Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants

Delgado-Vega, Angélica M.; Martínez-Bueno, Manuel; Oparina, N. Yu.; Herráez, David López; Kristjánsdóttir, Helga; Steinsson, Kristján; Kozyrev, Sergey V.; Alarcón‐Riquelme, Marta E.

doi:10.1038/s41598-018-26274-y

Cited by 26 publications

(16 citation statements)

References 95 publications

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“…Indeed, the team concluded that ATP depletion in combination with downregulation of ATP-dependent genes ERCC2 and ERCC5 suggest insufficient DNA repair in SLE patients, resulting in increased apoptosis and perpetuation of autoimmunity. Moreover, in order to identify rare alleles associated with SLE, Delgado-Vega and colleagues performed whole exome sequencing in SLE patients from well-studied Icelandic SLE multi-case families [122]. They found rare, possibly pathogenic variants in 19 genes, including the X-ray repair cross-complementation group 6 binding protein 1 (XRCC6BP1), also termed Ku70-binding protein 3 (KUB3).…”

Section: Increased Endogenous Dna Damage In Sle: Defective Repair or mentioning

confidence: 99%

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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Section: Increased Endogenous Dna Damage In Sle: Defective Repair or mentioning

confidence: 99%

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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“…We recently described the identification of many rare mutations in Icelandic families with multiple cases of SLE [14••]. By performing exome sequencing on the most distantly related affected individuals from two large families and verifying some of the mutations through genotyping or Sanger sequencing, we identified multiple rare and likely pathogenic variants in 19 genes co-segregating with disease through multiple generations.…”

Section: Towards a Molecular Stratification Of Sle—first Steps: The Rmentioning

confidence: 99%

New Attempts to Define and Clarify Lupus

Alarcón‐Riquelme

2019

Curr Rheumatol Rep

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Purpose of Review The purpose is to discuss the advances that genetics and genomics have provided to better understand the molecular mechanisms behind SLE and how to solve its heterogeneity. I propose new ideas that can help us stratify lupus in order to find the best therapies for each patient, and the idea of substituting clinical diagnosis with molecular diagnosis according to their molecular patterns, an idea that may not only include lupus but also other diseases. Recent Findings The study of rare mutations may provide insight into groups of lupus patients where type I interferon signature is important and help understand those with an atypical clinical presentation. Recent papers used longitudinal blood transcriptome data correlating with disease activity scores to stratify lupus into molecular clusters. The implication of neutrophils in the risk to develop nephritis was established, but also that neutrophils and lymphocytes may correlate with activity differentiating the mechanisms of flares and separating patients into clinically separate groups. Summary The role of type I interferon signature is important; however, the stratification of SLE patients according to the genes and cellular compartments being modulated during disease activity may be even more important to define those patients who may benefit the most with new anti-type I IFN receptor therapies.

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“…Whole exome sequencing (WES) of SLE family trios has identified de novo mutations and potential novel SLE genes (Pullabhatla et al 2018 ). WES has also successfully identified rare variants that are likely pathogenic in SLE (Delgado-Vega et al 2018 ) and WGS of monozygotic twins discordant for SLE has found CNVs that may be associated with difference in SLE phenotype between twins (Chen et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus

et al. 2019

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Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare ( ≤ 0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes ( C1S, DNASE1L3, DNASE1, IFIH1 , and RNASEH2A ) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported. Electronic supplementary material The online version of this article (10.1007/s00439-018-01966-7) contains supplementary material, which is available to authorized users.

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Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants

Cited by 26 publications

References 95 publications

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

New Attempts to Define and Clarify Lupus

Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus

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