2008 Barcelona - European Society of Human Genetics

Clinical genetics
sity School of Medicine, Tokyo, Japan, 3 Tokyo Women’s Medical University,
Tokyo, Japan, 4 Keio University, Tokyo, Japan, 5 StaGen Co., Ltd., Tokyo, Japan,
6 Tottori University, Yonago, Japan.
Renal hypouricemia is an inherited and heterogeneous disorder characterized
by impaired tubular uric acid transport . Impairment of URAT1,
the main transporter for uric acid reabsorption at the apical membrane
of the renal tubules, causes renal hypouricemia . G774A mutation in
SLC22A12 encoding URAT1 predominates in Japanese renal hypouricemia
. We investigated whether the uncertain predominance of hypouricemia
on survival or some effects such as founder effect leads to
the expansion of G774A mutation in SLC22A12 in Japanese despite
of the complications, nephrolithiasis and exercise-induced acute renal
failure . Molecular analysis have been undertaken in sixty-nine Japanese
renal hypouricemic patients and haplotypic analysis in 31 patients
with homozygous G774A mutation using flanking 13 markers (12
single nucleotide polymorphisms and a dinucleotide insertion/deletion
locus) around G774A locus . The sharing of the ancestral haplotype
clearly implied a common origin of the mutation, the age of that being
estimated to be approximately 6,820 years (95%CI 1,860 - 11,760
years, median 2,460 years) . The age indicates that the origin of G774A
mutation dates back from the time when Jomon people predominated
in Japan to the time when Yayoi people started to migrate to Japan
from the Korean peninsula . These data are consistent with a recent
finding that G774A mutation was also predominant in Korean hypouricemia
subjects and indicate that the Asian continent was the origin
of G774A mutation . The G774A mutation in Japanese hypouricemia
subjects had been brought by immigrant(s) from the continent and expanded
in Japanese population either by founder effect or genetic drift
(or both) .
P01.078
microarray Resequencing Analysis of Fumarylacetoacetate
Hydrolase (FAH) Gene in tyrosinemia Patients
R. K. Özgül 1 , L. Mesci 2 , A. Dursun 3 ;
1 Hacettepe University, Institute of Child Health&Department of Pediatrics, Metabolism
and Nutrition Unit, Ankara, Turkey, 2 Hacettepe University, Department
of Pediatrics, Ankara, Turkey, 3 Hacettepe University, Department of Pediatrics,
Metabolism and Nutrition Unit, Ankara, Turkey.
Hereditary tyrosinemia type I (OMIM; 276700) is an autosomal recessive
disease caused by defects in fumarylacetoacetate hydrolase
(FAH) gene involved in the last step in tyrosine catabolic pathway .
To date, over forty pathogenic mutations were described in the FAH
gene .
In this study, a total of 22 Turkish tyrosinemia patients were genotyped
to detect disease causing mutations in FAH by our design of a resequencing
microarray . Our microarray was designed to sequence
all exonic and their flanking intronic sequences of the FAH gene to
detect sequence variations. In brief, FAH gene has been amplified
from genomic DNA by short or long range PCR. After purification, all
PCR products were quantitated and equimolar amount of them were
pooled . After the fragmentation step, fragmented PCR products were
end labeled using a biotin-labeling reagent and hybridised with DNA
arrays . Then, arrays were processed by steps of washing and staining
on fluidics station. Scanned arrays were analyzed using Affymetrix
GeneChip Resequencing Analysis Software .
Mutation screening results showed that 12 different type of mutations
were responsible of disease development in our cohort of Turkish tyrosinemia
patients . Four different polymorphisms were also described in
our patients . Detected mutations by DNA resequencing chip technology
were also reevaluated and confirmed by direct DNA sequencing.
To our knowledge, this work is the first report showing the application
of DNA resequencing chip as rapid and reproducible mutation screening
tool for genetic analysis of patients with hereditary tyrosinemia .
(Supported by State Planning Organisation DPT2006K1206400603) .
P01.079
Molecular and clinical findings in two Coffin-Lowry syndrome
patients
D. Jurkiewicz, E. Popowska, K. Czornak, D. Piekutowska-Abramczuk, E. Ciara,
M. Borucka-Mankiewicz, P. Kowalski, M. Gajdulewicz, K. Spodar, K. Chrzanowska,
M. Krajewska-Walasek;
Children’s Memorial Health Institute, Warsaw, Poland.
Coffin-Lowry syndrome (CLS, MIM#303600) is an X-linked semidominant
disorder . Cardinal features in males include mental retardation,
facial dysmorphism, digital tapering, and progressive spinal deformity .
