2009 Vienna - European Society of Human Genetics

Molecular and biochemical basis of disease
Methods: We used the Family Tree Mortality Ratio (FTMR) method to
study all cause mortality in times when the disease was not elucidated
and patients were untreated (i.e. the natural course). Four large pedigrees
dating back to the 19 th century were obtained: a pedigree with
carriers for LQTS1 (n=55 persons), LQTS2 (n=76), LQTS3 (n=179)
and CPVT (n=178). All persons in the pedigrees had a 100 % or 50%
probability of carriership. All cause mortality was compared to the general
Dutch population in similar time intervals (SMR).
Results: For LQTS1; there was significant excess mortality in males
(SMR 1.9, CI 1.2-2.9), especially in the age categories 1-9 years (SMR
3.4,CI 1.3-7.4). For LQTS2 patients there was significant excess mortality
between 5-14 years (SMR 4.8, CI 1.3-12.3). For LQTS3; severe
excess mortality occurred in the age categories 10-49 (SMR 3.8, CI
2.4-5.7). For CPVT patients there was significant excess mortality in
the age category 20-29 years (SMR 3.91, CI 1.27-9.12).
Conclusions: We demonstrate by using the FTMR method significant
excess mortality in specific age categories that differ between
diseases. This information might help to guide timely screening and
treatment of (asymptomatic) patients who are carrier of an inherited
(cardiac) disorder.
P16.06
Obstructive Left-sided cardiac Lesion in A saudi Family
H. Y. Al-Abdulwahed1 , E. H. Bou-Holaigha2 , N. A. Al-Sannaa2 ;
1 2 Dhahran Health Center, Dhahrab, Saudi Arabia, Dhahran Health Center,
Dhahran, Saudi Arabia.
Congenital cardiac defects are relatively common and occur in about
1 in 200 births (Harper, 2004). They are known to be associated with
many well described genetic disorders. Here, we reviewed a highly
consanguineous Saudi family with left-sided obstructive cardiac lesion.
It was characterized by a small transverse aortic isthmus and small
aortic valve annulus that was affecting several members. The segregation
of this observed congenital anomalies was suggestive of an
autosomal recessive mode of inheritance. Karyotype and FISH study
for chromosome 22q11.2 was normal. There was no documented associated
malformation.
Carrying out a genetic study to identify the disease causing mutation
is necessary in order to provide appropriate genetic counseling interventions.
P16.07
Progress in development of UK inherited cardiovascular
conditions (ICC) services in the light of recent scientific
advances
H. Burton, C. Alberg, A. Stewart;
PHG Foundation, Cambridge, United Kingdom.
There are many different forms of rare inherited disease that cause
sudden cardiac death, arrhythmias and other cardiovascular conditions.
Together, individuals with these diseases represent a significant
component of both cardiac and genetics services. In the last ten years
rapid advances in our understanding of the pathological basis of inherited
cardiac disease, clinical features and associated risks has created
the potential for the effective clinical management of patients and
their families. In particular, highly specialised services combining both
cardiology and genetics expertise are required. In 2008 -09 the PHG
Foundation led a group of key experts and stakeholders including geneticists,
cardiologists, health service commissioners and managers
and representatives of relevant voluntary organisations, in a review
of UK provision in inherited cardiovascular conditions. Findings will
be presented including some estimates of current service need and
shortfall in the UK, a review of current services and agreed important
features of a high quality specialist ICC service. The potential impact
of new technologies will also be considered.
The presentation will include key recommendations for development
of ICC services in the UK that will be applicable in other European
countries.
P16.08
molecular testing of cardiomyopathy Families in the West of
scotland
I. N. Findlay 1 , V. A. Murday 2 , K. Thomson 3 ;
1 Western Infirmary, Glasgow, United Kingdom, Glasgow, United Kingdom, 2 Ferguson
smith Centre for Clinical Genetics,, Glasgow, United Kingdom, 3 Oxford
Regional Molecular Genetics Laboratory, Oxford, United Kingdom.
An Inherited Cardiac Clinic was established in the West of Scotland in
2007. Genotyping has been carried out in121 familes, 84 with hypertrophic
cardiomyopathy (HCM), 33 with definite familial dilated cardiomyopathy
(FDCM) and 4 with left ventricular non-compaction (LVNC).
