2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
posed to tobacco smoke (mother smoked actively) .
For the exposure scenario “mother smokes during the first trimester of
pregnancy”, the OR for AE within the first years of the children’s life are
statistically significant (at the age of 1 year: OR . [95%CI: 1 .0-41];
1 1 / 2 : OR . [95%CI: 2 .0-43 .9]; 2: OR . [95%CI: 1 .2-24 .6] as well as
6 years: OR . [95%CI: 0 .8-15 .5], adjusted to gender, positive family
history of atopy, vaccination and infections and refurbishing during
pregnancy) . Children without tobacco smoke exposure show no association
between the genotype combination and a higher risk for AE .
Additionally, “smoking after pregnancy” could confirm the previously
association, but only by a trend due to the small subgroup .
These associations show a putative role of the gene-environment-interactions
in the manifestation of AE. However, an identification of a
closer time-frame of risk toward the exposure “mother smokes” is not
yet possible .
P07.013
Prevalence of mutations in the OTOF, PJVK and DDP genes in
subjects with auditory neuropathy
M. Rodríguez-Ballesteros 1,2 , L. A. Aguirre 1,2 , H. del Águila 1 , R. Reynoso 3 , C.
Morera 4 , R. Santarelli 5 , E. Arslan 5 , C. Curet 3 , C. Völter 6 , C. Vincent 7 , E. Gómez-
Rosas 1,2 , M. Villamar 1,2 , M. A. Moreno-Pelayo 1,2 , J. Moreno-Barral 3 , F. Moreno 1,2 ,
I. del Castillo 1,2 ;
1 Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain, 2 Centro
de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),
ISCIII, Madrid, Spain, 3 Facultad de Ciencias Médicas, Univ. Nacional de Córdoba,
Córdoba, Argentina, 4 Servicio de ORL, Hospital Universitario La Fe, Valencia,
Spain, 5 Department of Medical and Surgical Specialities, Audiology and
Phoniatric Service, Univ. of Padova, Padua, Italy, 6 ENT Department, University
of Würzburg, Würzburg, Germany, 7 Department of Otology and Otoneurosurgery,
Centre Hospitalier Universitaire, Lille, France.
Auditory neuropathy (AN) encompasses a variety of disorders characterized
by normal otoacoustic emissions (OAE) and absent or grossly
abnormal auditory brainstem responses (ABR) in the affected subjects
. AN can result from environmental or genetic causes . It can be
part of a systemic neurodegenerative disorder or it can be an isolated
clinical entity . The primary lesion in AN can be located in the inner hair
cells, in the auditory nerve, or in the synapse in between . In the last
few years, several genes have been shown to be involved in AN . We
have investigated the prevalence of mutations in the genes encoding
otoferlin, pejvakin and TIMM8a (OTOF, DFNB59 and DDP1, respectively)
in subjects with isolated auditory neuropathy . A cohort of 36 unrelated
subjects with isolated auditory neuropathy were screened for
mutations in these genes by DNA sequencing of all exons and flanking
intronic sequences . In 25 subjects (69%), we found two mutant alleles
of OTOF, two of the mutations being novel . In one subject (2 .8%), we
found a novel mutation in the DDP1 gene . Mutations in this gene are
responsible for Mohr-Tranebjaerg syndrome, an X-linked condition associating
deafness and muscular dystonia . The affected child did not
present with dystonia at the age at which the study was performed .
No mutations were found in the DFNB59 gene . Our results show that
mutations in the OTOF gene are a major cause of inherited auditory
neuropathy and suggest that cohorts of apparently isolated auditory
neuropathy may contain additional cases of the rare Mohr-Tranebjaerg
syndrome .
P07.014
Specific genetic diagnoses in Autism Spectrum Disorders. A 10year
genetic study of 159 patients from 5 psychiatric outpatient
care units
S. Lapuyade 1 , M. Assouline 1 , S. Martin 1 , J. Malen 2 , G. Rolland-Manuel 3 , A.
Terkmani 4 , J. Lena 5 , J. Amiel 5 , J. Bonnefont 5 , L. Colleaux 5 , V. Cormier-Daire 5 ,
M. De Blois 5 , S. Lyonnet 5 , V. Malan 5 , A. Philippe 5 , O. Raoul 5 , M. Rio 5 , A. Munnich
5 , S. Whalen 5 ;
1 Hôpital de Jour Santos Dumont, Paris, France, 2 Hôpital de Jour Sésame Autisme,
Chevilly-La-Rue, France, 3 Hôpital de Jour d’Antony, Antony, France, 4 IME
Alternat, Antony, France, 5 Département de génétique, Hôpital Necker Enfants
Malades, Paris, France.
