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

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

doi:10.1093/hmg/ddab111

Abstract

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.

Highlights

PT In this study we investigated the effects of a rare ATP2C2 variant on language impairment and I related disorders
We found that this variant had a higher frequency in language impairment (LI) samples (1.8%, N CR = 360) compared to controls (1%, N = 681, ALSPAC) and subjects with dyslexia (0.8%, N = 520) S or attention deficit/hyperactivity disorder (ADHD) (0.7%, N = 150)
In a general population sample derived from the ALSPAC cohort, carriers of the N rare variants presented lower scores compared to non-carries on a range of language-related MA measures, with the stronger effect observed for the nonword reading measure (p = 0.002; Table 3)

Summary

RESULTS

T Whole exome sequencing (WES) analysis in six families selected for SLI led to the identification of IP a rare variant (Chr16:84405221) in the ATP2C2 gene (Figure 1). This variant was found in two R children and their father, all diagnosed with SLI. The frequency of the variant was 2.2% in the SLIC cohort selected for SLI and 1.8% UN across all the unrelated LI cases (combined LI samples, N = 360), including the discovery family and previously published data (49). RIP Mean score of language and reading-related phenotypes C We evaluated the effects of the variant on a range of language-related quantitative measures S available for the ALSPAC cohort (Supplementary Table S4). WB confirmed the overexpression of SPCA2 for the WT and mutated constructs while no protein was detected for the negative controls, suggesting a very minimal effect of baseline endogenous protein (Figure 2B)

DISCUSSION

Objective

E MutationTaster

E Abbreviations