Language
English
Publication Date
9-19-2024
Journal
Human Molecular Genetics
DOI
10.1093/hmg/ddae105
PMID
38970828
PMCID
PMC11413644
PubMedCentral® Posted Date
7-7-2024
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Scleroderma, Systemic, Whole Genome Sequencing, Genome-Wide Association Study, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Male, Female, Adult, NIMA-Related Kinases, Middle Aged, Fibroblasts, whole genome sequencing, transcriptome, rare variants, systemic sclerosis
Published Open-Access
yes
Recommended Citation
Dai, Hongzheng; Ketkar, Shamika; Tan, Taotao; et al., "Exploring the Complexity of Systemic Sclerosis Etiology by Trio Whole Genome Sequencing" (2024). Faculty and Staff Publications. 5001.
https://digitalcommons.library.tmc.edu/baylor_docs/5001
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons