{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T19:36:17Z","timestamp":1790537777114,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T00:00:00Z","timestamp":1640822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004919","name":"King Abdulaziz City for Science and Technology","doi-asserted-by":"publisher","award":["14-MED2007-20"],"award-info":[{"award-number":["14-MED2007-20"]}],"id":[{"id":"10.13039\/501100004919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A&gt;G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients\u2019 clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic.<\/jats:p>","DOI":"10.3390\/genes13010092","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T21:41:21Z","timestamp":1640900481000},"page":"92","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7288-8588","authenticated-orcid":false,"given":"Hesham","family":"Aldhalaan","sequence":"first","affiliation":[{"name":"Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albandary","family":"AlBakheet","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"AlRuways","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"},{"name":"Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouf","family":"AlMutairi","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"},{"name":"Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"AlNakiyah","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"},{"name":"Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reema","family":"AlGhofaili","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"},{"name":"Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7111-3609","authenticated-orcid":false,"given":"Kelly J.","family":"Cardona-Londo\u00f1o","sequence":"additional","affiliation":[{"name":"Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid Omar","family":"Alahmadi","sequence":"additional","affiliation":[{"name":"Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"AlQudairy","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-2874","authenticated-orcid":false,"given":"Maha M.","family":"AlRasheed","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-8768","authenticated-orcid":false,"given":"Dilek","family":"Colak","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan T.","family":"Arold","sequence":"additional","affiliation":[{"name":"Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8912-7507","authenticated-orcid":false,"given":"Namik","family":"Kaya","sequence":"additional","affiliation":[{"name":"Translational Genomic Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrm3742","article-title":"A day in the life of the spliceosome","volume":"15","author":"Matera","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1083\/jcb.148.6.1177","article-title":"Gemin4a novel component of the SMN complex that is found in both gems and nucleoli","volume":"148","author":"Charroux","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.1002\/1873-3468.12853","article-title":"Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation","volume":"591","author":"Lanfranco","year":"2017","journal-title":"FEBS Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1534\/g3.118.200874","article-title":"Composition of the Survival Motor Neuron (SMN) Complex in Drosophila melanogaster","volume":"9","author":"Matera","year":"2019","journal-title":"G3 Genes|Genomes|Genet."},{"key":"ref_5","first-page":"7","article-title":"Gemin4 is an essential gene in mice, and its overexpression in human cells causes relocalization of the SMN complex to the nucleoplasm","volume":"7","author":"Meier","year":"2018","journal-title":"Biol. Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1210\/en.2007-1237","article-title":"DEAD-Box Protein-103 (DP103, Ddx20) Is Essential for Early Embryonic Development and Modulates Ovarian Morphology and Function","volume":"149","author":"Mouillet","year":"2008","journal-title":"Endocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/s41436-018-0138-x","article-title":"Autozygome and high throughput confirmation of disease genes candidacy","volume":"21","author":"Maddirevula","year":"2018","journal-title":"Genet. Med."},{"key":"ref_8","first-page":"205","article-title":"Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract","volume":"136","author":"Patel","year":"2017","journal-title":"Qual. Life Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajhg.2018.08.005","article-title":"ClinPred: Prediction Tool to Identify Disease-Relevant Nonsynonymous Single-Nucleotide Variants","volume":"103","author":"Alirezaie","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/humu.22225","article-title":"Predicting the Functional, Molecular, and Phenotypic Consequences of Amino Acid Substitutions using Hidden Markov Models","volume":"34","author":"Shihab","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Choi, Y., Sims, G.E., Murphy, S., Miller, J.R., and Chan, A.P. (2012). Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046688"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pagel, K.A., Antaki, D., Lian, A., Mort, M., Cooper, D.N., Sebat, J., Iakoucheva, L.M., Mooney, S.D., and Radivojac, P. (2019). Pathogenicity and functional impact of non-frameshifting insertion\/deletion variation in the human genome. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1007112"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R232","DOI":"10.1186\/gb-2007-8-11-r232","article-title":"Determinants of protein function revealed by combinatorial entropy optimization","volume":"8","author":"Reva","year":"2007","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2019). UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res., 47, D506\u2013D515.","DOI":"10.1093\/nar\/gky1049"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/pro.3779","article-title":"ConSurf-DB: An accessible repository for the evolutionary conservation patterns of the majority of PDB proteins","volume":"29","author":"Masrati","year":"2020","journal-title":"Protein Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W402","DOI":"10.1093\/nar\/gkz297","article-title":"The PSIPRED Protein Analysis Workbench: 20 years on","volume":"47","author":"Buchan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1093\/bioinformatics\/btu744","article-title":"DISOPRED3: Precise disordered region predictions with annotated protein-binding activity","volume":"31","author":"Jones","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W430","DOI":"10.1093\/nar\/gkw306","article-title":"RaptorX-Property: A web server for protein structure property prediction","volume":"44","author":"Shiwang","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkaa913","article-title":"Pfam: The protein families database in 2021","volume":"49","author":"Mistry","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D344","DOI":"10.1093\/nar\/gkaa977","article-title":"The InterPro protein families and domains database: 20 years on","volume":"49","author":"Blum","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D227","DOI":"10.1093\/nar\/gkj063","article-title":"The PROSITE database","volume":"34","author":"Hulo","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_27","first-page":"583","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0378-4347(01)00100-1","article-title":"Clinical applications of tandem mass spectrometry: Ten years of diagnosis and screening for inherited metabolic diseases","volume":"758","author":"Rashed","year":"2001","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.celrep.2014.12.015","article-title":"Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families","volume":"10","author":"Alazami","year":"2015","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s00401-020-02128-8","article-title":"Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy","volume":"139","author":"Almuhaizea","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/ene.14082","article-title":"Genetic and phenotypic characterization of NKX6-2 -related spastic ataxia and hypomyelination","volume":"27","author":"Chelban","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/brain\/awaa459","article-title":"Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking","volume":"144","author":"Sanderson","year":"2021","journal-title":"Brain"},{"key":"ref_33","first-page":"34","article-title":"Genetics of ataxia telangiectasia in a highly consanguineous population","volume":"86","author":"Aldeeb","year":"2021","journal-title":"Ann. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/jmd2.12218","article-title":"SLC25A42 -associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion","volume":"60","author":"Aldosary","year":"2021","journal-title":"JIMD Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1528-1157.1980.tb04310.x","article-title":"Inhibition of the Glycine Cleavage System: Hyperglycinemia and Hyperglycinuria Caused by Valproic Acid","volume":"21","author":"Mortensen","year":"1980","journal-title":"Epilepsia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1248\/bpb.21.304","article-title":"Urinary Metabolites of Valproic Acid in Epileptic Patients","volume":"21","author":"Katayama","year":"1998","journal-title":"Biol. Pharm. Bull."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/92\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:47Z","timestamp":1760169347000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/92"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,30]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010092"],"URL":"https:\/\/doi.org\/10.3390\/genes13010092","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,30]]}}}