2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease 0
CI 0 .40-0 .96, p = 0 .030, under a recessive model) . Haplotype analysis
showed that only in STK11, one haplotype containing the minor T allele
of rs741765 was slightly associated with T2D (P=0 .04) . The association
of PRKAA2 haplotype reported previously in Japanese was not
replicated in our samples . Among the three genes investigated herein,
gene-gene (SNP-SNP) interaction studies provided evidence for an interaction
between STK11 and CRTC2 influencing susceptibility to type
2 diabetes . In conclusion, this study has found a weak evidence that
STK11, PRKAA2, or CRTC2 polymorphisms contribute to the susceptibility
to T2D in Japanese .
P06.269
Extremely High carrier Frequency of smA in iranian Population
M. Hasanzad 1,2 , M. Azad 3 , B. Shoja Saffar 1 , A. Aghajani Refah 1 , K. Kahrizi 1 , H.
Najmabadi 1,3 ;
1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences,
Tehran, Islamic Republic of Iran, 2 Islamic Azad University, Tehran Medical
Unit, Tehran, Islamic Republic of Iran, 3 Kariminejad-Najmabadi Pathology
and Genetics Center, 14665/154, Tehran, Islamic Republic of Iran.
Spinal muscular atrophy (SMA) is one of the most common autosomal
recessive diseases, affecting approximately one in 6000 to 10000 live
births and with a carrier frequency of approximately one in 40 to 60 .
About 94% of individuals with clinically typical SMA lack both copies
of SMN1 exon 7 .
Carrier frequency studies of SMA have been reported to be variable
in different population and no population-based studies has been
done in Iran, however our observations indicate that the incidence of
SMA is much higher in Iranian population partly because of high rate
of consanguineous marriages . The copy number of SMN1 gene was
determined in 400 normal individuals by quantitative real - time PCR
with SYBR Green I dye . The comparative threshold cycle (Ct) of each
sample was calculated and albumin was used as a reference gene .
The homozygous SMN1 deletion ΔΔCt ratio of patient was 0.00 and
the hemizygous SMN1 deletion ΔΔCt ratio of obligate carriers ranged
from 0.29 to 0.55. The ΔΔCt ratio of 92 persons among 400 normal
individuals was within the carrier range, 0 .31-0 .57 .
Our data indicated that the carrier frequency of SMA in Iranian population
is higher (1 out 5) than other countries .
P06.270
Determination of the smN1 and smN2 copy number based on
real-time PcR in Hungarian smA families
M. Nagymihaly 1 , A. Herczegfalvi 2 , L. Timar 3 , V. Karcagi 1 ;
1 National Institute of Environmental Health, Dept. of Molecular Genetics and
Diagnostics, Budapest, Hungary, 2 Bethesda Children’s Hospital, Dept. of Neurology,
Budapest, Hungary, 3 National Institute of Child Health, Genetic Counselling,
Budapest, Hungary.
Spinal muscular atrophy (SMA) is characterized by progressive muscle
weakness caused by degeneration of the spinal anterior horn cells .
Patients with SMA have been classified into three types on the basis
of clinical severity . The survival motor neuron gene is present in two
copies, SMN1 and SMN2, which differ by only five nucleotides. Only
SMN1 gene provides fully functional protein due to exon 7 skipping in
SMN2. On the other hand, the SMA phenotype can be modified by the
presence of several copies of SMN2 .
SMA is a common and fatal disorder, therefore the carrier detection is
essential for prevention and proper genetic counseling . Therefore, estimation
of the SMN1 and SMN2 copy number in patients by real-time
PCR has been recently introduced in Hungary . This technique is used
also for the detection of possible compound heterozygotes .
Until now, SMN1 copies were determined in 25 affected patients and
their 132 family members and twenty controls . Seven patients were
identified as being compound heterozygotes and thus, the diagnosis
of SMA was assumed. The intragenic pointmutations will be identified
later on by sequencing. Additionally, 151 SMA patients with undefined
genetic diagnosis still have to be tested for the SMN1 copy number .
For urgent family planning, 24 relatives of the known carrier parents
were tested and 8 were confirmed as carriers of the common SMN1
mutation . Additionally, SMN2 copy number were estimated in 64 patients
and in 33 family members and a good correlation was found
between copy number and severity of the disease .
P06.271
Highly significant association between Contactin Associated
Protein-like 2 (CNTNAP ) and non-word repetition in a language
impaired sample
D. F. Newbury, L. Winchester, L. Addis, S. L. I. Consortium (SLIC), A. P. Monaco;
Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
Specific Language Impairment (SLI) is defined as a substantial delay
in the development of language despite normal development in other
areas and in the absence of accompanying neurological conditions
like autism . Despite the diagnostic division between autism and SLI,
the two disorders share many clinical features and researchers have
proposed that they may share risk factors and involve mutual neurodevelopmental
pathways . The lack of any clear genetic candidates
has precluded the validation of this hypothesis at the molecular level .
However, converging evidence from genetic research has recently implicated
members of the neurexin gene family in autism . In the present
study we therefore investigated a neurexin gene, Contactin Associated
Protein-like 2 (CNTNAP2), within families affected by SLI . We typed 37
SNPs within 184 families ascertained by the SLI Consortium (SLIC) .
Quantitative TDT (QTDT) was used to assess marker-trait association
for three language-related measures . Expressive and receptive language
abilities were assessed with the Clinical Evaluation of Language
Fundamentals (CELF-R) and a test of non-word repetition (NWR) was
used to measure phonological short-term memory . We found a highly
significant level of association (max P=0.00005) between NWR and
a cluster of 9 SNPs within the CNTNAP2 gene . A suggestive level of
association was also observed in this region to both CELF measures
(max P=0 .003) . These results were supported by subsequent haplotype
and regression analyses. Our findings support the existence
of shared genetic risk factors between SLI and autism, a conclusion
which yields important consequences for the conceptualisation, diagnosis
and treatment of these disorders .
P06.272
An investigation of dyslexia risk loci in families with Specific
Language impairment, (sLi), implicates KIAA0 as a shared
genetic factor
L. Addis, D. F. Newbury, L. Winchester, S. L. I. Consortium (SLIC), A. P. Monaco;
Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
Specific Language Impairment, (SLI), is defined as a considerable
developmental delay in the acquisition and/or use of language in the
absence of other diagnostic features such as hearing loss and autism .
There is substantial co-morbidity of SLI with developmental dyslexia,
in which children are described as having unexpected difficulties in
learning to read, write and spell . This has lead researchers to investigate
the possibility of shared risk factors for the two disorders . Several
genomic regions have shown consistent association to dyslexia
on chromosomes 2, 6 and 15. We typed 16 SNPs identified within
these regions in 175 language-impaired families, ascertained by the
SLI Consortium (SLIC) . Quantitative TDT (QTDT) was used to assess
marker-trait association using both orthogonal (within family) and total
(within- and between- family) association to three reading-related
measures . These measures, taken from the Wechsler Objective Reading
Dimensions (WORD), assess basic reading, spelling, and reading
comprehension. Single SNP orthogonal analysis identified association
of these measures to SNPs within MRPL19/C2ORF3 on chromosome
2, and DCDC2 on chromosome 6 . Total association was found to the
same SNP in MRPL19/C2ORF3, and also to a SNP within KIAA0319
on chromosome 6 . We used the SNP data to reconstruct haplotypes
that had previously been reported to be associated with dyslexia . In
this analysis, association was replicated only in the KIAA0319 gene
and with all reading-related measures . This investigation therefore indicates
that the loci identified by studies of dyslexia, and in particular
KIAA0319, may also contribute to reading ability in language impaired
populations .