{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:41:46Z","timestamp":1790804506794,"version":"4.1.0"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2024,7,6]],"date-time":"2024-07-06T00:00:00Z","timestamp":1720224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-18-1-0499"],"award-info":[{"award-number":["W81XWH-18-1-0499"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["K01MH121659"],"award-info":[{"award-number":["K01MH121659"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Caroline Wiess Law Fund for Research in Molecular Medicine"},{"name":"ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine"},{"name":"NIH\/NIAMS","award":["R01AR073284"],"award-info":[{"award-number":["R01AR073284"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants (CNVs) were examined, with emphasis on de novo variants. We also performed enrichment test for rare variants in candidate genes previously proposed in association with systemic sclerosis. We identified 42 exonic and 34 ncRNA de novo SNV changes in 101 trios, from a total of over 6000 de novo variants genome wide. We observed higher than expected de novo variants in PRKXP1 gene. We also observed such phenomenon along with increased expression in patient group in NEK7 gene. Additionally, we also observed significant enrichment of rare variants in candidate genes in the patient cohort, further supporting the complexity\/multi-factorial etiology of systemic sclerosis. Our findings identify new candidate genes including PRKXP1 and NEK7 for future studies in SSc. We observed rare variant enrichment in candidate genes previously proposed in association with SSc, which suggest more efforts should be pursued to further investigate possible pathogenetic mechanisms associated with those candidate genes.<\/jats:p>","DOI":"10.1093\/hmg\/ddae105","type":"journal-article","created":{"date-parts":[[2024,7,6]],"date-time":"2024-07-06T20:01:36Z","timestamp":1720296096000},"page":"1643-1647","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-876X","authenticated-orcid":false,"given":"Hongzheng","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]},{"name":"Molecular Division, Baylor Genetics , 2450 Holcombe Blvd, Houston 77021,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamika","family":"Ketkar","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-8861","authenticated-orcid":false,"given":"Lindsay","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]},{"name":"Department of Genetics, Texas Children\u2019s Hospital , 6620 Main St, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim C","family":"Worley","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Christopher","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marka A","family":"Lyons","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Texas Health Science Center , 7000 Fannin St, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Texas Health Science Center , 7000 Fannin St, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen D","family":"Mayes","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Texas Health Science Center , 7000 Fannin St, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston 77030,","place":["United States"]},{"name":"Department of Genetics, Texas Children\u2019s Hospital , 6620 Main St, Houston 77030,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,7]]},"reference":[{"key":"2025070620013020500_ref1","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"2025070620013020500_ref2","volume-title":"Rheumatology 8th edition","author":"Jandali","year":"2021"},{"key":"2025070620013020500_ref3","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/BOR.0000000000000897","article-title":"Recent advances in elucidating the genetic basis of systemic sclerosis","volume":"34","author":"Villanueva-Martin","year":"2022","journal-title":"Curr Opin Rheumatol"},{"key":"2025070620013020500_ref4","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.jaad.2021.10.065","article-title":"Systemic sclerosis in adults. Part I: clinical features and pathogenesis","volume":"87","author":"Jerjen","year":"2022","journal-title":"J Am Acad Dermatol"},{"key":"2025070620013020500_ref5","doi-asserted-by":"crossref","first-page":"4955","DOI":"10.1038\/s41467-019-12760-y","article-title":"GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways","volume":"10","author":"L\u00f3pez-Isac","year":"2019","journal-title":"Nat Commun"},{"key":"2025070620013020500_ref6","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jaut.2017.05.004","article-title":"Unfolding the pathogenesis of scleroderma through genomics and epigenomics","volume":"83","author":"Tsou","year":"2017","journal-title":"J Autoimmun"},{"key":"2025070620013020500_ref7","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1136\/annrheumdis-2021-219884","article-title":"Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes","volume":"80","author":"Acosta-Herrera","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"2025070620013020500_ref8","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2025070620013020500_ref9","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41586-020-2434-2","article-title":"Whole-genome sequencing of patients with rare diseases in a national health system","volume":"583","author":"Turro","year":"2020","journal-title":"Nature"},{"key":"2025070620013020500_ref10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13059-016-1110-1","article-title":"New insights into the generation and role of de novo mutations in health and disease","volume":"17","author":"Acuna-Hidalgo","year":"2016","journal-title":"Genome Biol"},{"key":"2025070620013020500_ref11","doi-asserted-by":"crossref","first-page":"1182525","DOI":"10.3389\/fimmu.2023.1182525","article-title":"Pro-inflammatory polarization and colorectal cancer modulate alternative and intronic polyadenylation in primary human macrophages","volume":"14","author":"Wilton","year":"2023","journal-title":"Front Immunol"},{"key":"2025070620013020500_ref12","doi-asserted-by":"crossref","first-page":"ra84","DOI":"10.1126\/scisignal.2004592","article-title":"Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the Wnt inhibitor WIF-1 in systemic sclerosis and fibrosis","volume":"7","author":"Svegliati","year":"2014","journal-title":"Sci Signal"},{"key":"2025070620013020500_ref13","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ydbio.2011.05.673","article-title":"PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation","volume":"356","author":"Li","year":"2011","journal-title":"Dev Biol"},{"key":"2025070620013020500_ref14","doi-asserted-by":"crossref","first-page":"102515","DOI":"10.1016\/j.jaut.2020.102515","article-title":"Recent advances in the NEK7-licensed NLRP3 inflammasome activation: mechanisms, role in diseases and related inhibitors","volume":"113","author":"Zhao","year":"2020","journal-title":"J Autoimmun"},{"key":"2025070620013020500_ref15","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41586-019-1295-z","article-title":"Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome","volume":"570","author":"Sharif","year":"2019","journal-title":"Nature"},{"key":"2025070620013020500_ref16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.5582\/bst.2020.01029","article-title":"NEK7: a potential therapy target for NLRP3-related diseases","volume":"14","author":"Liu","year":"2020","journal-title":"Biosci Trends"},{"key":"2025070620013020500_ref17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/art.1780230510","article-title":"Preliminary criteria for the classification of systemic sclerosis (scleroderma). 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