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An overview of germline variations in genes of primary immunodeficiences through integrative analysis of ClinVar, HGMD® and dbSNP databases

Abstract

Primary immunodeficiencies (PID) are a diverse group of genetic disorders caused by inadequate development and function of immune system. Identifying genetic etiology is important for genetic counselling and treatment decisions. Clinical relevance of genetic variants is a complex problem depending on gene-specific and variant specific genotype–phenotype interactions. To address this challenge, we aimed to characterize the pathogenic landscape of PID genes by combining the analysis of germline variations reported in ClinVar and HGMD® and identification of damaging variations available in dbSNP. We generated a joint ClinVar/HGMD database, which included 111,940 variants, among them 32,452 were classified as pathogenic/likely pathogenic. From a total of 5,415,794 bi- or multiallelic variants in PID genes recorded in dbSNP, we retrieved 38,291 high impact (HI) biallelic variants with presumably disruptive impact in the protein, of them 25,500 variants were not present in ClinVar/HGMD. Using a functional prediction algorithm, we additionally identified 28,507 deleterious and 56,016 neutral missense variants among dbSNP variants and created a collection of damaging and neutral variations in PID genes, not currently present in ClinVar/HGMD, with their allele frequencies and mappings to protein domains. The distribution of pathogenic variants from ClinVar/HGMD, HI variants and deleterious missense variants from dbSNP was analyzed in the context of hereditary pattern and gene specific metrics, such as pLI and haploinsufficiency. Our report summarized data on complex gene-specific variability in PID genes and might be useful for the identification of the most promising variants and gene regions for further study.

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Availability of data and material

The datasets for this manuscript are available in Supplementary Materials. The joint version of ClinVar and HGMD public is available upon request.

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Acknowledgements

The authors would like to acknowledge QIAGEN for providing a free trial of HGMD®.

Funding

This work was supported by the state assignment of the Ministry of Education and Science of Russia (No. 0112-2019-0002 “Genetic technologies in biology, medicine, agriculture and environmental management activities)”.

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LS designed the study. LS, DK and DS collected data and prepared figures. DK conducted all bioinformatics analyses. LS and DK analyzed and interpreted data. LS wrote the manuscript. LS and SA supervised the project. All authors discussed the results and contributed to the final manuscript.

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Correspondence to Lyubov E. Salnikova.

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Salnikova, L.E., Kolobkov, D.S., Sviridova, D.A. et al. An overview of germline variations in genes of primary immunodeficiences through integrative analysis of ClinVar, HGMD® and dbSNP databases. Hum Genet 140, 1379–1393 (2021). https://doi.org/10.1007/s00439-021-02316-w

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