Background: Increased rates of Autism Spectrum Disorder (ASD) have been observed in individuals with copy number variations (CNVs) of the 22q11.2 region, including both deletions (Fine et al, 2005) and duplications (Wenger et al, 2016a). However, research has not yet identified which of the 30-40 genes in this region confer autism risk. One research strategy entails narrowing the search space to smaller regions by studying nested (termed “atypical”) CNVs within the full 22q11.2 region. The 22q11.2 region includes four low-copy repeats (LCRs); CNVs usually span LCR-A to LCR-D while smaller, nested CNVs (e.g., LCR-A to B, LCR-A to C) affect fewer patients. We have hypothesized that the region between LCR-A and LCR-B might be particularly important for ASD (Wenger et al, 2016b). This region contains a gene, RANBP1, involved in the metabatropic mGluR network, with important roles in neuronal excitation. mGluR signaling has been implicated in autism via syndromic ASD (Fragile X and tuberous sclerosis) and non-syndromic ASD (Hadley et al, 2014).
To compare autism risk associated with 22q11.2 in individuals with and without involvement of the LCR-A to LCR-B region.
Thirty-six individuals with atypical duplications (n=9) or deletions (n=27) of 22q11.2 were recruited from a genetic specialty clinical at the Children’s Hospital of Philadelphia. Participants included 13 individuals with affected LCR-A to B regions (LCR-A to B n=10, and LCR-A to C n=3) and 23 without (LCR-B to D n=17, and LCR-C to D n=6). Autism diagnoses were ascertained via review of the participants’ electronic health record and additional medical or psychoeducational records provided by participants. Proportions were analyzed with a chi-square test. Parents of a subset of participants completed measures of social communication and psychiatric symptoms (SRS n=16, SRS-2 n=5, SCQ n=17, and CASI-4R n=22). Comparisons will be made to existing data from typically developing controls (t=73), individuals with idiopathic ASD (n=70), and individuals with typical deletions (n=62) and duplications (n=28) of 22q11.2.
A significantly higher rate of ASD diagnoses (38.4%, 5/13) was observed for those individuals with a CNV involving the LCR-A to B region compared to those without involvement of LCR-A to B (8.7% rate, 2/23) χ2(1,N=36)=4.70, p=0.03. LCR-A to B involvement occurred only in individuals with deletions. In analysis restricted to deletions, rates remained similar (38.4% and 7.1%) and the result remained marginally significant χ2(1, N=27)=3.83, p=0.050. Record review results were supported by preliminary parent symptom report results. We observed higher mean scores in individuals with involvement of LCR-A to B on the SCQ (mean=16.0(9.4), range=5,30) and SRS (mean t-score=80.8(12.7), range=64,96) compared to individuals without involvement of the region (SCQ: mean=11.3(8.3), range=1,24; SRS: mean t-score=72.9(19.2), range=39,100). However, nota bene, group differences on continuous measures were not statistically significant, perhaps because of insufficient sample size; data collection is ongoing.
Conclusions: Among individuals with atypical CNVs in the 22q11.2 region, we identified a smaller region implicated in many but not all cases of ASD. LCR-A to B involves COMT and RANBP1, which may warrant further investigation for association with ASD.