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

Angela Martinelli, Mabel L. Rice, Joel B. Talcott, Rebeca Diaz, Shelley Smith, Muhammad Hashim Raza, Margaret J. Snowling, Charles Hulme, John Stein, Marianna E. Hayiou-Thomas, Ziarih Hawi, Lindsey Kent, Samantha J. Pitt, Dianne F. Newbury, Silvia Paracchini

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1160-1171
Number of pages12
JournalHuman Molecular Genetics
Issue number12
StatePublished - Jun 15 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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