PT  - JOURNAL ARTICLE
AU  - Neha Paranjape
AU  - Yu-Hsiu T. Lin
AU  - Quetzal Flores-Ramirez
AU  - Vishesh Sarin
AU  - Amanda Brooke Johnson
AU  - Julia Chu
AU  - Mercedes Paredes
AU  - Arun P. Wiita
TI  - A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion
AID  - 10.1101/2022.06.22.497212
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.22.497212
4099  - http://biorxiv.org/content/early/2022/06/24/2022.06.22.497212.short
4100  - http://biorxiv.org/content/early/2022/06/24/2022.06.22.497212.full
AB  - The 22q11.2 deletion syndrome (22q11.2DS), associated with congenital and neuropsychiatric anomalies, is the most common copy number variant (CNV)-associated syndrome. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPS models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ∼1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ∼3 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion and cell signaling. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes, both in vitro and in vivo. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.Competing Interest StatementThe authors have declared no competing interest.