BioProject

We recently identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental phenotypes, where severely affected probands carried an excess of rare pathogenic variants in the genome compared to mildly affected carrier parents. More...

We recently identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental phenotypes, where severely affected probands carried an excess of rare pathogenic variants in the genome compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, but other hits in the genetic background modulate the ultimate phenotypic trajectory. To test this model, we examined the individual contribution of 16p12.1 homologs towards neurodevelopmental, cellular and molecular phenotypes in Drosophila melanogaster and Xenopus laevis. We observed that 16p12.1 homologs affect multiple phenotypic domains, leading to developmental delay, seizure susceptibility, brain size alterations, abnormal neuronal morphology, and cellular proliferation defects. In contrast to genes within CNVs of higher de novo occurrence, such as 16p11.2 deletion, homologs of 16p12.1 genes did not interact with each other, were less connected in a human brain network, and were sensitive to variation in the genetic background. Moreover, 214 “two-hit” models in the fly eye identified additive (47%), suppressive (34.5%), and epistatic (18.5%) interactions between 16p12.1 homologs and 80 homologs of genes carrying “second-hits” in children with the deletion and genes within related neurodevelopmental pathways. In fact, homologs of the intellectual disability-associated “second-hit” gene SETD5 synergistically interacted with homologs of MOSMO, modifying brain and cellular phenotypes and leading to new neuronal defects. Our results provide functional evidence for the “two-hit” model of neurodevelopmental disorders, where multiple 16p12.1 genes sensitize the genome to developmental defects, and complex domain-specific interactions with “second-hit” genes define the final phenotypic manifestation. Overall design: mRNA-sequencing of Drosophila neuron-specific (Elav-GAL4 driver) RNAi knockdown (whole head) for four individual 16p12.1 homologs (CDR2, MOSMO, POLR3E, UQCRC2) and two VDRC GD wild-type controls (one with Dicer2 at 25°C, and one without Dicer2 at RT). Sequencing was performed using Illumina HiSeq 2000 on three biological replicates per sample (18 total replicates). Less...