Examining genotypic variation in autism spectrum disorder and its relationship to parental age and phenotype

Previous studies on genetic testing of chromosomal abnormalities in individuals diagnosed with autism spectrum disorder (ASD) found that ~80% have negative genetic test results (NGTRs) and ~20% have positive genetic test results (PGTRs), of which ~7% were probable de novo mutations (PDNMs). Research suggests that parental age is a risk factor for an ASD diagnosis. This study examined genotypic variation in ASD and its relationship to parental age and phenotype.

Phenotype was derived from detailed clinical information, and genotype was derived from high-resolution blood chromosome and blood whole-genome copy number variant genetic testing on a consecutive cohort (born: 1983-2009) of subjects diagnosed with ASD (N=218).

Among the subjects examined, 80.3% had NGTRs and 19.7% had PGTRs, of which 6.9% had PDNMs. NGTR subjects were born more recently (the risk of PDNMs decreasing by 12% per more recent birth year) and tended to have an increased male-female ratio compared to PDNM subjects. PDNM subjects had significantly increased mean parental age and paternal age at subject's birth (the risk of a PDNM increasing by 7%-8% per year of parental or paternal age) compared to NGTR subjects. PGTR and NGTR subjects showed significant improvements in speech/language/communication with increasing age. PGTR subjects showed significant improvements in sociability, a core feature of an ASD diagnosis, with increasing age, whereas NGTR subjects showed significant worsening in sociability with increasing age.

This study helps to elucidate different phenotypic ASD subtypes and may even indicate the need for differential diagnostic classifications.