2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.279
Dilated cardiomyopathy with hearing loss - a new form?
E. V. Zaklyazminskaya 1 , A. Revishvili 2 , T. Nikolaishvili 2 , A. Polyakov 1 ;
1 Center of Molecular Genetics, Odintsovo, Russian Federation, 2 Bakulev’s
Scientific Center for Cardiac Surgery, Moscow, Russian Federation.
Background: Dilated cardiomyopathy (DCM) is a myocardial disorder
characterized by ventricular dilatation, and impaired systolic function
leading to heart failure and death . To date 12 genes and 10 chromosomal
loci have been associated with this condition, but only autosomal-dominant
DCM, 1J (MIM: #605362) caused by mutations in EYA4
gene is also associated with sensorineural hearing loss (SNHL) .
Methods: Clinical examination of parents and four children was performed,
including ECG, Holter, Echo-CG; blood and urine biochemistry,
and tandem mass-spectrometry (to exclude mitochondrial diseases)
. The phenotype of a deceased sibling was obtained from hospital
and out-patient information . Genetic testing was performed by direct
sequencing of coding and adjacent intronic areas of the EYA4 gene .
Results: An Uygur family with DCM was investigated . The proband
and the oldest brother had progressive SNHL, complete A-V block,
DCM, and died due to heart failure at the age of 14 y .o . and 9 y .o .,
respectively . Two younger brothers had incomplete A-V block, LBBB,
and SNHL at the age 6 y .o . and 11 y .o . All symptoms became more
pronounced with age . A sister (9 y . o .) has normal hearing but A-B
block(I) and incomplete LBBB. Both parents are healthy. We didn’t find
any mutations of EYA4 gene . Unfortunately, the small size of the family
and unclear phenotype of the 9 y .o . girl precludes informative linkage
analysis . Pedigree analysis reveals recessive inheritance of DCM,
conduction defects and SNHL (autosomal or X-linked) in this Uygur
family . We propose that this family has a novel genetic form of DCM .
P01.280
Novel tyrosine Hydroxylase Gene mutation in three turkish
siblings With Dopamine-Responsive Dystonia
E. Karaca, S. Basaran Yılmaz, G. Yesil, A. Yuksel;
Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Genetics,
Istanbul, Turkey.
Dopa-responsive dystonia (DRD) is a rare, autosomal dominant (GTPcyclohydroxylase
gene mutation) or rarely recessive (tyrosine hydroxylase
gene mutation) inherited disorder . Both enzymes take part
in dopamine synthesis. Their deficiencies cause the dopamine level
reduction. The first clinical symptoms occur in the childhood
We report here three siblings who were borned to first cousins; with a
novel recessive mutation in Tyrosine hydroxylase gene that results in
dopa- responsive dystonia . Older brothers were monozygotic twins .
They are now at the age of 4 6/12 and 1 9/12 years . All of them have development
delay and also motor dysfunction . They displayed extrapyramidal
signs in early infancy. The clinical diagnoses were confirmed
by mutation analyses of Tyrosine hydroxylase gene which detected
a novel mutation of P492R (1475 C>G) in the homozygotic state . After
diagnosis, L-DOPA treatment was started, however clinical picture
did not change . Therefore selegiline (selective MAO-B inhibitor) was
added to therapy . Low dose L-DOPA and selegiline markedly improved
clinical picture .
Here we are presenting the clinical features and outcomes of the L-
DOPA/Selegiline treatment in three siblings with Dopa-responsive dystonia
results from a novel recessive mutation in Tyrosine hydroxylase
gene, reviewing of the literature .
P01.281
Familial duplication 8p without phenotypic effect
E. G. Okuneva, N. V. Shilova, N. Y. Kuzina, T. V. Zolotukhina;
Medical Genetics Research Center, Moscow, Russian Federation.
We report a family where 3 members have rearrangement of chromosome
8 with normal phenotype . A proband 14-year-old girl was tested
because of hypogonadism . G-banded chromosome studies were carried
out and showed karyotype 46, XX, der (8) . Her father’s karyotype
was normal - 46, XY, but mother and 28-year-old sister had the same
chromosome 8 rearrangement without any clinical signs . The elder
sister’s 3-year-old daughter had normal phenotype .
Later at the age of 18 the proband was tested again during pregnancy .
An abnormal chromosome 8 with additional material of unknown origin
on the terminal region of short arm was tested. To identify this finding
FISH analysis was performed using painting (wcp) and telomere spe-
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cific (tel) DNA-probes for chromosome 8. FISH characterization of the
abnormal chromosome with wcp 8 and tel 8p probes was estimated
as duplication of a short-arm segment 8p23: 46,XX, add(8)(p23) . ish
dup(8)(p23)(wcp8+,pter+) (ISCN 2005) . Euchromatic abnormality of no
phenotypic consequence such as euchromatic duplication in terminal
region p23 .1-p23 .3 of chromosome 8 is known as chromosome variant
. Variant chromosomes being normal chromosomes behave normally
at meiosis and show 1:1 segregation . A person carrying a variant
chromosome has no increased risk for having abnormal offspring . Normal
results of maternal serum biochemical screening and high quality
ultrasound scanning during the pregnancy had allowed to avoid an
invasive procedure . After 40 weeks of pregnancy there was born male
newborn without any clinical signs of chromosomal pathology .
P01.282
DYscERNE: An electronic Dysmorphology Diagnostic system
(DDs)
S. Gardner 1 , P. Griffiths 1 , K. Strong 1 , R. Day 1 , D. Donnai 1 , B. Kerr 1 , H. Brunner 2 ,
B. Dallapiccola 3 , K. Devriendt 4 , M. Krajewska-Walasek 5 , N. Philip 6 , J. Clayton-
Smith 1 ;
1 University of Manchester, Manchester, United Kingdom, 2 UMC St Radbound,
Nijmegen, The Netherlands, 3 IRCCS-CSS, San Giovanni Rotondo, Italy, 4 KU
Leuven, Leuven, Belgium, 5 IP-CZD, Warsaw, Poland, 6 Hopitaux de Marseille,
Marseille, France.
Over 2,500 rare and difficult to diagnose conditions presenting with
patterns of birth defects have been identified. The rarity of these dysmorphic
conditions means that even in Centres of Expertise, experience
may be limited resulting in delayed or uncertain diagnosis . Making
a correct diagnosis is the cornerstone of patient management, enabling
clinicians to locate other patients with the same condition, share
clinical experience and increase individual and collective knowledge
about rare conditions .
One of the main aims of the DYSCERNE project (www .dyscerne .org)
is to develop an electronic Dysmorphology Diagnostic System (DDS)
which will link existing European Centres of Expertise to form a powerful
diagnostic resource for rare dysmorphic conditions .
The DDS will allow clinicians to submit difficult to diagnose cases, for
evaluation by an international panel of experts . A diagnostic report including
suggested management plans for the patient will be prepared
from the consensus of expert opinions and sent to the submitting clinician
. Case histories will be stored in an archive which will be reviewed
periodically .
An on-line educational tool for the description of dysmorphic features
will also be developed which will increase diagnostic skills in the evaluation
of rare dysmorphic diseases .
The DDS will facilitate rapid and equitable access for clinicians from all
EU countries to expert opinions . It will increase capacity and accuracy
of diagnoses and decrease time from presentation to diagnosis . This
will facilitate definition and classification of rare dysmorphic conditions
and promote further clinical research into these complex disorders .
P01.283
clinical Variability in Acro-(cardio)-Facial-syndrome
A. Kariminejad 1 , B. Bozorgmehr 1 , M. A. Sedighi Gila 2 , N. Almadani 1 , M. H.
Kariminejad 1 ;
1 Kariminejad & Najmabadi Genetic and Pathology Center, Tehran, Islamic
Republic of Iran, 2 Department of Andrology, Royan Institute, Tehran, Islamic
Republic of Iran.
In 1987 Richieri-Costa and Orquizas described a Brazilian patient born
to consanguineous parents with ectrodactyly, cleft lip/palate and congenital
heart defect . Four additional cases with ectrodactyly, genital
anomalies, congenital heart defect and cleft lip/palate or high arched
palate have been published [Giannotti et al ., 1995; Guion-Almeida et
al ., 2000; and Mingarelli et al ., 2005] .
Giannotti et al . [1995] reported on a brother and sister with cleft palate,
cardiac defect, genital anomalies and ectrodactyly, suggesting the acronym
CCGE standing for cleft palate, cardiac defect, genital anomalies
and ectrodactyly . An autosomal recessive pattern of inheritance
was suggested considering these pedigrees . Guion-Almeida reported
on a 4-month-old infant with ectrodactyly, clefting ear anomaly, CHD,
cortical atrophy of the brain and growth retardation, with possible acrocardio-facial
Syndrome (ACFS) .
We report on a 25-year-old man with ectrodactyly and genital anoma-