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Chromosomal microarray (CMA) is now recognized as the first-tier genetic test for detection of copy number variations (CNVs) in patients with autism spectrum disorder (ASD). The aims of this study were to identify known and novel ASD associated-CNVs and to evaluate the diagnostic yield of CMA in Thai patients with ASD. The Infinium CytoSNP-850K BeadChip was used to detect CNVs in 114 Thai patients comprised of 68 retrospective ASD patients (group 1) with the use of CMA as a second line test and 46 prospective ASD and developmental delay patients (group 2) with the use of CMA as the first-tier test. We identified 7 (6.1%) pathogenic CNVs and 22 (19.3%) variants of uncertain clinical significance (VOUS). A total of 29 patients with pathogenic CNVs and VOUS were found in 22% (15/68) and 30.4% (14/46) of the patients in groups 1 and 2, respectively. The difference in detected CNV frequencies between the 2 groups was not statistically significant (Chi square = 1.02, df = 1, P = 0.31). In addition, we propose one novel ASD candidate gene, SERINC2, which warrants further investigation. Our findings provide supportive evidence that CMA studies using population-specific reference databases in underrepresented populations are useful for identification of novel candidate genes.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes and loci. To date, several intellectual disability (ID) susceptibility genes have frequently been identified in ASD. Here, whole exome sequencing was carried out on a proband with ASD and identified compound heterozygous mutations of the TRAPPC9, which plays a role in the neuronal NF-κB signaling pathway. These mutations consisted of a novel frameshift mutation (c.2415_2416insC, p.His806Profs∗9) and a rare splice site mutation (c.3349+1G>A) that were segregated from an unaffected father and unaffected mother, respectively. These two heterozygous mutations were also identified in the patient’s older brother with ID. Quantitative RT-PCR revealed a significant reduction of TRAPPC9 transcript in two siblings. This study first describes compound heterozygous mutations of the TRAPPC9 gene in two siblings with ASD and ID, which is notable as only homozygous mutations or compound heterozygous for copy number variations and rare variant in this gene have been reported to date and associated with autosomal recessive intellectual disability. The two siblings carrying compound heterozygous TRAPPC9 mutations presented with ID, developmental delay, microcephaly and brain abnormalities similarly to the clinical features found in almost cases with homozygous TRAPPC9 mutation in previous studies. Together this study provides evidence that clinical manifestations of TRAPPC9 mutations as seen in our patients with ID and autism may be broader than previous case reports have indicated.

To identify the underlying genetic cause of autism spectrum disorder (ASD), we performed whole-exome sequencing in 10 unrelated Thai patients with ASD. We identified a novel heterozygous missense variant (c.425C>G, p.Pro142Arg) in the Engrailed 2 (EN2) gene in two patients. The G variant has never been reported in public databases and was absent in 100 Thai patients with ASD and 435 Thai controls. A case-control study showed that the G allele of c.425C>G was significantly associated with ASD (Fisher's exact test, P=0.0359). In addition, the new variant was predicted to be possibly damaging to the EN2 protein by the PolyPhen-2 and FATHMM bioinformatic programs. Our findings suggest that the arginine variant of the EN2 protein may play an important role in the pathology of ASD. Therefore, EN2 protein functional studies should be carried out to determine whether the novel variant has an effect on protein expression.

Supplemental Digital Content is available in the text, Autism spectrum disorder (ASD) is a form of pervasive developmental disorder manifested by impairment in social interactions and repetitive behaviors. Although genetic contribution is strongly suspected in autism, the specific genetic factors remain unidentified. Hyperserotoninemia has been reported in some autistic patients, and several studies have demonstrated an association between 5-hydroxytryptamine-transporter-linked promoter region (5-HTTLPR) polymorphisms and rs25531 single nucleotide polymorphism in the serotonin transporter gene (solute carrier family 6 member 4; SLC6A4) and ASD, indicating a possible involvement of the serotonin system in the etiology of ASD. To explore this situation further, a case-control association study of 5-HTTLPR and rs25531 polymorphisms on Thai ASD patients was conducted. A total of 188 ASD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria (156 males and 32 females) and a total of 250 normal controls were recruited from the same ethnic backgrounds. 5-HTTLPR polymorphisms (Long, L; Short, S) and rs25531 (A/G) single nucleotide polymorphism were genotyped and compared between the patients and normal controls using chi-square statistics. The L/L genotype was more common in patients than in the controls (13.8% vs 5.2%, P = .006), and the LA haplotype was found in patients more than the controls (16.9% vs 12.2%, P = .048). When male patients were analyzed alone (156 individuals), the associations were also statistically significant with P = .017 for L/L genotype, and P = .019 for LA haplotype distribution. Our findings support previous reports suggesting an association between the 5-HTTLPR and rs25531 polymorphisms of SLC6A4 and patients with ASD.

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.