Maternal, but Not Paternal, Interstitial Duplications of Chromosome 15q11.2-q13 Are Associated with ASD in 9 Individuals

Background: It has been estimated that as many as ~3-5% of all autism cases may be the result of duplications of the 15q11-q13 region. Unfortunately, genotype-phenotype correlations have not consistently demonstrated that these duplications are the sole cause of ASD in these cases. Maternally transmitted 15q duplications consistently show autistic features with variable degrees of developmental delay. Only a few cases of paternally transmitted 15q duplication have been reported and are associated with speech delay and behavior problems, but not autism.
Objectives: to perform an in depth phenotype analysis of individuals with interstitial 15q duplications and determine if maternal duplication is required for the diagnosis of autism spectrum disorder (ASD

Methods: We used neuropsychological, language and ASD diagnostic tools for phenotypic analysis in patients recruited through the IDEAS parent support group (www.idic15.org).  In addition we performed High Resolution Melting analysis (HRM) of the maternally methylated SNRPN locus to determine the parent of origin of the duplications

Results: Nine pediatric subjects with interstitial duplication 15q have participated in the study. Eight patients scored as ASD upon ADOS/ADI-R analysis and one scored “no ASD” on both tests. In the neuropsychological evaluations 3/9 patients had a low average IQ score, 3/9 were borderline and the others had mental retardation, although the patients were noted to have a higher verbal IQ than performance, they had a low-moderate adaptive functioning score on the Vineland II evaluation. All patients performed below age corrected average for receptive vocabulary (Peabody Picture vocabulary test).  HRM analysis was done in all patients: 8/9 had a maternal duplication and 1/9 had a paternal duplication. The sizes of the duplications ranged from 5Mb to 12.77Mb and included typical BP1-BP3, BP2-BP3 and duplications including the BP1-BP3 region plus additional regions upstream or downstream of the BP1-BP3 region. The size of the duplication involved does not appear to correlate with the severity of the phenotype or the ASD diagnosis.

Conclusions: in our study only maternally derived interstitial duplications result in ASD, not paternal duplications. It should be noted that several of our patients were adopted so parental DNA was unavailable for genotype analysis. HRM analysis for maternal specific methylation patterns at the SNRPN locus allowed us to determine the parental origin of the duplication in all samples tested.