{"doi":"10.1016/j.gim.2022.11.001","title":"Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities","abstract":"PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.","journal":"Genetics in Medicine","year":2022,"id":244323,"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":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9411,"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":878082,"name":"Madison Chilian","orcid":null,"position":1,"is_corresponding":false},{"id":322427,"name":"Ehsan Ghayoor Karimiani","orcid":"0000-0003-3858-7073","position":2,"is_corresponding":false},{"id":771936,"name":"Helga Progri","orcid":null,"position":3,"is_corresponding":false},{"id":322414,"name":"Daniela Buhaş","orcid":"0000-0002-9688-4677","position":4,"is_corresponding":false},{"id":877595,"name":"Melis Köse","orcid":"0000-0003-2255-3725","position":5,"is_corresponding":false},{"id":454373,"name":"Rebecca Ganetzky","orcid":"0000-0001-6238-8109","position":6,"is_corresponding":false},{"id":472836,"name":"Mehran Beiraghi Toosi","orcid":"0000-0002-0569-1117","position":7,"is_corresponding":false},{"id":877596,"name":"Paria Najarzadeh Torbati","orcid":"0000-0001-7583-4614","position":8,"is_corresponding":false},{"id":877597,"name":"Reza Shervin Badv","orcid":"0000-0002-7477-4688","position":9,"is_corresponding":false},{"id":877598,"name":"Ivan Shelihan","orcid":"0000-0001-7793-7860","position":10,"is_corresponding":false},{"id":877599,"name":"Hui Yang","orcid":"0000-0001-5060-787X","position":11,"is_corresponding":false},{"id":526097,"name":"Houda Zghal Elloumi","orcid":null,"position":12,"is_corresponding":false},{"id":321525,"name":"Sukyeong Lee","orcid":"0000-0001-6054-6628","position":13,"is_corresponding":false},{"id":55736,"name":"Yalda Jamshidi","orcid":"0000-0003-0151-6482","position":14,"is_corresponding":false},{"id":520492,"name":"Alan Pittman","orcid":"0000-0002-8112-2987","position":15,"is_corresponding":false},{"id":52692,"name":"Henry Houlden","orcid":"0000-0002-2866-7777","position":16,"is_corresponding":false},{"id":877600,"name":"Erika Ignatius","orcid":"0000-0002-3574-6510","position":17,"is_corresponding":false},{"id":232562,"name":"Shamima Rahman","orcid":"0000-0003-2088-730X","position":18,"is_corresponding":false},{"id":281488,"name":"Reza Maroofian","orcid":"0000-0001-6763-1542","position":19,"is_corresponding":false},{"id":321528,"name":"Wan Hee Yoon","orcid":"0000-0002-9459-3139","position":20,"is_corresponding":false},{"id":297735,"name":"Christopher J. Carroll","orcid":"0000-0002-2814-6955","position":21,"is_corresponding":false},{"id":877594,"name":"Ella F. Whittle","orcid":"0000-0001-9988-6056","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T00:23:25.718788Z","pmid":"36520152","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":[]}