{"doi":"10.1101/2022.06.22.497212","title":"A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion","abstract":"ABSTRACT 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":301440,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":28921,"name":"Yu-Hsiu T. Lin","orcid":"0000-0002-7157-4330","position":1,"is_corresponding":false},{"id":992571,"name":"Quetzal Flores-Ramirez","orcid":"0000-0003-0309-3428","position":2,"is_corresponding":false},{"id":352936,"name":"Vishesh Sarin","orcid":"0009-0003-2270-7621","position":3,"is_corresponding":false},{"id":992572,"name":"Amanda Johnson","orcid":"0000-0003-3519-8283","position":4,"is_corresponding":false},{"id":331767,"name":"Julia Chu","orcid":"0009-0001-7404-5688","position":5,"is_corresponding":false},{"id":226816,"name":"Mercedes F. Paredes","orcid":"0000-0003-2503-1447","position":6,"is_corresponding":false},{"id":28927,"name":"Arun P. Wiita","orcid":"0000-0002-7465-6964","position":7,"is_corresponding":false},{"id":646308,"name":"Neha Paranjape","orcid":"0000-0001-7788-0497","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:02.193874Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}