers1 , K. Caliskan1 , M. Michels1 , I. Frohn - Mulder1 , J. van der
Smagt2 , J. E. Phefferkorn1 , F. J. ten Cate1 , D. Dooijes1 , D. F. Majoor - Krakauer1
;
1 2 Erasmus Medical Center, Rotterdam, The Netherlands, University Medical
Center Utrecht, Utrecht, The Netherlands.
Background: Noncompaction cardiomyopathy (NCCM) features a
thickened bilayered left ventricular wall with a thin, compact epicardial
layer and a thick endocardial layer with prominent intertrabecular recesses.
NCCM is genetically heterogeneous. Similarly to hypertrophic
(HCM) and dilated cardiomyopathy (DCM), NCCM has been associated
with mutations in sarcomere genes. In order to contribute to a genetic
classification for NCCM a systematic cardiologic family study was
performed in a cohort of 56 consecutively diagnosed and molecularly
screened patients with isolated NCCM (47 adults and nine children).
Methods and Results: Cardiologic screening with electrocardiography,
echocardiography and physical examination of 169 relatives
from 46 unrelated NCCM probands revealed familial cardiomyopathy
in 34 families (74%), including NCCM, HCM and DCM. Seventy-four
percent of the relatives newly diagnosed with cardiomyopathy were
asymptomatic, explaining that 54% of familial disease remained undetected
by ascertainment of family history prior to cardiologic screening.
The molecular screening included analysis of 17 genes yielding 29
different mutations in 23 probands (41%); 18 adult and five children.
Fifteen single mutations and one double mutation on the same allele
were transmitted in an autosomal dominant mode. Six adults and two
children were compound or double heterozygous for two different mutations.
In 19/34 (56%) of familial NCCM the genetic defect remained
unknown.
Conclusion: NCCM is predominantly a genetic disorder, requiring genetic
counseling, DNA diagnostics and, also in absence of a genetic
cause, cardiologic family screening.
P16.29
takotsubo and congenital LQts in a patient with a novel
mutation in the KCNH gene
F. Fellmann 1 , E. Pruvot 2 , L. Sintra Grilo 3 , M. Grobéty 4 , V. Castella 5 , J. S. Beckmann
1,6 , H. Abriel 3 ;
1 Service of Medical Genetics, CHUV, Lausanne, Switzerland, 2 Service of Cardiology,
CHUV, Lausanne, Switzerland, 3 Department of Pharmacology and
Toxicology, University of Lausanne, Lausanne, Switzerland, 4 Clinique Cécil,
Lausanne, Switzerland, 5 University Center of Legal Medicine, Lausanne, Switzerland,
6 Dept of Medical Genetics, UNIL, Lausanne, Switzerland.
Delayed cardiac repolarization may be caused by inherited mutations
in cardiac ion channel gene subunits (congenital long QT syndrome,
LQTS) or secondary to cardiac pathologies, including the recently-described
Takotsubo cardiomyopathy.
We report the case of a female patient admitted at the emergency
ward of the Lausanne university hospital because of a sudden convulsive
syncopal event. The observation of a transient alteration of the
ECG repolarization with a torsades de pointes episode 9 days after a
surgical stress suggested a Takotsubo cardiomyopathy. After transient
normalization of the ECG, congenital LQTS was diagnosed on the basis
of a persistent QT prolongation. Genetic analyses identified a 7
amino-acid duplication (nc.343-363dup) located in the PAS domain of
hERG1 N-terminus in the gene KCNH2 coding for the hERG1 channel.
This mutation has not been reported yet.
Three recent case reports suggested that both LQTS and Takotsubo
syndrome may be causally related but no mutation in the LQTS genes
have been identified yet.In conclusion, we describe a patient with Takotsubo
uncovering a congenital form of LQTS. We show that LQTS is
caused by an unusual KCNH2 mutation that has been characterized
at the biophysical and biochemical levels. A putative causal relationship
between LQTS and Takotsubo is discussed. However, the mechanisms
underlying the link between the two disorders, if any, remain to
be investigated.
