2009 Vienna - European Society of Human Genetics

Molecular and biochemical basis of disease 0
on the signal-averaged-ECG and typical abnormalities of the right ventricle
on cardiac imaging. We documented right ventricular arrhythmia
with frequent spontaneous ventricular ectopies and fast ventricular
tachycardia with left-bundle-branch block morphology induced by the
electrophysiological study. The genetic screening of the four desmosomal
genes known to be involved in ARVC (plakophilin-2, desmoplakin,
desmoglein-2 and desmocollin-2) identified the heterozygous
missense mutation R49H in the desmoglein-2 gene. This mutation is
located in the highly conserved cleavage motif RXK/RR that is recognized
by pro-protein convertases and is thus predicted to prevent efficient
pro-desmoglein-2 maturation. The mutation was absent in both
parents, and we demonstrated that it was a de novo mutation. To our
knowledge, this is the first description of a de novo mutation in ARVC.
Appearance of a de novo mutation in the desmoglein-2 gene (that is an
essential component of desmosome that mediates cell-to-cell adhesion)
provides compelling genetic evidence for the involvement of this
gene in ARVC. The recognition of de novo mutations has important implications,
including for clinical practice, since individuals with sporadic
ARVC caused by a de novo mutation can transmit the disease gene
to 50% of their offspring. This suggests that the benefit of molecular
genetics can be extended to sporadic ARVC, and may improve genetic
counselling.
P16.11
implications of consanguinity in families with hypertrophic
cardiomyopathy
K. van Engelen, M. J. H. Baars, A. A. M. Wilde, R. H. Lekanne dit Deprez, I. M.
van Langen;
Academic Medical Centre, Amsterdam, The Netherlands.
Introduction: By presenting two cases, we illustrate the implications
of consanguinity in families with hypertrophic cardiomyopathy (HCM),
with respect to patient care and DNA-analysis techniques.
Case reports: Case 1: A man with HCM due to the c.2609G>A mutation
in MYH7 died suddenly at age 43. His wife was asymptomatic, but
because she was a second cousin of the proband, we performed DNAanalysis
on her. She carried the same mutation. DNA-analysis in their
asymptomatic 5 year-old son showed homozygosity for this mutation.
At cardiologic exam, he had severe signs of HCM and is now carefully
followed at a paediatric cardiology department.
Case 2: The son of an asymptomatic consanguineous couple (first
cousins) had a myectomy because of obstructive HCM at age 10 and
ICD-implantation at age 17 because of ventricular tachycardia. Using
DHPLC, no mutations were identified in MYH7, MYBPC3 and TPM1.
Because this boy had the same family name as the man in case 1,
we performed sequence analysis to see if the c.2609G>A mutation
in MYH7 could be detected. The mutation was found to be present in
homozygous state, which had been missed by DHPLC.
Conclusion: These cases illustrate that in consanguineous families with
HCM, presence of a pathogenic mutation in both persons of a couple
must be considered, with the subsequent possibility of homozygosity
in their children. (Presymptomatic) DNA-analysis is recommended for
at risk consanguineous partners and young children who are at risk for
homozygosity. Mutation analysis techniques that allow the detection of
homozygous mutations must be used.
P16.12
Geno-phenotype characterisation of hypertrophic
cardiomyopathy patients that evolve through end-stage heart
failure
N. Marziliano, M. Grasso, M. Pasotti, M. Tagliani, A. Pilotto, E. Serafini, P.
Cassini, B. Digiorgio, A. Serio, E. Arbustini;
Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy.
Heart transplantation (HTx) is the sole therapeutic option for selected
patients with hypertrophic cardiomyopathy (HCM) and congestive
heart failure (CHF). We aimed at determining the prevalence and the
outcomes of a consecutive series of genotyped patients diagnosed
with HCM with a dilatative or restrictive evolution. The clinical series is
constituted of 146 unrelated probands diagnosed with HCM and 244
genotyped relatives. HCM was diagnosed according to the WHO criteria.
