{"doi":"10.1002/mds.29147","title":"<i>MED27</i>, <i>SLC6A7,</i> and <i>MPPE1</i> Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia","abstract":"BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","journal":"Movement Disorders","year":2022,"id":272989,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"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":939953,"name":"Robert Spaull","orcid":"0000-0003-4096-6945","position":1,"is_corresponding":false},{"id":940520,"name":"Smrithi Salian","orcid":null,"position":2,"is_corresponding":false},{"id":456146,"name":"Katy Barwick","orcid":"0000-0002-8885-470X","position":3,"is_corresponding":false},{"id":939954,"name":"Esther Meyer","orcid":"0009-0005-0641-9317","position":4,"is_corresponding":false},{"id":939955,"name":"Juan Zhen","orcid":"0000-0002-6111-9692","position":5,"is_corresponding":false},{"id":593519,"name":"Hiromi Hirata","orcid":"0000-0002-3769-7441","position":6,"is_corresponding":false},{"id":939956,"name":"Diba Sheipouri","orcid":"0000-0002-4416-6710","position":7,"is_corresponding":false},{"id":940521,"name":"Hind Benkerroum","orcid":null,"position":8,"is_corresponding":false},{"id":518185,"name":"Kathleen M. Gorman","orcid":"0000-0002-5488-1507","position":9,"is_corresponding":false},{"id":684861,"name":"Apostolos Papandreou","orcid":"0000-0001-5093-6075","position":10,"is_corresponding":false},{"id":4381,"name":"Michael A. Simpson","orcid":"0000-0002-8539-8753","position":11,"is_corresponding":false},{"id":940522,"name":"YOSHINOBU HIRANO","orcid":null,"position":12,"is_corresponding":false},{"id":939957,"name":"Irene Farabella","orcid":"0000-0002-7473-6227","position":13,"is_corresponding":false},{"id":685340,"name":"Maya Topf","orcid":"0000-0002-8185-1215","position":14,"is_corresponding":false},{"id":598298,"name":"Detelina Grozeva","orcid":"0000-0003-3239-8415","position":15,"is_corresponding":false},{"id":417879,"name":"Keren Carss","orcid":"0000-0003-4939-156X","position":16,"is_corresponding":false},{"id":939958,"name":"Martin Smith","orcid":"0000-0002-2404-2972","position":17,"is_corresponding":false},{"id":296825,"name":"Hardev Pall","orcid":null,"position":18,"is_corresponding":false},{"id":939959,"name":"Peter Lunt","orcid":"0000-0001-5575-0923","position":19,"is_corresponding":false},{"id":940523,"name":"Susanna De Gressi","orcid":null,"position":20,"is_corresponding":false},{"id":471766,"name":"Erik‐Jan Kamsteeg","orcid":"0000-0001-6480-1892","position":21,"is_corresponding":false},{"id":57003,"name":"Tobias B. Haack","orcid":"0000-0001-6033-4836","position":22,"is_corresponding":false},{"id":921811,"name":"Lucinda Carr","orcid":"0000-0001-9238-108X","position":23,"is_corresponding":false},{"id":331123,"name":"Rita Guerreiro","orcid":"0000-0001-5879-3486","position":24,"is_corresponding":false},{"id":52693,"name":"José Brás","orcid":"0000-0001-8186-0333","position":25,"is_corresponding":false},{"id":760961,"name":"Eamonn R. Maher","orcid":"0000-0002-6226-6918","position":26,"is_corresponding":false},{"id":218173,"name":"Richard H. Scott","orcid":"0000-0002-9113-2978","position":27,"is_corresponding":false},{"id":564607,"name":"Robert J. Vandenberg","orcid":"0000-0003-1523-4814","position":28,"is_corresponding":false},{"id":259398,"name":"F. Lucy Raymond","orcid":"0000-0003-2652-3355","position":29,"is_corresponding":false},{"id":939960,"name":"W Kling Chong","orcid":"0000-0002-3840-9771","position":30,"is_corresponding":false},{"id":939961,"name":"Sniya Sudhakar","orcid":"0000-0002-7632-9705","position":31,"is_corresponding":false},{"id":615361,"name":"Kshitij Mankad","orcid":"0000-0001-5979-9337","position":32,"is_corresponding":false},{"id":356906,"name":"Maarten E. A. Reith","orcid":"0000-0002-1900-842X","position":33,"is_corresponding":false},{"id":242567,"name":"Philippe M. Campeau","orcid":"0000-0001-9713-7107","position":34,"is_corresponding":false},{"id":366334,"name":"Victoria L. Harvey","orcid":"0000-0001-5956-6664","position":35,"is_corresponding":false},{"id":397614,"name":"Manju A. Kurian","orcid":"0000-0003-3529-5075","position":36,"is_corresponding":false},{"id":939952,"name":"Kimberley M. Reid","orcid":"0000-0002-8132-3105","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"35876425","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":[]}