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Increased Risk of Autism Among Individuals with Atypical 22q11.2 Deletions or Duplication Involving COMT and RANBP1
Objectives: To compare autism risk associated with 22q11.2 in individuals with and without involvement of the LCR-A to LCR-B region.
Methods: 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.
Results: 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.
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