2009 Vienna - European Society of Human Genetics

Concurrent Sessions
had immotile cilia and no outer dynein arms, were transduced by the
lentivirus. Cilia beating was recorded and electron microscopy of the
cilia was performed.
Results: Transcription and translation of the transduced DNAI1 gene
were detected in human cells treated with the lentivirus. In addition,
immotile cilia recovered a normal beat and outer dynein arms reappeared.
Conclusion: This is the first time that recovery of cilia beating is demonstrated
in this disease. This preliminary step constitutes a conceptual
proof which is indispensable in the perspective of Primary Ciliary
Dyskinesia’s in vivo gene therapy.
c13.1
clinical characteristics of distantly related families with
idiopathic ventricular fibrillation linked to chromosome 7q36
I. Christiaans 1,2 , M. Alders 1 , T. T. Koopmann 3 , P. G. Postema 2 , K. P. Loh 4 , K.
Zeppenfeld 5 , C. R. Bezzina 3 , A. A. M. Wilde 2,3 ;
1 AMC, Department of Clinical Genetics, Amsterdam, The Netherlands, 2 AMC,
Department of Cardiology, Amsterdam, The Netherlands, 3 AMC, Department
of Experimental Cardiology, Heart Failure Research Centre, Amsterdam, The
Netherlands, 4 UMCU, Department of Cardiology, Utrecht, The Netherlands,
5 LUMC, Department of Cardiology, Leiden, The Netherlands.
Introduction: Idiopathic ventricular fibrillation (IVF) is characterised by
VF in the absence of structural or electrical heart disease. With genome
wide haplotype sharing analysis we identified an IVF locus on
chromosome 7q36. This locus harbors the DPP6 gene and was found
in 10 distantly related families with IVF and unexplained sudden cardiac
death (SCD).
Methods: We studied echocardiograms, MRIs, ECG characteristics at
baseline, exercise and at ajmaline/flecainide provocation, and eventfree
survival.
Results: We identified 254 relatives, 117 carriers (mean age 43±20
years, 56% males) and 137 noncarriers (mean age 40±21 years,
44% males). Echocardiography (n=33) and MRI (n=43) did not reveal
significant or consistent abnormalities. Baseline and exercise
ECG characteristics were not different between groups and provocation
with ajmaline/flecainide was negative in six resuscitated carriers.
SCD/IVF had occurred in 37 carriers (32%, median age 34 years).
Kaplan-Meier curves showed severely decreased survival for carriers
with only 50% event-free at 60 years of age. Male carriers seemed to
be more severely affected with 50% event-free survival at 48 years of
age (p=0.004). At present, an implantable defibrillator seems the only
treatment option in carriers.
Conclusions: We identified a novel IVF locus on chromosome 7q36
which harbors the DPP6 gene. The associated phenotype is extremely
malignant and presents as premature IVF/SCD. Genetic testing for
the responsible haplotype is currently the only risk marker in these
patients. This raises the unique possibility to assess the risk status
of, and treat accordingly, presymptomatic individuals with a potentially
fatal disease that does not express otherwise.
c13.2
the yield of family screening in sudden unexplained death in the
young
C. Van der Werf, N. Hofman, H. L. Tan, I. M. Van Langen, A. A. M. Wilde;
Academic Medical Center, Amsterdam, The Netherlands.
Introduction: Sudden death of a young person is not explained by autopsy
in 6-65%, which is termed sudden unexplained death (SUD). In
these cases, molecular autopsy and cardiological and genetic examination
in surviving first degree relatives might unmask its cause, especially
primary arrhythmia syndromes. We sought to determine the yield
of family screening in a large series of young SUD victims.
Methods: At the cardiogenetics department of our university hospital,
we studied all consecutive families who presented with ≥1 first degree
related SUD victim aged 1-50 years. Autopsy was not performed
(53.8%) or did not reveal a cause of death. The initial examination of
the relatives consisted of personal and family medical history and a
resting ECG. Cardiac autopsy was revised if possible. Additional cardiological
examinations were performed on indication. Genetic analysis
of the associated candidate gene(s) was performed in material
obtained from the deceased person or in those relatives with clinical
abnormalities.
Results: The families of 115 SUD victims (mean age at death 29.1
years, 67.8% male) were examined. Per family, a mean of 2.5 (1-8)
first-degree relatives were examined (N=242). A (probable) diagnosis
was made in 36 of the families (31.3%). Catecholaminergic polymorphic
ventricular tachycardia (N=8) and long QT syndrome (N=7) were
the most common diagnoses.
