{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:42:24Z","timestamp":1790329344149,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005117","name":"Birjand University of Medical Sciences","doi-asserted-by":"publisher","award":["455747"],"award-info":[{"award-number":["455747"]}],"id":[{"id":"10.13039\/501100005117","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Laboratory Analysis"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early\u2010onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with <jats:italic>ATP8A2<\/jats:italic> mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non\u2010progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR\u2010based Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel homozygous missense variant (c.1339G\u00a0&gt;\u00a0A, p.Gly447Arg) in the\u00a0<jats:italic>ATP8A2<\/jats:italic>\u00a0gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand\u2010binding pocket. The novel sequence variant\u00a0occurred\u00a0within an extremely conserved subregion of the ATP\u2010binding domain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings expand the spectrum of <jats:italic>ATP8A2<\/jats:italic> mutations and confirm the reported genotype\u2010phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcla.23484","type":"journal-article","created":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T05:26:30Z","timestamp":1595049990000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6255-5376","authenticated-orcid":false,"given":"Malihe","family":"Mohamadian","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine Birjand University of Medical Sciences Birjand Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7828-6465","authenticated-orcid":false,"given":"Pegah","family":"Ghandil","sequence":"additional","affiliation":[{"name":"Diabetes Research Center Health Research Institute Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran"},{"name":"Department of Medical Genetics School of Medicine Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3100-6344","authenticated-orcid":false,"given":"Mohsen","family":"Naseri","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Research Center Birjand University of Medical Sciences Birjand Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afsane","family":"Bahrami","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Research Center Birjand University of Medical Sciences Birjand Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali Akbar","family":"Momen","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology Golestan Medical, Educational, and Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409230903193307"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201967"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/00207450500455330"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-13-80"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073809332696"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37421"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.126110.111"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000487"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.31227"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/1179573518759682"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10741-z"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms14047897"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.05.018"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.126"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09579-4"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.170"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119061199"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-016-0496-y"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2017.04.935"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0825-3"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17040512"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.2142\/biophysico.13.0_157"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.03.028"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23889"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a003392"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0864-9"}],"container-title":["Journal 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