2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.266
clinical characterization and NiPBL mutation analysis of 42
Portuguese patients with cornelia de Lange syndrome
C. Dias 1 , E. Costa 2 , J. Oliveira 2 , J. Silva 1 , M. Martins 1 , A. M. Fortuna 1 , A. B.
Sousa 3 , J. P. Basto 1 , I. Soares-Silva 2 , T. Kay 4 , H. Santos 5 , A. Medeira 3 , I. Cordeiro
3 , T. Lourenço 4 , L. Nunes 4 , R. Santos 2 , M. Reis-Lima 1 ;
1 Unidade de Genética Médica, Centro de Genética Médica Doutor Jacinto
Magalhães, INSA, Porto, Portugal, 2 Unidade de Genética Molecular, Centro de
Genética Médica Doutor Jacinto Magalhães, INSA, Porto, Portugal, 3 Serviço de
Genética Médica, Hospital de Santa Maria, Lisboa, Portugal, 4 Serviço de Genética
Médica, Hospital Dona Estefânia, Lisboa, Portugal, 5 Genomed, Instituto de
Medicina Molecular, Lisboa, Portugal.
Cornelia de Lange Syndrome [CdLS (MIM#122470)] is a rare multisystem
disorder (prevalence1:10 .000) characterized by psychomotor
developmental and growth delay, distinctive facial dysmorphism,
microcephaly and limb anomalies . Mutations in the NIPBL [5p13 .1
(MIM*608667)] gene that encodes for delangin, a protein involved in
sister chromatid cohesion, have been described in 27-56% of patients .
A smaller number of patients have been found to have mutations in
two other genes SMC1A [Xp11 .2 (MIM*300040)] and SMC3 [10q25
(MIM*606062)] thought to be involved in chromatin cohesion .
We present data on 42 Portuguese patients with Cornelia de Lange
Syndrome, observed by Clinical Geneticists according to the same
clinical protocol, including prenatal and birth history, development,
physical features and multisystem involvement . According to their
phenotype patients were classified as mild, moderate or severe. The
entire coding region (exons 2 to 47) and exon-intron junctions of the
NIPBL gene was sequenced . Population screening was carried out for
undocumented variants . In mutation positive cases sequence analysis
was extended to the parents . Ongoing sequencing of NIPBL to date
revealed the presence of heterozygous mutations in 11 patients from
10 unrelated families, 7 of which are novel . Two individuals with a
nonsense mutation in NIPBL are siblings with a mild phenotype, providing
further evidence that CdLS familial cases may remain under
diagnosed . We highlight the importance of a thorough clinical assessment
in order to recognize milder phenotypes of CdLS . We discuss
phenotype-genotype correlation and it’s implication in terms of clinical
prognosis and the importance of molecular diagnosis for genetic
counselling .
P01.267
clinical-epidemiological study of the congenital anomalies of the
corpus callosum
I. Ejarque 1,2 , E. Bermejo 1,3 , J. Mendioroz 1,3 , E. ECEMC working group. 4 ;
1 ECEMC (Spanish Collaborative Study of Congenital Malformations), Institute
of Health Carlos III., Madrid, Spain, 2 Dpt of Clinical Analysis. Universitary
Hospital La Fe., Valencia, Spain, 3 Centro de Investigación Biomédica en Red
de Enfermedades Raras (CIBERER), ISCIII., Madrid, Spain, 4 ECEMC working
group, Several cities of Spain., Spain.
The corpus callosum is the largest interhemispheric commisure of euterius
mammals . We’ve studied the Epidemiology of the Congenital
Anomalies of the Corpus Callosum (CACC) throughout the ECEMC
[Spanish Collaborative Study of Congenital Malformations] database .
ECEMC is a hospital-based case-control study covering, in 2005,
22,96% of total of newborns in Spain . Here we present the results of
the epidemiological study of some clinical and etiological characteristics
of infants with CACC registered by ECEMC programme .
The ECEMC calculated a frequency of 1 .08/10,000 births for the
CACC. Non-specified type of agenesia was the most frequent group
and total agenesia the most infrequent . Taking into account the clinical
features, the isolated cases represented only 6% of total newborns;
the syndromic ones accounted for 29%, and multiply malformed (several
congenital defects without an identified etiologic link) represented
65% . If we correlate the clinical and the anatomopathologic types, the
most frequent among the isolated cases was non-specified agenesia.
