2008 Barcelona - European Society of Human Genetics

Clinical genetics
aim of this study was to analyze a sample of autistic patient without
FRAXA full mutation to know the correlation of premutation and intermediate/grey
zone size FMR1 alleles and autism . The results show
that the prevalence of premutation alleles is 2/10 in patients, however
we did not found intermediate/grey zone alleles . Beside the overall
repeat size and the AGG interspersion pattern suggest instability .
P01.249
Autosomal dominant Alport syndrome: molecular analysis of the
COL A gene and clinical outcome
E. Marcocci 1 , V. Uliana 1 , M. Silengo 2 , M. Zerial 3 , F. Bergesio 4 , A. Amoroso 5 , M.
Pennesi 6 , D. Giachino 7 , C. Rosatelli 8 , C. Dresch Martinhago 9 , M. Carmellini 10 , F.
Mari 1 , M. Bruttini 1 , I. Longo 1 , A. Renieri 1 ;
1 Medical Genetics, Department Molecular Biology, University of Siena, Italy,
2 Clinical Genetic Unit, Department of Pediatrics, University of Turin, Italy, 3 Department
of Paeditrics, M. Bufalini Hospital, Cesena, Italy, 4 Nephrology and
Dialysis Units, Azienda Ospedaliera Careggi, Florence, Italy, 5 Transplantation
Immunology, San Giovanni Battista Hospital, Torino, Italy, 6 Department of
Paeditrics, IRRCS Burlo Garofolo, Trieste, Italy, 7 Department of Clinical and
Biological Sciences, Division of Medical Genetics, University of Turin, Orbassano,
Italy, 8 Department of Biomedical Sciences and Biotechnology, University
of Cagliari, Italy, 9 Department of Genetics, Ribeirão Preto Medical School, University
of São Paulo, Brazil, 10 UOC Chirurgia dei Trapianti, Azienda Ospedaliera
Universitaria Senese, Siena, Italy.
Alport syndrome is a clinically and genetically heterogeneous nephropathy
characterized by irregular thinning, thickening, and splitting
of the glomerular basement membrane often associated with hearing
loss and ocular symptoms . While the X-linked and the autosomal recessive
forms are well known, the autosomal dominant form is not well
acknowledged . We have investigated 37 patients with a clinical and
molecular diagnosis of autosomal ATS belonging to 8 different families .
The mean age of patients was 38 .7 years ranging from 6 to 76 years .
Only 9 out of 37 (24 .3%) patients reached the ESRD, at the mean age
of 51 .2 years . Four patients (13 .8%) had hearing loss and none ocular
changes . DHPLC analysis revealed 8 novel private COL4A4 gene
mutations: 3 frameshift, 3 missense and 2 splice-site mutations . These
data indicate autosomal dominant Alport syndrome as a disease with
a low risk of ocular and hearing anomalies but with a significant risk to
develop renal insufficiency although at an older age than autosomal
recessive and X-linked forms .
These clinical features make difficult differential diagnosis with the
benign familial hematuria due to heterozygous mutations of COL4A4 .
On the other hand, we are unable to demonstrate a genotype-phenotype
correlation with the type and the site of the COL4A4 mutations . A
correct diagnosis and prognosis is based on a comprehensive clinical
investigation in as many family members as possible .
P01.250
cOL4A1 mutation in Axenfeld-Rieger anomaly with
leukoencephalopathy and stroke
I. Coupry 1 , I. Sibon 2 , I. Orignac 1 , I. Burgelin 1 , J. Orgogozo 2 , D. Lacombe 3,1 , B.
Arveiler 1,3 , C. Goizet 1,3 ;
1 Laboratoire de Génétique Humaine, Bordeaux, France, 2 Fédération des
Neurosciences Cliniques, Bordeaux, France, 3 Service de Génétique Médicale,
Bordeaux, France.
INTRODUCTION : Axenfeld-Rieger anomalies (ARA), refer to a wide
variety of abnormalities of the anterior segment of the eye that belong
to the heterogenous family of the anterior segment dysgenesis . ARA
appears to be genetically heterogeneous: it has been associated with
mutations in three genes: PITX2 (on chromosome 4q25), FOXC1 (also
named FKHL7) (6p25), and PAX6 (11p13) .
SUBJECTS AND METHODS : Five members of a three-generation
family affected by vascular leukoencephalopathy and ARA, were clinicaly
and geneticaly investigated .
