2008 Barcelona - European Society of Human Genetics

Clinical genetics
ered at the 33 rd gestational week for maternal reasons He experienced
severe respiratory distress for four weeks. Diagnosis was confirmed
clinically and radiologically . Genomic DNA analysis revealed a new
missense mutation in exon 54 (c4339 A>T ) of the COL2A1 gene .
This case demonstrates the relevance of correct diagnosis even in
the adult age, when people have the right to know: recurrence risk,
risk of pregnancy and delivery and possible neonatal problems of the
affected newborn .
P01.152
more surprises in FGFR2: atypical mutations in Apert syndrome
E. G. Bochukova 1 , T. Roscioli 2 , D. J. Hedges 3 , I. B. Taylor 1 , A. Colley 4 , G. Elakis
2 , M. Buckley 2 , D. Johnson 1 , D. J. David 5 , P. L. Deininger 3 , A. O. M. Wilkie 1 ;
1 Weatherall Institute of Molecular Medicine, Oxford, United Kingdom, 2 Sydney
South West Integrated Genetics Service, Royal Prince Alfred hospital, University
of Sydney, Sydney, Australia, 3 Tulane Cancer Center and Department of
Epidemiology, Tulane University Health Sciences Center, New Orleans, LA,
United States, 4 Department of Clinical Genetics, Liverpool Health Service, New
South Wales, Australia, 5 Australian Craniofacial Unit, Women’s and Children’s
Hospital, Adelaide, Australia.
Apert syndrome (AS) is one of the most severe craniosynostosis syndromes,
characterized by premature fusion of multiple craniofacial
sutures and complex syndactyly of the hands and feet . Two heterozygous
gain-of-function mutations (Ser252Trp and Pro253Arg) in fibroblast
growth factor receptor 2 (FGFR2) are responsible for >98%
of AS cases. Here, we have identified different novel mutations in the
FGFR2 gene in the last two outstanding Apert patients with unidentified
mutation from a cohort of 227 patients. One is a 1.9 kb deletion,
removing the entire exon IIIc of the gene and substantial portions of
the flanking introns. This is the first large FGFR2 deletion described
in any patient with craniosynostosis . The other mutation is a de novo
Alu insertion into the IIIc exon of FGFR2. This is the third identified
AS-related Alu insertion within 105 bp of sequence, a remarkable enrichment
considering that only ~30 new Alu insertions have been described
in all human diseases . Computational analysis revealed that
the inserted Alu element belongs to a new subfamily, not previously
known to be mobile, which we characterize and term Alu Yk . Previous
analysis of an AS patient with Alu insertion, and a mouse model with
an engineered exon IIIc deletion, indicate that both types of mutation
are likely to cause AS by driving ectopic expression of an FGFR2 isoform
containing the alternatively spliced IIIb exon in mesenchymal tissues
. We speculate that the Alu insertions, all of which have arisen on
the paternal allele, are enriched because of positive selection during
spermatogenesis .
P01.153
mutations in aggrecan (AGc1) cause Dexter cattle
chondrodysplasia
R. Savarirayan 1 , J. Cavanagh 2 , I. Tammen 3 , P. Windsor 3 , J. F. Bateman 1 , F.
Nicholas 3 , H. Raadsma 3 ;
1 Murdoch Childrens Research Institute, Melbourne, Australia, 2 University of
Sydney, Camden, Australia, 3 Univeristy of Sydney, Camden, Australia.
Lethal “bulldog” chondrodysplasia in Dexter cattle is one of the earliest
Mendelian traits described in animals . Affected (homozygous) fetuses
display extreme disproportionate dwarfism, a short vertebral column,
marked micromelia, short ribs, large head with a retruded muzzle, cleft
palate, protruding tongue, and abdominal hernia . Carriers (heterozygotes)
show a milder phenotype, having rhizomelic limb shortening in
addition to radiographic spinal abnormalities .
Homozygosity mapping in an Australian Dexter cattle pedigree identified
the gene AGC1 as a positional candidate . Homozygous AGC1
mutations have been shown to cause the lethal chondrodysplasia,
cartilage matrix deficiency (cmd) in mice and nanomelia in chicks. Heterozygous
AGC1 mutations cause dwarfism and shortened skeletal
elements in mouse and chick, and a spondylo-epiphyseal dysplasia
(Kimberley type) associated with severe premature joint and spinal
arthritis in humans .