Correlating the anatomopathology and the genetic aetiology, 48,21%
of them had a chromosomal origin . It has been described an association
of CACC with several chromosomic alterations: del(5p), del(1qter),
del(18q), del(6p25), dup(3q) and del(10q) .
In order to carry out a right follow-up of the cases with CACC, whether
prenatal or postnatal, the most important points to take into account
are: 1) detailed ultrasound of Central Nervous System, 2) precise
familial anamnesis including three generations, 3) foetal or neonatal
high-resolution karyotype, and 4) Magnetic Resonance Imaging . All
these facts will lead us to a genetic counselling in the best conditions .
P01.268
New case of cranio-Lenticulo-sutural Dysplasia - a recently
described genetic syndrome with late-closing fontanels
S. A. Boyadjiev Boyd 1 , C. Nauta 1 , E. Zackai 2 , J. Kim 1 ;
1 Section of Genetics, Department of Pediatrics, University of California Davis,
Sacramento, CA, United States, 2 Division of Human Genetics, The Children’s
Hospital of Philadelphia, Philadelphia, PA, United States.
We delineated Cranio-lenticulo-sutural dysplasia (CLSD; Boyadjiev-
Jabs syndrome) as a new autosomal-recessive syndrome in a consanguineous
family where five males and one female have similar
craniofacial features (large and late-closing fontanels, hypertelorism),
early onset cataracts, and mild generalized skeletal dysplasia . Linkage
analysis mapped the locus to chromosome 14q13-q21 and a F382L
causative mutation was identified in SEC23A . Detailed molecular and
biochemical analysis of wild type and mutant SEC23A, an integral
member of the COPII-mediated ER-to-Golgi trafficking pathway, led to
better characterization of intracellular trafficking in health and disease.
A zebrafish morpholino model recapitulated the human phenotype.
Recently, an unrelated individual with clinical features consistent with
CLSD was identified. Molecular analysis of SEC23A identified a novel
heterozygous SEC23A mutation involving a highly conserved residue .
This missense mutation was inherited from the unaffected father and
was not present in 400 control chromosomes . No mutations were
found in the maternal alleles and SEC23A real-time PCR analysis
showed normal expression of the alleles . Biochemical characterization
by in vitro COPII budding assay is in progress . Our data suggest
that CLSD may be more common than previously thought and should
be considered in the evaluation of patients with late-closing fontanels .
Alternative inheritance patterns may exist for this syndrome .
P01.269
A 340 kb de novo 16p13.3 microduplication encompassing only
5 genes
S. Gimelli 1 , A. Bottani 1 , I. Bouchardy 1 , D. Martinet 2 , J. Beckmann 2 , S. Antonarakis
1 , M. A. Morris 1 , F. Béna 1 ;
1 Service of Medical Genetics, Geneva University Hospitals, Geneve, Switzerland,
2 Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois
(CHUV), Lausanne, Switzerland.
We describe an 8-year-old female who was shown by MLPA to have
a de novo interstitial duplication of the Rubinstein-Taybi Syndrome
region . Characterization by array CGH (Agilent) revealed a 340 kb
duplication of 16p13 .3 containing only 5 genes, one of them being
CREBBP .
The patient was born at term after an uneventful pregnancy .
Dysmorphic facial features and a left hip dysplasia, initially treated by
cast and later by a Pavlik harness, were noted . Aged 19 months, global
psychomotor delay was noted (sitting at 11 months, but no speech
or walking), as well as dysmorphic facial features, with round face,
erythematous cheeks, short hypoplastic nose, long convex philtrum,
microstomia, and low-set small ears . Pelvis X-rays showed changes
in the left femoral head, atypical for classical congenital hip dysplasia .
Based on these findings, the hypothesis of some form of chondrodysplasia
punctata was raised, but could not be substantiated radiologically.
Follow-up confirmed the mild global learning disability with normal
growth parameters, apart from a leg-length discrepancy, the left
being 2 cm shorter .
The rarity of published patients with comparable duplications make
genotype-phenotype correlations difficult. Given a previous report
of a duplication 16p13 in a patient with chondrodysplasia punctata
(Hunter, 1985), we hypothesise that overexpression of gene(s) in the
microduplication is responsible for abnormal bone development leading
to teratological hip dysplasia . Given the known role of CREBBP in
skeletal and mental development, this gene represents an excellent
candidate .