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This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N\u2009=\u2009360) compared with cohorts selected for dyslexia (0.8%, N\u2009=\u2009520) and ADHD (0.7%, N\u2009=\u2009150), which presented frequencies comparable to reference databases (0.9%, N\u2009=\u200924\u2009046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N\u2009=\u200942, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N\u2009=\u20091825; minimum P\u2009=\u20090.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.<\/jats:p>","DOI":"10.1093\/hmg\/ddab111","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T20:36:49Z","timestamp":1618432609000},"page":"1160-1171","source":"Crossref","is-referenced-by-count":16,"title":["A rare missense variant in the\n                    <i>ATP2C2<\/i>\n                    gene is associated with language impairment and related measures"],"prefix":"10.1093","volume":"30","author":[{"given":"Angela","family":"Martinelli","sequence":"first","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mabel L","family":"Rice","sequence":"additional","affiliation":[{"name":"Child Language Doctoral Program, University of Kansas, Lawrence, KS, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel B","family":"Talcott","sequence":"additional","affiliation":[{"name":"Aston Brain Centre, School of Life and Health Sciences, Aston University, Birmingham, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebeca","family":"Diaz","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelley","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, University of Nebraska Medical Center, Lincoln, NE, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Hashim","family":"Raza","sequence":"additional","affiliation":[{"name":"Child Language Doctoral Program, University of Kansas, Lawrence, KS, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret J","family":"Snowling","sequence":"additional","affiliation":[{"name":"Department of Experimental Psychology and St John's College, University of Oxford, Oxford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Hulme","sequence":"additional","affiliation":[{"name":"Department of Education, University of Oxford, Oxford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Oxford, Oxford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna E","family":"Hayiou-Thomas","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of York, York, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziarih","family":"Hawi","sequence":"additional","affiliation":[{"name":"Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey","family":"Kent","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha J","family":"Pitt","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dianne F","family":"Newbury","sequence":"additional","affiliation":[{"name":"Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Paracchini","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St Andrews, St Andrews, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"2021070819105832300_ref1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/1460-6984.12101","article-title":"Ten questions about terminology for children with unexplained language problems","volume":"49","author":"Bishop","year":"2014","journal-title":"Int. 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