| Summary: | 博士 === 慈濟大學 === 醫學研究所 === 98 === Autism is a complex neuro-developmental disorder and a highly genetic psychiatric disorder
characterized by impaired verbal communications, poor social interactions, and the presence of
stereotyped behaviors and restricted interests. The heritability of autism was estimated more than 90%.
Several studies have indicated strong involvement of multiples genes in the etiology of autism. There is
little understanding of the pathogenesis of autism, and the treatment of autism is limited. Several
strategies have been used to dissect the genetic complexity of autism, including cytogenetic examination,
genome-wide linkage and association study, candidate gene analysis, and gene expression profile analysis.
The allelic spectra of autism may include multiple polymorphic variants that increase the susceptibility of
autism, or rare genetic mutations that cause clinical symptoms of autism. The goal of this study was to
identify genes of autism in Han Chinese population in Taiwan. My specific aims are: 1) Using
karyotype analysis and oligonucleotide-based whole-genome comparative genome hybridization array
(array CGH) to detect chromosomal aberrations in a sample of autism from Taiwan. 2) Replicating the
genetic association of glyoxalase I gene (GLO1) and mitochondrial aspartate/glutamate carrier gene
(SLC25A12) with autism in our population. 3) Using the genetic association study with the genes within
the chromosomal abnormality regions.
Cytogenetic studies of autism have shown that chromosomal structural aberrations such as
translocation, inversion, deletion, and duplication account for approximately 5-10% of autism cases,
indicating that the genomic rearrangement may contribute to the genetic mechanism of autism. With the
advent of array CGH, copy number variants can be detected at submicroscopic level. As a result,
several recent studies showed that CNVs are associated with neuropsychiatric disorders, including autism.
My first study was to identify chromosomal aberrations in autism in Han population. In karyotype
analysis, we identified two different abnormalities in two different patients among 289 ASD cases. One
male patient was found to have an approximately 7 Mb interstitial deletion at chromosome 4q35, while
the other male patient has a balanced chromosomal translocation t(4;14)(q31.1;q24.1). Furthermore, we
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also used CGH arrays from NimbleGen and Affymetrix to detect CNVs in our 102 autistic cases from
Taiwan. Among 102 autistic cases, we also identified three different chromosomal aberrations in three
different autism cases. One male patient was found to have an approximately 2.4 Mb terminal deletion
at 8p23.3; another two male patients has an approximately 1.1 Mb microdeletion at 22q11.2 and an
approximately 4.2Mb interstitial duplication at 15q11-q13, respectively.
In our candidate gene studies, we first attempted to replicate genetic associations with GLO1 gene
and SLC25A12 reported as candidate genes of autism in ASD cases in Han population. In GLO1
association study, except for C419A reported in previous studies, we identified two SNPs at 5’UTR in this
sample, g.-264 G/T and g.-7 T/C. But in SNP-and haplotype-based analysis among the three SNPs, we
did not find association of these SNPs with autism. Further, in SLC25A12 gene study, we also wanted
to replicate the two single nucleotide polymorphism, rs2056202 and rs2292813, whether associated with
autism. We found no significant association of these two SNPs with autism in 465 autistic patients and
450 controls.
We searched for some candidate genes harbored in chromosomal aberration regions in our autism.
Notably, at least four genes including DLGAP2, CLN8, FBXO25, and ARHGEF10, at 8p23.3 can be
considered as candidate genes of autism. We have first screened mutations in DLGAP2, FBXO25, and
CLN8 genes in our patients; however, no mutations were found to be associated with autism so far.
In summary, we identified one male patient with a balanced chromosomal translocation
t(4;14)(q31.1;q24.1). This finding is worthy of further investigation to identify whether there are gens
disrupted or affected at the breakpoints. In the CGH study, we are the first to report the presence of
CNV associated with autism in our subjects to our knowledge. The genes in the deleted or duplicated
regions can be considered as candidate genes of autism for future study. Our study is limited by the
small sample size; however, our findings warrant further large-scale screening of CNV in our patients to
find more genetic defects in our patients. And we suggest that array-CGH technology is a useful
laboratory tool in clinical practice to help in diagnosing autism in the future.
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