Probands and relatives underwent genetic testing after genetic
counselling and written consent. Of 390 genotyped individuals, 280
were affected and 110 healthy carriers. The mean age of affected
members was significantly higher compared to those of the healthy
carriers (34.8±17.2 vs 28.5±16.3 years, p=0.004). The molecular
genetic analysis identified mutations in one of the following disease
genes: MYH7 (n=104, 27%), MYBPC3 (n=177, 45%), TNNT2 (n=25,
6%), TNNI3 (n=22, 6%), LAMP2 (n=3, 0.5%), PRKAG2 (n=3, 0.5%),
tCAP (n=8, 2%), MYOZ1 (n=2, 1%), mtDNA (n=15, 4%). Patients with
Anderson-Fabry disease were excluded. 31 patients (8%) were found
to carry a compound or double heterozigosity. After 90±70 months,
76 (27%) affected patients had dilatative (n=51) or restrictive (n=25)
evolution. Among the former 51 patients, 38 (74.5%) had one of the following
events: CHF death while awaiting for HTx (n=10); HTx (n=13);
appropriate ICD intervention plus HTx (n=5); sudden cardiac death or
appropriate ICD intervention (n=10). One fourth of genotyped HCM
patients developed dilatative or restrictive evolution. The HCM that
evolves through dilatation show more HF-related events than those
that evolve through restrictive hemodynamics (p=0.004).
P16.13
Phenotypic characterization of hypertrophic cardiomyopathy
associated with K600fs mutation in cardiac myosin-binding
protein c gene
M. I. Rodríguez-García, L. Monserrat, E. Maneiro, X. Fernández, L. Cazón,
L. Núñez, R. Barriales-Villa, M. Ortiz, E. Veira, A. Castro-Beiras, M. Hermida-
Prieto;
Instituto Universitario Ciencias de la Salud-CHUAC, A Coruña, Spain.
Introduction: MyBPC3 mutations are the most frequent causes of hypertrophic
cardiomyopathy. A high percentage of these mutations are
frameshift. K600fs was previously reported in only one French patient
and is predicted to encode a truncated peptide, that may be unable to
be incorporated into sarcomere A-bands.
Methods: Clinical study and phenotypic characterization of probands
and family members of eight Spanish families where K600fs was detected.
Results: We found 21 carriers in 8 families from a region of Galicia.
Penetrance >90% in >30 years and cosegregation was found in all
families. Mean maximal wall thickness was 20mm. Morphology of
hypertrophy and late enhancement localization at cardiac MRI was
reproducible in several families. Carriers were in NYHA-II and left
ventricular outflow tract obstruction was present in 4 patients. Left
atrium dilation and early atrial fibrillation (AF) were present in 9 and
6 carriers, respectively. Surgical miectomy was done in 1 carrier and
automatic defibrillators were implanted in 2 (primary prevention at 26
and 37 years). Two sudden deaths (18 and 42 years) and one cardiac
transplant (35 years) were reported in young family members. Stroke
related death was reported in two young carriers (41 and 55 years).
Conclusions: Correct familial and clinical evaluation in suitable number
of mutation carriers allow us to establish genotype-phenotype correlations,
which are difficult when the number of cases reported is limited.
K600fs mutation could have a common founder effect in Galicia. Mutation
carriers develop left ventricular hypertrophy at young age and
main complications are AF and strokes.
P16.14
investigation of polymorphisms in non-coding region of human
mitochondrial DNA in 31 iranian Hypertrophic cardiomyopathy
(Hcm) Patients
E. Mohamadi Pargo, M. Houshmand;
Special Medical Center, Tehran, Islamic Republic of Iran.
The D-loop region is a hot spot for mitochondrial DNA (mtDNA) alterations,
containing two HyperVariable Segments, HVS-I and HVS-II. In
order to identify polymorphic sites and potential genetic background
accounting for Hypertrophic CardioMyopathy (HCM) disease, the complete
non-coding region of mtDNA from 31 unrelated HCM patients
and 45 normal controls were sequenced. The sequences were aligned
upon the revised Cambridge Reference Sequence (rCRS) and any
incompatibilities were recorded as numerical changes in homoPolymeric
C Tract (PCT), single base substitutions (SBS), insertions and
deletions (Indels). Nucleotide substitutions were found to make up the
majority of the mutations, rather than indels. We drew significantly
high transition rate (81.8%) versus lower frequency of transversions
(18.2%). 12 polymorphisms were identified in this study which had not
been published in the MitoMap database. PCT changes at position
303-309 were detected in 83% of our samples. Our results suggest
that an increased level of HVS-I and HVS-II substitutions may be an