AGC1 mutation screening revealed a common 4bp insertion in exon 11
(2266_2267insGGCA) (BD1) and a second, rarer transition in exon 1
(-198C>T) (BD2) that co-segregated with the disorder . We performed
allele-specific primer extension analysis of mRNA isolated from chondrocytes
of cattle heterozygous for the common insertion (BD1) mutation
. This demonstrated that mutant mRNA was subjected to non-
sense-mediated decay, showing only 7% of normal expression, suggesting
haploinsufficiency for aggrecan as the pathogenetic basis for
the carrier phenotype . Genotyping in Dexter cattle families worldwide
has shown that these two mutations account for all cases and segregate
fully with the heterozygous or homozygous phenotype .
We anticipate that these Dexter cattle will prove extremely useful as
a model for investigating and understanding corresponding human
chondrodysplasias and arthritis phenotypes .
P01.154
Analysis of the Q289P mutation in the FGFR2 gene: populational
and computational studies
B. L. N. Passarinho, E. C. Freitas, V. L. Gil-da-Silva-Lopes;
FCM, Campinas, Brazil.
The Q289P mutation in the FGFR2 gene was identified in some individuals
of a family with clinical features of a Saethre-Chotzen Syndrome
(SCS) . Considering the variable expressivity of this condition
and in this specific family as well, some hypotheses were suggested.
The aims of this study were to verify the prevalence of this mutation
in different populations and to simulate the effects of this mutation by
computational analyses . Three different populations were investigated:
40 individuals with syndromic craniosynostosis and 200 normal
controls and all members clinically evaluated from mentioned family .
This investigation also includes the search for mutations in hot spots
for all individuals with craniosynostosis . Computational approaches
were applied to simulate the effects of the mutation in the protein and
predict its deleterious potential . Except by the patients in whom the
Q289P mutation was previously detected, no more cases were identified.
Simulated computational approaches indicated a deleterious potential
. We suggested that the Q289P mutation is deleterious, rare and
associated to the craniosynostosis phenotype only and not strongly
related to the facial and neurological phenotype .
Key words: Craniosynostosis; Saethre-Chotzen; FGFR2; Mutation;
SIFT; PolyPhen; Grantham
P01.155
characterization of two translocation-associated ectrodactyly
related loci in distal 2q14.1 and proximal 2q14.2 and the
corresponding candidate genes
D. David 1 , B. Marques 1 , C. Pires 1 , P. Vieira 1 , C. Reis 1 , S. Malveira 1 , A. Corona-
Rivera 2 , J. C. Ferreira 3 , H. van Bokhoven 4 ;
1 Centre of Human Genetics, National Institute of Health “Dr. Ricardo Jorge”,
Lisboa, Portugal, 2 Department of Physiology, University of Guadalajara, Guadalajara,
Mexico, 3 Garcia de Orta Hospital, Almada, Portugal, 4 Radboud University
Nijmegen Medical Centre,, Nijmegen, The Netherlands.
Split hand-split foot malformation (SHFM) or ectrodactyly, is a heterogeneous
congenital defect of digit formation . The aim of this study is
the mapping of the breakpoints and detailed molecular characterization
of the candidate genes for an isolated form of bilateral split foot
malformation (SFM) and for a syndromic form (holoprosencephaly,
hypertelorism, and ectrodactyly syndrome (HHES)) both associated
with de novo apparently balanced chromosome translocations involving
the same chromosome 2q14 .2 subband, [t(2;11)(q14 .2;q14 .2)] and
[t(2;4)(q14.2;q35)], respectively. Breakpoints were mapped by fluorescence
in situ hybridisation (FISH) using BAC clones . Where possible,
these breakpoints were further delimited using PCR fragments
as FISH probes. The identified candidate genes were screened for
pathogenic mutations by direct sequencing . The SFM associated chromosome
2 breakpoint was localised at 120 .9 Mb, between the two
main candidate genes, GLI-Kruppel family member GLI2 (GLI2) and
inhibin beta B (INHBB). No clear pathogenic mutation was identified in
these . The second breakpoint associated with HHES was mapped 2 .5
Mb proximal at 118.4 Mb and the candidate genes identified from this
region were the insulin induced protein 2 (INSG2) and the homeobox
protein engrailed-1 (EN1). In conclusion we have confirmed the presence
of a new SHFM7 locus in the intergenic region between INHBB
and GLI2 . Furthermore, a locus for HHES is proposed 2 .5 Mb proximal
to the previous one . The molecular mechanism proposed for these
congenital anomalies is a sequence of alterations induced by the positional
effects introduced by the translocations leading to spatiotemporal
misregulated expression of the candidate genes .