A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures


At least 5% of children present unexpected difficulties in expressing and understanding spoken language. 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 = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 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.

Publication DOI: https://doi.org/10.1093/hmg/ddab111
Divisions: College of Health & Life Sciences > School of Psychology
College of Health & Life Sciences > Clinical and Systems Neuroscience
College of Health & Life Sciences
College of Health & Life Sciences > School of Optometry > Vision, Hearing and Language
Additional Information: © The Author(s) 2021. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: Genetics(clinical),Genetics,Molecular Biology,General Medicine
Publication ISSN: 1460-2083
Last Modified: 14 May 2024 07:23
Date Deposited: 27 Apr 2021 14:36
Full Text Link:
Related URLs: https://academi ... ddab111/6230988 (Publisher URL)
PURE Output Type: Article
Published Date: 2021-06-15
Published Online Date: 2021-04-16
Accepted Date: 2021-04-12
Authors: Martinelli, Angela
Rice, Mabel
Talcott, Joel B (ORCID Profile 0000-0001-7958-8369)
Diaz, Rebeca
Smith, Shelley
Raza, Muhammad Hashim
Snowling, Margaret J
Hulme, Charles
Stein, John
Hayiou-Thomas, Marianna E
Hawi, Ziarih
Kent, Lindsey
Pitt, Samantha J
Newbury, Dianne F
Paracchini, Silvia



Version: Accepted Version

License: Creative Commons Attribution

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