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Abstract
22q11.2 deletion syndrome, 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 insight into this condition. However, patient-derived iPS cells may harbor underlying genetic heterogeneity that can confound analysis. Furthermore, almost all available models reflect the commonly-found ~ 3 Mb “A-D” deletion at this locus. The ~ 1.5 Mb “A-B” deletion, a variant of the 22q11.2 deletion which may lead to different syndromic features, and is much more frequently inherited than the A-D deletion, remains under-studied due to lack of relevant models. Here we leveraged a CRISPR-based strategy to engineer isogenic iPS models of the 22q11.2 “A-B” deletion. Differentiation to excitatory neurons with subsequent characterization by transcriptomics and cell surface proteomics identified deletion-associated alterations in proliferation and adhesion. To illustrate in vivo applications of this model, we further implanted neuronal progenitor cells into the cortex of neonatal mice and found potential alterations in neuronal maturation. The isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.
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1 University of California, San Francisco, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
2 University of California, San Francisco, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of Texas Health Science Center at San Antonio, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880)
3 University of California, San Francisco, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
4 University of California, San Francisco, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco State University, San Francisco, USA (GRID:grid.263091.f) (ISNI:0000000106792318)
5 University of California, San Francisco, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Chan Zuckerberg Biohub-San Francisco, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175)
6 University of California, San Francisco, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Chan Zuckerberg Biohub-San Francisco, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175); University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)