{"doi":"10.1016/j.gim.2024.101087","title":"De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity","abstract":"PURPOSE: Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. METHODS: Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. RESULTS: De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION: De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects.","journal":"Genetics in Medicine","year":2024,"id":453267,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"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":910315,"name":"Gaëlle Friocourt","orcid":"0000-0001-6681-7644","position":1,"is_corresponding":false},{"id":919486,"name":"Florent Marguet","orcid":"0000-0001-7306-0520","position":2,"is_corresponding":false},{"id":1275792,"name":"Maryline Lecointre","orcid":"0000-0003-1589-4097","position":3,"is_corresponding":false},{"id":318913,"name":"Morgane Le Mao","orcid":null,"position":4,"is_corresponding":false},{"id":1276187,"name":"Rodrigo Muñoz Díaz","orcid":null,"position":5,"is_corresponding":false},{"id":242579,"name":"Cyril Mignot","orcid":"0000-0002-3462-3463","position":6,"is_corresponding":false},{"id":242574,"name":"Boris Keren","orcid":"0000-0001-6172-8247","position":7,"is_corresponding":false},{"id":274393,"name":"Bénédicte Héron","orcid":"0000-0002-7707-4521","position":8,"is_corresponding":false},{"id":1276188,"name":"Charlotte de Bie","orcid":null,"position":9,"is_corresponding":false},{"id":286602,"name":"Koen L.I. van Gassen","orcid":"0000-0001-7934-0662","position":10,"is_corresponding":false},{"id":1276189,"name":"D. 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