RESULTS : Diffuse leukoencephalopathy associated with ocular malformations
of the Axenfeld-Rieger type was observed in the 5 affected
individuals . Genetic linkage analyses directed toward three loci associated
with hereditary vasculopathies and on the four loci known to be
associated with ARA showed a possible association with the two loci
11p13(PAX6) and 13q34 (COL4A1) . Direct sequencing of the COL4A1
gene led to the identification of a novel missense mutation p.G720D,
which cosegregates with the disease .
CONCLUSION : We delineate a novel association between the Axen-
feld-Rieger anomaly and leukoencephalopathy and stroke . Our data
confirm that mutations in the COL4A1 gene can be responsible for
ARA in humans, as suggested by previous studies in Col4a1-mutated
mice .
P01.251
De novo balanced chromosomal translocation (2;10)(q11.2;q24)
associated with dysmorphic features and mental retardation.
case report.
D. Locmele1 , B. Lace1,2 , D. Bauze1 , G. Kalnberza1 , A. Dzalbs1 ;
1Children Clinical University Hospital, Medical Genetic Clinic, Riga, Latvia,
2Rigas Stradins University, Department of Medical Biology and Genetics, Riga,
Latvia.
We report a clinical case of a reciprocal translocation between the long
arms of the 2nd and 10th chromosomes observed in a 12 years old male
with dysmorphic features, mental retardation and compulsive - obsessive
behaviour .
From anamnesis: boy was born from uncomplicated 1st pregnancy
from nonconsanguinous marriage . Delivery on 40th week of gestation,
birth weight 3450g, height 58cm. At the age of 6 months he had first
episode of seizures after injury of the head . Seizures repeated two
times till 12 months of age, later they have never been observed . Motor
and speech development were normal. Behavioural problems first
noticed at 4 years of age .
Psychiatric findings: marked hyperactive behaviour, always in motion,
restless, enthusiastic, frequently clownish, mincing, dyslalia and
echolalia, might be aggressiveness to others and to himself, moderate
mental retardation .
Dysmorphic features: downslanting palpebral fissures, facial asymmetry,
left eyelid ptosis, hypotelorism, esotropia, and irregular tooth
placement .
There was performed a conventional GTG karyotyping . Result: 46,XY,
t(2;10)(q11.2;q24). Chromosomal breakpoint was confirmed with FISH
(Kreatech MYCN (2p24) & LAF (2q11)) analysis .
It still remains a question of discussion if balanced translocation could
be associated with dysmorphic features and mental retardation . To
evaluate possibility of certain genes loss in breakpoint regions, further
SNPs analysis of regions is in progress .
P01.252
Bardet Bidl syndrome Analysis Among iranian Families
M. Dehghan Manshadi, M. Rostami, T. Majidizadeh, K. Banihashemi, M.
Houshmand.;
Special Medical Center, Tehran, Islamic Republic of Iran.
Bardet-Biedl syndrome (BBS) is characterized by cone-rod dystrophy,
truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic
hypogonadism, complex female genitourinary malformations,
and renal dysfunction .Birth weight is usually normal, but
significant weight gain begins within the first year and becomes a lifelong
issue for most individuals. A majority of individuals have significant
learning difficulties, but only a minority has severe impairment on
IQ testing . Renal disease is a major cause of morbidity and mortality .
In our own study the initial diagnosis of Bardet-Biedl syndrome is established
by clinical findings in our specialists’ thorough exam.
Twelve genes are known to be associated with Bardet-Biedl syndrome:
BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7,
TTC8/BBS8, B1/BBS9, BBS10, TRIM32/BBS11, and BBS12 . Indirect
molecular diagnosis using Bardet-Biedle markers facilitate prenatal diagnosis
of Bardet-Bidel children .
During the period of 2007 all referred patients to our lab have undergone
molecular genetics analysis . Five molecular markers: D11S913,
D16S408, D3S1254, D15S131, D4S402 are used for covering the
analysis according to the previous surveys .
The primary results showed that in all families’ segregation of alleles
are according to mandelian inheritance and affected chromosomes
are distinguishable from unaffected ones . The patients’ molecular
genetics profile has been completed through PCR amplifications and
Electrophoresis in PAGE gel and the final linkage analysis showed that
BBS4, BBS7 were the most associated gene with the Bardet-Bidel in
Iranian families .