Maternal Interstitial 15q-11q13 Duplication Is Sufficient to Produce and Autism Phenotype

Background: Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. As many as 3% of autistic cases may be the result of duplications of chromosome 15q. The 15q11-q13 region has a cluster of genes preferentially expressed from one parental allele. Most 15q duplication cases that present clinically are maternally derived and de novo, although paternal cases have also been identified. There are two main classes of deletion/duplication in this region: class I CNVs with breakpoints from BP1 to BP3 and class II CNVs with breakpoints from BP2 to BP3.

Objectives: The aim of the present study was to determine if maternal duplication is sufficient for the diagnosis of autism spectrum disorder and characterize differentiating symptomatology between maternal Class I and Class II subjects. 

Methods: Subjects were recruited through the 15q Alliance parent support group (www.dup15qalliance.net).  We used neuropsychological and ASD diagnostic tools for phenotypic analysis. Methylation Sensitive High Resolution Melting (MS-HRM) analysis of the maternally methylated SNRPN locus was used to determine the parent of origin of the duplication. 

Results: Fifteen subjects were recruited. Twelve were de novo and 3 inherited cases. MS-HRM Indicated 11 maternal and 4 paternally derived or inherited cases. All maternal subjects tested (10) with ADOS/ADI-R scored in the autism spectrum, while just half of paternal duplication cases were autistic. There is no significant difference in the ADOS, ADI-R and SRS parameters between maternal class I and class II subjects. IQ testing in 6 subjects with maternal duplication indicated only mild intellectual disability (76.8±9.3). The 10 maternal autistic subjects in the study had a low-moderate adaptive functioning score in all Vineland scales with no differences among groups. There was a negative correlation between ADOS severity and the Vineland II scores but it was not significant. 

Conclusions:   Our results suggest that a maternally expressed gene, most likely UBE3A, is primarily responsible for the autism phenotype in interstitial duplication 15q cases since all maternal duplication cases presented on the autism spectrum. The size of these duplications did not correlate with autism severity and symptomatology