In females the intensity of symptoms is variable . The estimated frequency
is 1:50000 - 1:100000 births . CLS is caused in the majority
of cases by mutations of the RSK2 gene (RPS6KA3), which maps to
Xp22 .2 and is split into 22 exons . The gene encodes for a serine/threonine
kinase, RSK2, acting at the distal end of the MAPK/ERK signalling
pathway .
We present two Polish patients with the clinical diagnosis of Coffin-
Lowry syndrome confirmed on the molecular level. Patient 1 is a boy
aged 4 years . He has moderate mental retardation, hypotonia, facial
dysmorphism, digital tapering, dental anomalies, spinal deformities,
seizure and cataplexia . Molecular analysis of the RSK2 gene revealed
the presence of a substitution G to A in the first position of intron 10
(c .845+1G>A) . The mutation appeared de novo . Besides, a polymorphism
in exon 10 (c.798C>A) was identified. Patient 2 is a girl aged 9
years . She presents moderate intellectual disability, hypotonia, a characteristic
facial appearance, hands typical of CLS, dental anomalies .
The rather severe symptoms of the female may be due to the presence
of de novo one-nucleotide deletion (c .896delT) in exon 11 resulting in
loss of important RSK2 domains, as well as observed non-random Xchromosome
inactivation .
The study was supported by Polish Ministry of Science Project 0624/
P01/2006/31 (N40103131/0624) .
P01.080
MECP gene R167W mutation in a girl with autism/Rett-like
syndrome and her mildly mentally retarded mother
E. Popowska1 , A. Tylki-Szymanska1 , D. Jurkiewicz1 , M. Borucka-Mankiewicz1 ,
K. Czornak1 , E. Ciara1 , A. Kloska2 , P. Kowalski1 , D. Piekutowska-Abramczuk1 ,
M. Olszaniecka1 , K. Chrzanowska1 , M. Krajewska-Walasek1 ;
1 2 The Children’s Memorial Health Institute, Warsaw, Poland, University of
Gdansk, Gdansk, Poland.
Rett syndrome (RTT) is a neurodevelopmental disorder affecting almost
exclusively females . The disease is caused by mutations in the
X-linked MECP2 gene, encoding methyl CpG binding protein . Most
cases of RTT are sporadic with the majority (99 .5%) being caused
by de novo mutation on the paternal copy of MECP2 . Familial cases
and clinically atypical cases (RTT variants, like preserved speech variant,
congenital RTT) show a lower incidence of MECP2 mutations .
Recently MECP2 mutations in males with severe encephalopathy or
mental retardation have been described .
We report identification of MECP2 gene R167W mutation in a 3 year
old girl and her mother .
The girl presents unusual behavioral features: anxiety, emotional and
eye contact disturbances, stereotypes (jigging, running, head shaking),
sleep and awake breathing rhythm and peripheral circulation disturbances,
stretching and paroxysmal cry or clamor . Besides, normal
somatic and mental development with preserved speech and voluntary
hand use is observed . Mother of the girl, obese woman with development
on the edge of normal, presented in her infancy mild psychomotor
retardation, hypoactivity, somnolence and lack of criticism . Currently
she presents essential tremor and she is still clumsy and talk active .
The identified R167W mutation results in substitution of tryptophan in
place of arginine-167, situated in the region between MBD and TRD .
The mutation occurred on the grandmothernal allele and was de novo
in the mother . MECP2 R167W mutation has been previously found
in three-generation family with four non-specific X-linked mentally retarded
males and unaffected mothers .
The study was supported by MNiSW Project 2P05A12129 .
P01.081
cerebral anomalies in a case of Xq12q13.1 duplication
encompassing the Oligophrenin 1 Gene
V. Bianchi 1 , M. F. Bedeschi 1 , A. Novelli 2,3 , L. Bernardini 2,3 , C. Parazzini 4 , G.
Uziel 5 , B. Torres 2,3,6 , F. Natacci 1 , M. G. Giuffrida 2,3,6 , B. Dallapiccola 2,3 , F. Lalatta 1 ;
1 Clinical Genetics Unit, Fondazione IRCCS, Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Milano, Italy, 2 CSS-Mendel Institute, Roma, Italy,
3 CSS-Hospital, San Giovanni Rotondo, Italy, 4 Department of Radiology and
Neuroradiology, Children’s Hospital “V.Buzzi”, Milano, Italy, 5 Neurophsychiatric
Unit, Istituto Neurologico C. Besta, Milano, Italy, 6 Department of Pathology, “La