Conclusions: By screening family members of a young SUD victim an
inherited heart disease is identified in approximately 31% of families.
Family screening at a specialized cardiogenetics department should
be recommended to relatives of SUD victims.
c13.3
mutations in the ANKRD1 gene encoding cARP are responsible
for human dilated cardiomyopathy
L. Duboscq-Bidot 1,2 , P. Charron 3,2 , V. Ruppert 4 , L. Fauchier 5 , A. Richter 4 , L.
Tavazzi 6 , T. Wichter 7 , B. Maish 4 , M. Komajda 8,2 , R. Isnard 8,2 , E. Villard 1,9 ;
1 INSERM UMR956, Paris, France, 2 Groupe hospitalier Pitié-Salpêtrière, Paris,
France, 3 Département de génétique, Paris, France, 4 Universitätsklinikum
Gießen und Marburg GmbH, Marburg, Germany, 5 CHU Trousseau, Tours,
France, 6 Fondazione IRCCS Policlinico San Matteo, pavi, Italy, 7 Department
of Cardiology and Angiology, Münster, Germany, 8 Département de cardiologie,
Paris, France, 9 Centre d’investigation Biomédicale Pitié Salpétriére, Paris,
France.
Dilated Cardiomyopathy (DCM) is familial in about 30% of cases, and
to date, 15 responsible genes have been identified in isolated forms
and up to 25 associated with additional phenotypes including myopathy,
arrythmias or more complex syndromes. No major gene for the
disease has been identified, demonstrating the genetic heterogeneity
of DCM. However, in a majority of families the responsible genes are
still to be discovered.
The ANKRD1 gene is overexpressed in heart failure in human or animal
models. The encoded protein CARP is interacting with partners
such as Myopalladin or Titin, previously involved in DCM. We hypothesised
that mutations in ANKRD1 could be responsible for DCM.
We have screened a DCM affected population consisting on 231
caucasian independent familial (158) and sporadic (73) cases by direct
sequencing of PCR-amplified coding exons. We identified 5 missense
mutations : 3 sporadic (mutations p.Glu57Gln, p.Arg66Gln and
p.Leu199Arg ) and 2 familial (mutations p.Thr116Met and p.Ala276Val)
absent from 400 controls and affecting highly conserved residues.
Expression of the mutant CARP proteins in rat neonate cardiomyocytes
indicated that at least 3 of the mutations identified (p.Glu57Gln,
p.Leu199Arg, p.Ala276Val) led both to significant less repressor activity
and to greater phenylephrin induced hypertrophy suggesting altered
function of CARP mutant proteins. Based on genetic and functional
analysis of CARP mutations, we have identified ANKRD1 as a new
gene associated with DCM, accounting for about 4% of cases.
c13.4
clinical Features and Outcome of Hypertrophic cardiomyopathy
Associated with triple sarcomere Protein Gene mutations
F. Girolami 1 , I. Olivotto 2 , C. Giuliani 1 , A. Mariottini 1 , I. Passerini 1 , M. Ackerman 3 ,
F. Cecchi 2 , F. Torricelli 1 ;
1 AOU Careggi-SOD Diagnostica Genetica, Florence, Italy, 2 AOU Careggi-Regional
Referral Center for Myocardial Diseases, Florence, Italy, 3 Mayo Clinic
College of Medicine, Rochester, MN, United States.
Double or compound sarcomere gene mutation heterozygosity have
been described in 3-6% of hypertrophic cardiomyopathy (HCM) patients,
and is associated with early disease onset and severe outcome.
In the present study, we provide the first description of the clinical profile
associated with triple sarcomere gene mutations in a large, consecutive
HCM cohort.
A total of 247 unrelated index HCM patients underwent screening for myofilament
gene mutations by automatic DNA sequencing of eight genes:
MYBPC3, MYH7, TNNT2, MYL2, MYL3, TNNI3, TPM1, and ACTC.
Of the 247 index patients, 3 (1%) harboured triple gene mutations, as
follows: MYH7-R869H, MYBPC3- E258K and TNNI3-A86fs in a 32year
old female; MYH7-R273C, MYH7-E1455X and MYBPC3-E165D
in a 46-year old male; and MYBPC3-insC1065, MYBPC3-P371R and
MYH7- R869H in a 45-year old female. All 3 experienced early onset
of severe HCM phenotype, marked symptoms and progression of disease
towards the end-stage phase by the fourth decade, requiring, in
one instance, cardiac transplantation. Moreover, all had multiple risk
factors for sudden cardiac death, including resuscitated cardiac arrest