Predictive Impact of Rare Genomic Copy Number Variations in Infant Siblings of Individuals with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder characterized by social communication deficits and the display of restrictive, repetitive behaviors. Given the extensive genetic landscape of ASD, profiling genetic risk in individuals with a higher probability of developing the disorder due to family history would complement the observation of behavioral markers in infancy and assist in diagnosing ASD early in development when therapeutic interventions would be most beneficial. In this work, I present the first copy number variant (CNV) analysis in 288 prospectively recruited infant sibling cohort from 253 families as part of the Baby Sibling Research Consortium. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings had CNVs at ASD-relevant loci: 6 with ASD, 5 atypically developing, and 2 typically developing. Eleven of 157 infant siblings (7%) with a confirmed ASD diagnosis or who were deemed atypically developing at 36 months of age had a genetic finding that would have been predictive of their developmental outcome. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83. Most notably, I identified a 90 kb deletion of the third exon of PTCHD1-AS, located on chromosome X (Xp22.11), in 3 related male siblings with ASD. I present genomic and phenotypic data for 109 males and 45 females with disruptive variants in PTCHD1 obtained from ASD and clinical genetic datasets. Investigation of their phenotypes revealed that males with exclusive disruptions of the lncRNA present with an increased frequency of ASD and a Broader Autism Phenotype (BAP) and fewer comorbidities than males with deletions spanning the upstream protein coding gene PTCHD1. To further study the function of this gene, I have identified the syntenic transcript in the mouse brain and profiled its isoforms. Expression analysis on various brain regions identified highest expression in the mouse cortex, in early development (post-natal day 7). I have generated 3 mouselines with disruptions of Ptchd1-as, of which one is currently being characterized as part of a collaborative effort to uncover the function of this lncRNA.Ph.D