{"doi":"10.1093/brain/awae395","title":"<i>De novo</i> variants disrupt an <i>LDB1</i> -regulated transcriptional network in congenital ventriculomegaly","abstract":"Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is among the most common and least understood paediatric neurosurgical disorders. We have identified, in the largest assembled cerebral ventriculomegaly cohort (2697 parent-proband trios), an exome-wide significant enrichment of protein-altering de novo variants in LDB1 (P = 1.11 × 10-15). Eight unrelated patients with ventriculomegaly, developmental delay and dysmorphic features harboured loss-of-function de novo variants that truncate carboxy-terminal LIM interaction domain of LDB1, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest that LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through its binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging de novo variants in our cohort, with SMARCC1 (P = 5.83 × 10-9) and ARID1B (P = 1.80 × 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest that an LDB1-regulated transcriptional programme is essential for human brain morphogenesis.","journal":"Brain","year":2024,"id":449738,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1041365,"name":"Neel H. Mehta","orcid":"0000-0002-5144-4635","position":1,"is_corresponding":false},{"id":305458,"name":"Evan Dennis","orcid":"0000-0002-9741-9275","position":2,"is_corresponding":false},{"id":509698,"name":"Kedous Y. Mekbib","orcid":"0000-0003-2508-387X","position":3,"is_corresponding":false},{"id":240751,"name":"Benjamin C. Reeves","orcid":"0000-0002-5924-6991","position":4,"is_corresponding":false},{"id":335491,"name":"Emre Kiziltug","orcid":null,"position":5,"is_corresponding":false},{"id":1010517,"name":"Shuang Chen","orcid":"0000-0001-5254-6353","position":6,"is_corresponding":false},{"id":896386,"name":"Shujuan Zhao","orcid":"0000-0003-0248-0119","position":7,"is_corresponding":false},{"id":240753,"name":"Phan Q. Duy","orcid":"0000-0002-4513-7348","position":8,"is_corresponding":false},{"id":1270019,"name":"Maha Saleh","orcid":null,"position":9,"is_corresponding":false},{"id":1269561,"name":"Lee Cyn Ang","orcid":"0000-0003-0940-4995","position":10,"is_corresponding":false},{"id":6897,"name":"Baojian Fan","orcid":"0000-0002-6851-2737","position":11,"is_corresponding":false},{"id":333800,"name":"Carol Nelson‐Williams","orcid":"0000-0003-0768-4751","position":12,"is_corresponding":false},{"id":875970,"name":"Andrés Moreno-De-Luca","orcid":"0000-0002-2732-4043","position":13,"is_corresponding":false},{"id":333811,"name":"Shozeb Haider","orcid":"0000-0003-2650-2925","position":14,"is_corresponding":false},{"id":36512,"name":"Richard P. Lifton","orcid":"0000-0002-5745-5984","position":15,"is_corresponding":false},{"id":54021,"name":"Seth L. Alper","orcid":"0000-0002-6228-2512","position":16,"is_corresponding":false},{"id":1038398,"name":"Stephen McGee","orcid":"0000-0003-3553-0354","position":17,"is_corresponding":false},{"id":65952,"name":"Sheng Chih Jin","orcid":"0000-0002-5777-7262","position":18,"is_corresponding":false},{"id":240759,"name":"Kristopher T. Kahle","orcid":"0000-0002-5922-7547","position":19,"is_corresponding":false},{"id":634509,"name":"Garrett Allington","orcid":"0000-0002-5458-6129","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:02:20.585759Z","pmid":"39680505","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":[]}