In HCM families we have detected sarcomeric protein mutations in
59 (70%) , 58% of these are in MYBPC3, 27% in MYH7 and 7% in
TNNT2, 3 families have two mutations in MYH7/MYBPC3. In sporadic
HCM the detection rate was only 40%, in those with a FH it was 84%,
and in those with FH of sudden cardiac death detection rate 93%.
In 33 with FDCM, 30 families have had sarcomeric proteins analysis,
seven in addition had lamin A and three families had Lamin A only.
Only 6 mutations were detected (18%), 2 MYH7, 1 TNNT2, 1TNNI3
and 2 Lamin A mutations (+ one variant of unknown significance) .
In 4 families with LVNC we have detected 2 sarcomeric mutations (1
MYH7 and 1 MYBPC3)
Conclusion. Mutations were identified in 70% of families with HCM,
with a high detection of 93% in those with a family history of sudden
cardiac death but only 40% in sporadic cases. The turn around time for
results from the index case is now down to around 3 months making
cascade screening efficient and realistic in patients with HCM. This
is not the case yet in FDCM and a reassessment of the genes to be
screened is underway.
P16.09
Novel desmocollin-2 gene mutation associated with
arrhythmogenic biventricular cardiomyopathy
L. Núñez, L. Monserrat, R. Barriales-Villa, M. I. Rodríguez, M. Ortiz, E. Maneiro,
X. Fernández, L. Cazón, E. Veira, A. Castro-Beiras, M. Hermida-Prieto;
Instituto Universitario de Ciencias de la Salud-CHUAC, A Coruña, Spain.
Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC)
is a frequent cause of sudden death. The disease is usually caused
by mutations in desmosomal genes (desmoplakin,desmocollin-2,desmoglein-2,plakophilin-2
and plakoglobin), which have been associated
with left ventricular involvement.
Material and methods: Clinical, familial and genetic (direct sequencing
of five desmosomal genes) study of a Spanish group of no related
patients with ARVC was done.
Results: A novel splice site mutation in intron 11 of desmocollin-2 gene
(IVS11+2T>C) was detected in a 44 year old ex-professional polevault-jumper
who had suffered a cardiac arrest while jogging. This
change was absent in 100 caucasian healthy controls and a truncation
of the protein in exon 11 was predicted. His baseline electrocardiogram
showed negative T-waves in right precordial leads. The echocardiogram
showed left ventricle dilation (56 mm) and systolic dysfunction
(ejection-fraction:45%), and mild global right ventricle dilation with
hypo- and akinetic areas in the outflow tract. A cardiac defibrillator was
implanted and a single appropriate intervention was recorded five years
later. At family screening, the mutation was found in his asymptomatic
70 year old father, who showed left ventricular dilation (60 mm) with
systolic dysfunction (ejection-fraction:50%), and mild right ventricular
dilation with doubtful areas of hypertrabeculation and hypokinesia.
Conclusions: Only 5 ARVC related mutations have been previously
described desmocollin-2. Most of them have left ventricular involvement,
as we found in our two carriers. Competitive sport practice could
have contributed to an earlier and more severe disease expression
with malignant ventricular arrhythmias. Desmocollin-2 gene mutations
could early affect left ventricle.
P16.10
sporadic arrhythmogenic right ventricular cardiomyopathy due
to a de novo mutation
E. Gandjbakhch 1,2 , V. Fressart 3 , G. Bertaux 4 , L. Faivre 5 , F. Simon 3 , R. Frank 2 ,
G. Fontaine 2 , E. Villard 1 , C. Coirault 6 , B. Hainque 3,6 , P. Charron 2,1 ;
1 Inserm U956, Paris, France, 2 Département de Cardiologie, Hôpital Pitié-Salpêtrière,
Paris, France, 3 Service de Biochimie, Unité de Cardiogénétique et Myogénétique,
Hôpital Pitié-Salpêtrière, Paris, France, 4 Département de Cardiologie,
Centre hospitalier universitaire, Dijon, France, 5 Département de Génétique,
Centre hospitalier universitaire, Dijon, France, 6 Inserm U582, Paris, France.
We report the case of a 41-year-old man with a diagnosis of sporadic
arrhythmogenic right ventricular cardiomyopathy (ARVC). The diagnosis
fulfilled the International Task Force diagnostic criteria with extensive
T-wave inversion on the electrocardiogram (ECG), late potentials