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.
References
1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74. https://doi.org/10.1038/nature15393
Abolhassani H, Azizi G, Sharifi L, Yazdani R, Mohsenzadegan M, Delavari S, Sohani M, Shirmast P, Chavoshzadeh Z, Mahdaviani SA, Kalantari A, Tavakol M, Jabbari-Azad F, Ahanchian H, Momen T, Sherkat R, Sadeghi-Shabestari M, Aleyasin S, Esmaeilzadeh H, Al-Herz W, Bousfiha AA, Condino-Neto A, Seppänen M, Sullivan KE, Hammarström L, Modell V, Modell F, Quinn J, Orange JS, Aghamohammadi A (2020) Global systematic review of primary immunodeficiency registries. Expert Rev Clin Immunol 16(7):717–732. https://doi.org/10.1080/1744666X.2020.1801422
Alyousfi D, Baralle D, Collins A (2019) Gene-specific metrics to facilitate identification of disease genes for molecular diagnosis in patient genomes: a systematic review. Brief Funct Genom 18(1):23–29. https://doi.org/10.1093/bfgp/ely033
Anderson D, Lassmann T (2018) A phenotype centric benchmark of variant prioritisation tools. NPJ Genom Med 3:5. https://doi.org/10.1038/s41525-018-0044-9
Babbi G, Martelli PL, Profiti G, Bovo S, Savojardo C, Casadio R (2017) eDGAR: a database of Disease-Gene Associations with annotated Relationships among genes. BMC Genom 18(Suppl 5):554. https://doi.org/10.1186/s12864-017-3911-3
Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, Abel L (2013) Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol 33(1):1–7. https://doi.org/10.1007/s10875-012-9751-7
Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Torgerson TR, Casanova JL, Sullivan KE, Tangye SG (2020) Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol 40(1):66–81. https://doi.org/10.1007/s10875-020-00758-x
Bucciol G, Meyts I (2020) Recent advances in primary immunodeficiency: from molecular diagnosis to treatment. F1000Res. 9:F1000 Faculty Rev-194. https://doi.org/10.12688/f1000research.21553.1
Collins A (2015) The genomic and functional characteristics of disease genes. Brief Bioinform 16(1):16–23. https://doi.org/10.1093/bib/bbt091
Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H (2013) Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 132(10):1077–1130. https://doi.org/10.1007/s00439-013-1331-2
Dawes R, Lek M, Cooper ST (2019) Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality. NPJ Genom Med 4:8. https://doi.org/10.1038/s41525-019-0081-z
Dolinski K, Botstein D (2007) Orthology and functional conservation in eukaryotes. Annu Rev Genet 41:465–507. https://doi.org/10.1146/annurev.genet.40.110405.090439
Edgar JD, Buckland M, Guzman D, Conlon NP, Knerr V, Bangs C, Reiser V, Panahloo Z, Workman S, Slatter M, Gennery AR, Davies EG, Allwood Z, Arkwright PD, Helbert M, Longhurst HJ, Grigoriadou S, Devlin LA, Huissoon A, Krishna MT, Hackett S, Kumararatne DS, Condliffe AM, Baxendale H, Henderson K, Bethune C, Symons C, Wood P, Ford K, Patel S, Jain R, Jolles S, El-Shanawany T, Alachkar H, Herwadkar A, Sargur R, Shrimpton A, Hayman G, Abuzakouk M, Spickett G, Darroch CJ, Paulus S, Marshall SE, McDermott EM, Heath PT, Herriot R, Noorani S, Turner M, Khan S, Grimbacher B (2014) The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years’ activity 2008–2012. Clin Exp Immunol 175(1):68–78. https://doi.org/10.1111/cei.12172
Eilbeck K, Quinlan A, Yandell M (2017) Settling the score: variant prioritization and Mendelian disease. Nat Rev Genet 18(10):599–612. https://doi.org/10.1038/nrg.2017.52
Fodil N, Langlais D, Gros P (2016) Primary immunodeficiencies and inflammatory disease: a growing genetic intersection. Trends Immunol 37(2):126–140. https://doi.org/10.1016/j.it.2015.12.006
Franz M, Rodriguez H, Lopes C, Zuberi K, Montojo J, Bader GD, Morris Q (2018) GeneMANIA update 2018. Nucleic Acids Res 46(W1):W60–W64. https://doi.org/10.1093/nar/gky311
Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, Ritterbusch H, Baumann U, Meyer-Bahlburg A, Witte T, Schmidt R, Borte M, Borte S, Linde R, Schubert R, Bienemann K, Laws HJ, Dueckers G, Roesler J, Rothoeft T, Krüger R, Scharbatke EC, Masjosthusmann K, Wasmuth JC, Moser O, Kaiser P, Groß-Wieltsch U, Classen CF, Horneff G, Reiser V, Binder N, El-Helou SM, Klein C, Grimbacher B, Kindle G (2013) The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol 173(2):372–380. https://doi.org/10.1111/cei.12105
