Neurodevelopmental genetic drivers of the human 22q11.2 region

Despite substantial progress have been made to understand the wide spectrum of congenital anomalies and birth defects associated with 22q11.2 segmental aneuploidies, the highest comorbidity rate for neurodevelopmental disorders (NDDs) has been also recently showed in this cohort compared to any other genetic conditions. To further define, hence to experimentally confirm, the pivotal neurodevelopmental role of the 22q11.2 region we applied different approaches to identify those genes whose impairment may not only impinge on 22q11.2 rearrangements’ medical history as modifying factors, but that may also constitute per se NDDs’ driver-genes. Through a “genotype-first” approach we identified 8 genes (ARVCF, CLDN5, DGCR8, RANBP1, TRMT2A, MED15, AIFM3 and LZTR1) that, according to the enrichment criteria applied, can exert a downstream functional convergence upon those circuits involved in physiological neurodevelopment as well as in pathophysiological behaviors. By targeted resequencing two prioritized genes, ARVCF and LZTR1, we proved that: (i) their impairment can contribute to the genetic background toward variability of neurodevelopmental phenotypes seen in individuals carrying 22q11.2 CNVs; (ii) these genes may constitute per se NDD driver. Hence, in order to identify novel NDD genes potentially sensitive to dosage imbalance within the distal 22q11.2 chromosomal region, we developed a “phenotype-first” approach building the distal 22q11.2 CNVs “co-morbidity” map that allowed us: (i) to elucidate that the 22q11.2 distal deletion and duplication events respectively clinically define a syndromic versus a non-syndromic neurodevelopmental disorder; (ii) to identify two small NDD genomic regions of interest harbored within. Deeply investigating two rearranged 22q11.22q11.23 carriers’ families, whose segmental aneuploidies were retrieved fully incorporating one of our predicted pathogenic frames, we functionally showed that the RAB36 gene may play a role in NDD pathogenesis acting in a dosage-dependent manner. Overall, these research project’s results added new insights on the elucidation of 22q11.2-related neurobehavioral outcomes as well as of NDDs’ neuroscience physiopathology, widening the scope on those dynamics that constantly shape and re-shape the human brain.