2008 Barcelona - European Society of Human Genetics

Clinical genetics
FRAXA is the most common cause associated to mental family inherited
and represents among 15 to 20% of the total mental delay related
to X cr. This illness has its origin in the deficiency of FMR1 protein
synthesis . The expansion of the “dynamic” and repetitive region CGG,
5´ to Fmr-1, causes it´s methylation and repression of expression . According
repetitions number of the CGG tri-nucleotide, this region is
considered normal (200 CGGn) .
In this poster we present the results of this extense study . In conclusion,
we found 21 (0,92 % ) premutation carriers; 49 (2,15%) “intermediate”
carriers and 1/33 women were excluded from the donation
program .
The knowledge of the fragile X premutation carrier condition or full
mutation carrier will permit the donor to receive the appropriate genetic
counsel for reproductive end . On the other hand, the exclusion from
the oocyte donation program of possibly “expanded” trinucleotids of
this region, provides greater security to the receptor patients in our
processing of Assisted Reproduction .
P01.117
Genotype-phenotype correlation in Rubinstein-taybi syndrome
S. Naudion;
Service de genetique, CHU de Bordeaux, Bordeaux, France.
The Rubinstein-Taybi Syndrome is an autosomal dominant disease .
It is characterised by typical facial dysmorphism, abnormalities of the
extremities, growth retardation and psychomotor development delay .
Mutations have been identified in two genes, CREBBP and EP300 .
We report a series comprising 93 patients with CREBBP mutations,
and 2 patients with EP300 mutations . Point mutations were searched
for by DHPLC followed by sequencing, and microrearrangements
were identified by array-CGH and/or Quantitative Multiplex Fluorescent
PCR (QMF-PCR) . Among the CREBBP mutations, 24% were
nonsense, 24% led to a translation reading frame shift, 26% were microrearrangements
(24% deletions, 2% duplications), 18% affected a
splice site, and 8% were missense . It is noteworthy that no mutation
was ever found in exons 7, 9, 11, 18, 22, 23 and 29 . Whatever the
mutation type and localisation along the gene, the dysmorphic and
osseous phenotypes were comparable to the typical RTS phenotype .
However, patients carrying a nonsense mutation presented associated
anomalies such as cardiopathy (33% vs 26%) or neurological anomalies
(hypotonia in 81% vs 60%, hyperreflexia in 37% vs 29%) more
frequently than patients with any other type of mutation . Conversely,
patients carrying missense mutations presented with less severe phenotypes,
since none of them presented any associated malformation
or anomaly .
Concerning the 2 patients with an EP300 mutation, our data were in
accordance with those of the literature, since they presented with a
typical dysmorphic phenotype with a less severe osseous phenotype .
Only one of the two patients had broad thumbs and halluces, without
any associated osseous anomaly .
P01.118
chromosomal imbalances in Rubinstein-taybi patients negative
to cREBBP mutational test
C. Gervasini 1 , R. Ciccone 2 , F. Mottadelli 1 , P. Castronovo 1 , D. Milani 3 , F. Bedeschi
4 , M. Uzielli 5 , A. Bentivegna 6 , A. Pilotta 7 , G. Cocchi 8 , G. Scarano 9 , A. Selicorni
3 , O. Zuffardi 2 , L. Larizza 1 ;
1 Genetica Medica Dip. Med., Chir. e Odont., Università Milano Polo Osp. San
Paolo, Milano, Italy, 2 Biologia Generale e Genetica Medica, Università di Pavia,
Pavia, Italy, 3 I Clinica Pediatrica, Fondazione Policlinico, Mangiagalli, Regina
Elena, Milano, Milano, Italy, 4 Ambulatorio di Genetica Medica, Fondazione
Policlinico, Mangiagalli, Regina Elena, Milano, Milano, Italy, 5 Unità di Genetica,
Dip Pediatria, Osp. Meyer Università di Firenze, Firenze, Italy, 6 Dipartimento
di Neuroscienze e Tecnologie Biomediche, Milano, Italy, 7 Auxoendocrinologia,
Ospedale Pediatrico Brescia, Brescia, Italy, 8 Centro per lo Studio delle Malformazioni
Congenite, Istituto Clinico di Pediatria preventiva e Neonatologia,
Università di Bologna, Bologna, Italy, 9 Unità Operativa complessa di Genetica
Medica, Az. Osp. Rummo, Benevento, Benevento, Italy.
Rubinstein-Taybi syndrome (RSTS, OMIM #180849) is a rare autosomal
dominant congenital disorder characterized by postnatal growth
retardation and psychomotor developmental delay, skeletal anomalies
and specific facial dysmorphisms. RSTS is associated with chromosomal
microdeletion or point mutations of CREBBP gene in 16p13 .3 and
mutations of EP300 gene in 22q13, observed in 56% and 3% of the
tested patients respectively .