Gruber C, Bogunovic D (2020) Incomplete penetrance in primary immunodeficiency: a skeleton in the closet. Hum Genet 139(6–7):745–757. https://doi.org/10.1007/s00439-020-02131-9
Hsu JS, Kwan JS, Pan Z, Garcia-Barcelo MM, Sham PC, Li M (2016) Inheritance-mode specific pathogenicity prioritization (ISPP) for human protein coding genes. Bioinformatics 32(20):3065–3071. https://doi.org/10.1093/bioinformatics/btw381
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database Consortium, Neale BM, Daly MJ, MacArthur DG (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434–443. https://doi.org/10.1038/s41586-020-2308-7
Kinsella RJ, Kähäri A, Haider S, Zamora J, Proctor G, Spudich G, Almeida-King J, Staines D, Derwent P, Kerhornou A, Kersey P, Flicek P (2011) Ensembl BioMarts: a hub for data retrieval across taxonomic space. Database (oxford) 2011:bar030. https://doi.org/10.1093/database/bar030
Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B, Hart J, Hoffman D, Jang W, Kaur K, Liu C, Lyoshin V, Maddipatla Z, Maiti R, Mitchell J, O’Leary N, Riley GR, Shi W, Zhou G, Schneider V, Maglott D, Holmes JB, Kattman BL (2020) ClinVar: improvements to accessing data. Nucleic Acids Res 48(D1):D835–D844. https://doi.org/10.1093/nar/gkz972
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation Consortium (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. https://doi.org/10.1038/nature19057
Liu X, Li C, Mou C, Dong Y, Tu Y (2020) dbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs. Genome Med 12(1):103. https://doi.org/10.1186/s13073-020-00803-9
MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, Jostins L, Habegger L, Pickrell JK, Montgomery SB, Albers CA, Zhang ZD, Conrad DF, Lunter G, Zheng H, Ayub Q, DePristo MA, Banks E, Hu M, Handsaker RE, Rosenfeld JA, Fromer M, Jin M, Mu XJ, Khurana E, Ye K, Kay M, Saunders GI, Suner MM, Hunt T, Barnes IH, Amid C, Carvalho-Silva DR, Bignell AH, Snow C, Yngvadottir B, Bumpstead S, Cooper DN, Xue Y, Romero IG, 1000 Genomes Project Consortium, Wang J, Li Y, Gibbs RA, McCarroll SA, Dermitzakis ET, Pritchard JK, Barrett JC, Harrow J, Hurles ME, Gerstein MB, Tyler-Smith C (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335(6070):823–828. https://doi.org/10.1126/science.1215040
McCafferty CL, Sergeev YV (2016) In silico mapping of protein unfolding mutations for inherited disease. Sci Rep 6:37298. https://doi.org/10.1038/srep37298
McCarthy DJ, Humburg P, Kanapin A, Rivas MA, Gaulton K, Cazier JB, Donnelly P (2014) Choice of transcripts and software has a large effect on variant annotation. Genome Med. 6(3):26. https://doi.org/10.1186/gm543
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The ensembl variant effect predictor. Genome Biol 17(1):122. https://doi.org/10.1186/s13059-016-0974-4
Miosge LA, Field MA, Sontani Y, Cho V, Johnson S, Palkova A, Balakishnan B, Liang R, Zhang Y, Lyon S, Beutler B, Whittle B, Bertram EM, Enders A, Goodnow CC, Andrews TD (2015) Comparison of predicted and actual consequences of missense mutations. Proc Natl Acad Sci USA 112(37):E5189–E5198. https://doi.org/10.1073/pnas.1511585112
Ozcomak MS, Kartal M, Senger O, Celik AK (2013) Comparison of the powers of the Kolmogorov-Smirnov two-sample test and the Mann-Whitney test for different Kurtosis and Skewness coefficients using the Monte Carlo simulation method. J Stat Econ Methods 2(4):81–98
Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB (2013) Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 9(8):e1003709. https://doi.org/10.1371/journal.pgen.1003709
Rausell A, Luo Y, Lopez M, Seeleuthner Y, Rapaport F, Favier A, Stenson PD, Cooper DN, Patin E, Casanova JL, Quintana-Murci L, Abel L (2020) Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes. Proc Natl Acad Sci USA 117(24):13626–13636
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Laboratory Quality Assurance Committee ACMG (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30
Salnikova LE, Chernyshova EV, Anastasevich LA, Larin SS (2019) Gene- and disease-based expansion of the knowledge on inborn errors of immunity. Front Immunol 10:2475. https://doi.org/10.3389/fimmu.2019.02475
Sapra KT, Balasubramanian GP, Labudde D, Bowie JU, Muller DJ (2008) Point mutations in membrane proteins reshape energy landscape and populate different unfolding pathways. J Mol Biol 376(4):1076–1090. https://doi.org/10.1016/j.jmb.2007.12.027
Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, Scheible R, Rusch S, Gasteiger LM, Grimbacher B, Mahlaoui N, Ehl S, ESID Registry Working Party Collaborators (2019) The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract 7(6):1763–1770. https://doi.org/10.1016/j.jaip.2019.02.004
Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN (2020) The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet 139(10):1197–1207. https://doi.org/10.1007/s00439-020-02199-3
Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, Erichsen HC, Forbes LR, Gu S, Yuan B, Jhangiani SN, Muzny DM, Rødningen OK, Sheng Y, Nicholas SK, Noroski LM, Seeborg FO, Davis CM, Canter DL, Mace EM, Vece TJ, Allen CE, Abhyankar HA, Boone PM, Beck CR, Wiszniewski W, Fevang B, Aukrust P, Tjønnfjord GE, Gedde-Dahl T, Hjorth-Hansen H, Dybedal I, Nordøy I, Jørgensen SF, Abrahamsen TG, Øverland T, Bechensteen AG, Skogen V, Osnes LTN, Kulseth MA, Prescott TE, Rustad CF, Heimdal KR, Belmont JW, Rider NL, Chinen J, Cao TN, Smith EA, Caldirola MS, Bezrodnik L, Lugo Reyes SO, Espinosa Rosales FJ, Guerrero-Cursaru ND, Pedroza LA, Poli CM, Franco JL, Trujillo Vargas CM, Aldave Becerra JC, Wright N, Issekutz TB, Issekutz AC, Abbott J, Caldwell JW, Bayer DK, Chan AY, Aiuti A, Cancrini C, Holmberg E, West C, Burstedt M, Karaca E, Yesil G, Artac H, Bayram Y, Atik MM, Eldomery MK, Ehlayel MS, Jolles S, Flatø B, Bertuch AA, Hanson IC, Zhang VW, Wong LJ, Hu J, Walkiewicz M, Yang Y, Eng CM, Boerwinkle E, Gibbs RA, Shearer WT, Lyle R, Orange JS, Lupski JR (2017) Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol 139(1):232–245. https://doi.org/10.1016/j.jaci.2016.05.042
Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Picard C, Puck J, Torgerson TR, Casanova JL, Sullivan KE (2020) Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 40(1):24–64. https://doi.org/10.1007/s10875-019-00737-x
Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F, Primary Immunodeficiency Consortium for the NIHR Bioresource, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, Smith KGC (2020) Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583(7814):90–95. https://doi.org/10.1038/s41586-020-2265-1
Thévenin A, Ein-Dor L, Ozery-Flato M, Shamir R (2014) Functional gene groups are concentrated within chromosomes, among chromosomes and in the nuclear space of the human genome. Nucleic Acids Res 42(15):9854–9861. https://doi.org/10.1093/nar/gku667
Walsh R, Mazzarotto F, Whiffin N, Buchan R, Midwinter W, Wilk A, Li N, Felkin L, Ingold N, Govind R, Ahmad M, Mazaika E, Allouba M, Zhang X, de Marvao A, Day SM, Ashley E, Colan SD, Michels M, Pereira AC, Jacoby D, Ho CY, Thomson KL, Watkins H, Barton PJR, Olivotto I, Cook SA, Ware JS (2019) Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy. Genome Med 11(1):5. https://doi.org/10.1186/s13073-019-0616-z
Wang K, Li M, Hakonarson H (2010) ANNOVAR: Functional annotation of genetic variants from next-generation sequencing data. Nucleic Acids Res 38:e164. https://doi.org/10.1093/nar/gkq603
Wolfe D, Dudek S, Ritchie MD, Pendergrass SA (2013) Visualizing genomic information across chromosomes with PhenoGram. BioData Min 6(1):18. https://doi.org/10.1186/1756-0381-6-18
Yi G, Sze SH, Thon MR (2007) Identifying clusters of functionally related genes in genomes. Bioinformatics 23(9):1053–1060. https://doi.org/10.1093/bioinformatics/btl673
Zhang Q, Frange P, Blanche S, Casanova JL (2017) Pathogenesis of infections in HIV-infected individuals: insights from primary immunodeficiencies. Curr Opin Immunol 48:122–133. https://doi.org/10.1016/j.coi.2017.09.002
Ziegler A, Colin E, Goudenège D, Bonneau D (2019) A snapshot of some pLI score pitfalls. Hum Mutat 40(7):839–841. https://doi.org/10.1002/humu.23763
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The authors would like to acknowledge QIAGEN for providing a free trial of HGMD®.
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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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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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DOI: https://doi.org/10.1007/s00439-021-02316-w