ASSOCIATION OF COPY NUMBER VARIANTS IN THE ASMT GENE WITH AUTISM

Background: Sleep disorders and abnormal melatonin secretion have been reported in autism subjects. Melatonin was also reported effective to treat insomnia in children with autism. The ASMT gene, located in pseudo-autosomal region 1 (PAR1) of the sex chromosomes, is involved in melatonin biosynthesis, and was recently proposed as a susceptibility gene for autism.    

Objectives: The goal of this study was to investigate whether copy number variants (CNVs) at the ASMT locus might contribute to autism susceptibility.

Methods: Three hundred unrelated subjects with autism spectrum disorders (ASD) and 248 controls were screened using an MLPA probe directed to the ASMT gene. Fine-mapping of CNVs was performed by quantitative polymerase chain reaction (Q-PCR) probes directed to ASMT exons.

Results: Eighteen unrelated ASD subjects showed microduplications with probes within ASMT. The microduplications were significantly more frequent (p=0.009) in individuals with ASD compared to controls (4 subjects). Three subjects showed four copies of the microduplication. A single microdeletion was observed in an ASD subject, but not in controls. Q-PCR revealed that the CNV includes a ~18 Kb fragment spanning exon 2 to exon 8 of the gene. Typically the microduplication was transmitted (either from the mother or father), but in certain cases did not appear to segregate with affected phenotype amongst siblings. In those individuals for which sleep disorder symptoms were recorded, 75% reported sleep disorder symptoms, compared to about 50% of cases without the duplication.

Conclusions: CNVs in the ASMT gene at PAR1 were found to be associated with ASDs in this study. Further studies on the ASMT gene, the effects of the CNV on gene expression, and the relationship of this CNV to both ASDs and sleep disorders are warranted.