Here we report the identification by a-CGH of duplications/deletions in
6 of 25 RSTS patients found negative to point mutations of CREBBP
and to chromosomal rearrangements affecting CREBBP and EP300
regions . The imbalances are: i) a de novo 9Mb deletion in 2q24 .3q31 .1
involving the HOXD genes, ii) a 5,5 Mb duplication in 2q34q35 inherited
by the healthy father, probably representing a private CNV, iii)
a 500Kb duplication in 17q11 .2 upstream the NF1 gene in a region
delimited by NF1 REP-P1/P2 iv) a 1,2Mb deletion in 18q21 .33q22 .1
harbouring one gene, v) a 4,3Mb deletion in 2q22 .3q23 .1 involving
five genes among which ZFHX1B, the gene mutated in Mowat-Wilson,
vi) a 466Kb deletion in 7p21 .1 containing TWIST1, a proposed
candidate for RSTS . The parental origin, gene content and genomic
characterization of the last four imbalances is in progress . Although
the pathogenetic role is yet unproven in a few cases, this study shows
a high fraction of chromosomal rearrangements in regions other than
those of CREBBP/EP300 genes. In addition a-CGH is confirmed to
be a suitable approach for diagnostic purposes and to highlight novel
positional RSTS candidate genes . Supported by A .S .M . (Associazione
Italiana Studio Malformazioni) .
P01.119
two cases of Rubinstein taybi syndrome caused by two new
mutations that create premature stop codons and truncated
cREBBP protein
V. I. Guerci 1 , A. Fabretto 1 , F. Faletra 1 , C. C. G. Gervasini 2 , L. Larizza 2 , P. Gasparini
3,1 ;
1 Genetica Medica Dipartimento di Scienze della Riproduzione e Sviluppo,
Trieste, Italy, 2 Genetica Medica. Università degli Studi di Milano, Ospedale San
Paolo, Milano, Italy, 3 Genetica Medica, IRCCS Burlo Garofolo, Trieste, Italy.
Rubinstein-Taybi syndrome (RSTS; MIM 180849) is a congenital disorder
characterized by growth retardation and psychomotor delay, broad
thumbs and halluces and a wide range of dysmorphic features . RSTS
was shown to be associated with microdeletions and point mutations in
the gene encoding the CREB-binding protein, located in 16p13 .3 .
The first case was born from a twin pregnancy. While the sister was normal
during pregnancy and postnatal period, the patient had IUGR and
typical dysmorphic features since the first weeks of life. Cardiac valvular
anomalies were found as well as a bilateral conductive hypoacusia .
RSTS was then suspected and was confirmed by molecular analysis.
A new mutation was found: c .5838_5857dup20, with the formation of
a premature stop codon (p .Pro1953HisfsX30) resulting in a truncated
protein of 1982 aminoacids . Second case was an Haitian girl . Pregnancy
was terminated at 32 weeks for preeclampsia and IUGR . She
was hospitalized because of respiratory distress, feeding difficulties
and severe growth retardation . A recurrent infection condition secondary
to gastroesophageal reflux was suspected. However, encephalic
NMR demonstrated corpus callosum agenesis; oculistic examination
revealed severe strabismus and nasolacrimal duct obstruction and
bone age was marked delayed . Furthermore, physical examination
demonstrated typical RSTS dysmorphisms . Molecular analysis of the
CREBBP gene revealed a 7 nucleotide deletion: c .3608_3609+5del,
eliminating the donator splicing site of exon 18 with the formation of
a premature stop codon . This mutation produces a truncated protein
(1204 aminoacids). The identification of these two new alleles may increase
the knowledge of CREBBP function and the prediction of genotype-phenotype
correlation .
P01.120
A predominantly sensorial case of cHARGE: towards a
refinement of CHD disease spectrum
B. Brasseur1 , N. Revencu1 , P. Clapuyt2 , M. Maes3 , Y. Gillerot1 ;
1 2 Center for Human Genetics, Brussels, Belgium, Pediatric Radiology, Brussels,
Belgium, 3Pediatric Endocrinology, Brussels, Belgium.
Introduction: We present here a novel CHD7 mutation in a mildly affected
boy . The implications for further delineation of CHD7 disease
spectrum are underlined .
Clinical case: BM was born from unrelated Caucasian parents, with
microphallus and bilateral cryptorchidism . Hypogonadotropic hypogonadism
was diagnosed in neonatal period . Ophtalmologic examination
revealed relative microphtalmy with right chorioretinal coloboma
and left retroretinal cysts . Psychomotor development and cardiac ul-