Journal Article

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 to 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 nonword 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.

Attached files


Martinelli, Angela
Rice, Mabel B.
Talcott, Joel B.
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

Oxford Brookes departments

Department of Biological and Medical Sciences


Year of publication: Not yet published.
Date of RADAR deposit: 2021-04-12

Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License

Related resources

This RADAR resource is Identical to A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures


  • Owner: Joseph Ripp
  • Collection: Outputs
  • Version: 1 (show all)
  • Status: Live
  • Views (since Sept 2022): 330