P16.30
Does δ-sarcoglycan-associated autosomal dominant
cardiomyopathy exist?
A. Sarkozy 1 , R. Bauer 1 , J. Hudson 1 , H. D. Müller 2 , C. Sommer 2 , G. Dekomien 3 ,
J. Bourke 4 , D. Routledge 1 , K. Bushby 1 , J. Klepper 5 , V. Straub 1 ;
1 Institute of Human Genetics, Newcastle University, International Centre for
Life, Newcastle upon Tyne, United Kingdom, 2 Department of Neuropathology,
University of Mainz, Mainz, Germany, 3 Institute of Human Genetics, Ruhr-
University Bochum,, Bochum, Germany, 4 Department of Cardiology, Freeman
Hospital, Newcastle upon Tyne, United Kingdom, 5 Department of Pediatrics,
Klinikum Aschaffenburg, Aschaffenburg, Germany.
The sarcoglycans are part of the dystrophin-glycoprotein-complex
(DGC), an oligomeric complex spanning the plasma membrane of
skeletal and cardiac muscle fibres. The sarcoglycan deficient limb
girdle muscular dystrophies (LGMDs) are characterized by progressive
weakness of the pelvic and shoulder girdle musculature and affected
patients often develop a progressive and potentially fatal dilated
cardiomyopathy (DCM). Dominant inheritance has not been reported
in sarcoglycan-deficient LGMD. However, a previous report described
autosomal dominant mutations in the δ-sarcoglycan (SGCD) gene in
patients with familial and sporadic cases of DCM without significant
skeletal muscle involvement. Here we clinically and genetically characterize
a consanguineous family with a homozygous novel missense
mutation (p.A131P) in the SGCD gene and a second δ-sarcoglycan
mutation that has previously been reported to cause a fatal autosomal
dominant DCM at young age. This second heterozygous mutation
(p.S151A) was found in 4 heterozygous carriers for the A131P mutation,
aged 3 to 64 years. Comprehensive clinical and cardiac investigation
in all of the compound heterozygous family members revealed no
signs of cardiomyopathy or LGMD. Even in the presence of a second
disease causing mutation, the p.S151A mutation in the SGCD gene
does not result in cardiomyopathy. This finding questions the pathological
relevance of this sequence variant for causing familial autosomal
dominant DCM and thereby the role of the SGCD gene in general as a
disease causing gene for autosomal dominant DCM.
P16.31
Blood pressure changes associated with eNOs gene
polymorphism at patients with stress cardiomyopathy
E. Kovaleva, E. Zemtsovskiy, V. Larionova;
Pediatric Medical Academy, St.-Petersburg, Russian Federation.
Objective: Possibility of pathological changes in myocardium caused
by acute stress influence is well-known at this moment. At the same
time chronic psychoemotional stress (PES) could be an independent
reason of stress cardiomyopathy (SKMP) at the high-risk professional
group’s person, which may have genetic markers of «low stress resistance»,
associated with vascular reactions caused by PES. We investigate
blood pressure (BP) level and endothelial NO-synthase gene
(eNOS) polymorphism at the persons exposed to chronic professional
PES’ influence and also with noncoronarogenic heart’ damages.
Design and methods. The subjects of research were railway’ engine-drivers:
58 men with SKMP diagnosed in case finding clinically
significant arrhythmia and electrical conductivity disturbance at 24-h
ECG monitoring and also non-ischemic repolarization abnormalities
on ECG and/or ECG stress test. Exception criteria were coronary disease,
arterial hypertension (above 140/90 mmHg), Primary/secondary
cardiomyopathy other genesis, including inflammatory compared
with 78 men without a cardiovascular pathology. All patients underwent
clinical BP measurement and analysis for 4a/4b eNOS gene polymorphism
by PCR.
Results. The systolic (SBP) and diastolic (DBP) blood pressure levels
at 4a (genotypes 4a/4b and 4a/4a) SKMP patients were signifi-