Since 1998, a collaborative study has been undertaken between the
genetic department of Necker Enfants Malades hospital and 5 psychiatric
outpatient care units of Île-de-France region . From 1998 to 2008,
159 patients with autistic spectrum disorders (ASDs) have undergone
on-site genetic consultation gathering the following data: family and
personal medical history, detailed psychiatric evaluation, dysmorphological
and neurological clinical examination . Blood and/or urine samples
were collected for genetic testing each time a specific disorder
was suggested after the first consultation, or for systematic screening
of common ASD-related disorders . Systematic screening comprised
high resolution banding karyotype, with 22q13 and 15q11q13
FISH analyses, FMR1 gene triplet expansion testing, and metabolic
screening (blood aminoacid and urine organic acid chromatographies,
AICAR, urinary creatin and guanidinoacetate, N-glycosylation, lactate,
pyruvate, ammonium). CGH-array analysis was undertaken in 6% of
patients thus far . Most of the 159 ASD patients (50 females and 106
males) had associated mental retardation ranging from mild to profound
.
21 specific diagnoses were obtained for 30 patients: fragile X (8 patients),
15q11q13 duplication (2 patients), 22qter deletion, 22q11 .2 deletion,
1p36 deletion, Williams syndrome, trisomy X, Turner syndrome,
interstitial 19q deletion, mosaic ring 15, 8q23q24 duplication, 17p11 .2
duplication, 1q31 duplication, 1q21 duplication, AP1S2 mutation,
Prader-Willi, Cornelia de Lange, CHARGE and Rubinstein-Taybi syndromes,
creatin transporter deficiency (2 patients), GAMT deficiency,
phenylketonuria, and histidinaemia . We present a cohort of 159 patients
with ASD. 23 specific genetic disorders were found in 32 patients
(20,1 %) . These results emphasize the importance of on site evaluation
of these patients .
P07.015
Analysis of AcE and At1R gene polymorphisms in Balkan
Endemic Nephropathy
Z. Krcunovic 1 , I. Novakovic 1 , N. Maksimovic 1 , D. Bukvic 2 , S. Simic-Ogrizovic 3 ,
L. Djukanovic 3 , S. Jankovic 4 ;
1 Institute of Human Genetics, School of Medicine, Belgrade, Serbia, 2 Institute of
Endemic Nephropathy, Lazarevac, Serbia, 3 Institute of Nephrology and Urology,
Belgrade, Serbia, 4 Institute of Epidemiology, Belgrade, Serbia.
Balkan endemic nephropathy (BEN) is a multifactorial disorder with
still unexplained hereditary component . Similarity of BEN and cyclosporine
nephropathy suggests possible common ethiopathogenetic
mechanisms . Considering the role of renin-angiotensin system in
emergence of cyclosporine nephropathy and other types of kidney
disease, candidate genes for association studies in BEN were chosen
. We performed analysis of I/D polymorphism in gene encoding for
angiotensin-converting enzyme (ACE) and A1166C polymorphism in
gene encoding for type I receptor for angiotensin II (AT1R) . The study
was carried out in a group of 50 patients with BEN diagnosis according
to criteria of Danilovic, derived from endemic region in Kolubara district
. Two control groups consisted of 50 healthy persons (C) and of 45
patients with other nephropathies (NBEN), both matched by age and
gender . DNA for gene analysis was extracted from peripheral blood
leukocytes . For detection of ACE I/D and AT1R A1166C gene polymorphisms
PCR and PCR/RFLPS methods were used, respectively . We
found that frequency of ACE DD genotype was 41 .66%, 43 .14% and
84 .61% in BEN, C and NBEN group, respectively . For AT1R A1166C
gene polymorphism frequency of CC genotype was 10 .41%, 8 .69%
and 5 .72%, respectively . Our results showed no difference in analysed
genotypes between BEN and C group. However, we found significantly
higher frequency of ACE DD genotype and lower frequency of AT1R
1166 CC genotype in NBEN group . Although these results do not indicate
significant role of ACE and AT1R gene polymorphisms in BEN,
we will proceed in investigation of other members of renin-angiotensin
system .
P07.016
compound heterozygosity between Hbs and b-thalassemia.
implication for the neonatal diagnostic of hemoglobinopathies
S. Pissard 1,2 , N. Ellachtar 3 , C. Albert 1 , C. Godart 1 , F. Galacteros 4 , H. Puehringer
5 , C. Oberkanins 5 , H. Wajcman 3 ;
1 laboratory of genetics, AP-HP,Hop Henri Mondor, creteil, France, 2 INSERM,
U841 eq 11, Creteil, France, 3 INSERM, U841 eq 11, creteil, France, 4 UMGGR,
AP-HP, Hop Henri mondor, creteil, France, 5 ViennaLab Diagnostics, Vienna,
Austria.
Compound heterozygosity between Hb S and b-thalassemia is a form
of sickle cell anemia (SCA) with a clinical severity varying considerably .
The clinical phenotype depend upon the type of thalassemic defect but
also on other factors . To clarify the spectrum of b-thal associated with