Genetic screening of early-onset patients with systemic lupus erythematosus by a targeted next-generation sequencing gene panel

Daşdemir, Selçuk; Yıldız, Mehmet; Çelebi, Damla; Şahin, Sezgin; Aliyeva, N.; Haşlak, Fatih; Günalp, Aybüke; Adroviç, Amra; Barut, Kenan; Artim‐Esen, Bahar; Kasapçopur, Özgür

doi:10.1177/09612033221076733

Cited by 21 publications

(11 citation statements)

References 30 publications

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“…The use of NGS (next-generation sequencing) in early-onset SLE will provide further insights in understanding the molecular mechanisms of the disease, but also of tolerance maintenance, leading to a personalized medicine with less adverse events and increased efficacy [ 154 ].…”

Section: Pathophysiology Of Systemic Monogenic Autoimmune Disorders A...mentioning

confidence: 99%

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

et al. 2023

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Monogenic autoimmune disorders represent an important tool to understand the mechanisms behind central and peripheral immune tolerance. Multiple factors, both genetic and environmental, are known to be involved in the alteration of the immune activation/immune tolerance homeostasis typical of these disorders, making it difficult to control the disease. The latest advances in genetic analysis have contributed to a better and more rapid diagnosis, although the management remains confined to the treatment of clinical manifestations, as there are limited studies on rare diseases. Recently, the correlation between microbiota composition and the onset of autoimmune disorders has been investigated, thus opening up new perspectives on the cure of monogenic autoimmune diseases. In this review, we will summarize the main genetic features of both organ-specific and systemic monogenic autoimmune diseases, reporting on the available literature data on microbiota alterations in these patients.

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Section: Pathophysiology Of Systemic Monogenic Autoimmune Disorders A...mentioning

confidence: 99%

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

et al. 2023

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“…However, these methods only detect the immuno- reactivities of target complement components, and do not necessarily reflect their activity states. For the studies of congenital complement deficiency or for the study of genetic polymorphisms in populations, next-generation sequencing (NGS) and qPCR are often deployed to analyze particular components ( 91 ). Therefore, there are no validated C1s quantification assays available in clinical practice currently, and the quantification of C1s in research is also difficult due to limited reliable antibodies and lack of standardized assays.…”

Section: C1s Determination In Biological Samplesmentioning

confidence: 99%

Complement C1s as a diagnostic marker and therapeutic target: Progress and propective

Yang

Yang³

et al. 2022

Front. Immunol.

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The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.

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“…High-throughput sequencing can detect genetic alterations in an entire genome, an exome, or a group of genes. Patients with early-onset lupus often carry a high frequency of pathogenic variants, highlighting the importance of genetic testing for pSLE (21,22). We then applied WES and identified three new mutations in this patient, all inherited from her father and mother.…”

Section: The Germline Rare Mutations Of Acp5 and Samhd1 Identified In...mentioning

confidence: 99%

Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus

et al. 2022

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BackgroundThe study of genetic predisposition to pediatric systemic lupus erythematosus (pSLE) has brought new insights into the pathophysiology of SLE, as it is hypothesized that genetic predisposition is greater in children. Furthermore, identifying genetic variants and linking disrupted genes to abnormal immune pathways and clinical manifestations can be beneficial for both diagnosis and treatment. Here, we identified genetic alterations in a patient with childhood-onset SLE and analyzed the immunological mechanisms behind them to support future diagnosis, prognosis, and treatment.MethodsWhole exome sequencing (WES) was adopted for genetic analysis of a patient with childhood-onset SLE. Gene mutations were confirmed by Sanger sequencing. Clinical data of this patient were collected and summarized. Ingenuity Pathway Analysis was used to provide interacting genes of the perturbed genes. Online Enrichr tool and Cytoscape software were used to analysis the related pathways of these genes.ResultsWe present a case of a 2-year-old girl who was diagnosed with idiopathic thrombocytopenic purpura (ITP) and SLE. The patient was characterized by cutaneous bleeding spots on both lower extremities, thrombocytopenia, decreased serum complements levels, increased urinary red blood cells, and positive ANA and dsDNA. The patient was treated with methylprednisolone and mycophenolate, but clinical remission could not be achieved. The genomic analysis identified three novel mutations in this pSLE patient, a double-stranded missense mutation in ACP5 (c.1152G>T and c.420G>A) and a single-stranded mutation in SAMHD1 (c.1423G>A). Bioinformatic analysis showed that these two genes and their interacting genes are enriched in the regulation of multiple immune pathways associated with SLE, including cytokine signaling and immune cell activation or function. Analysis of the synergistic regulation of these two genes suggests that abnormalities in the type I interferon pathway caused by genetic variants may contribute to the pathogenesis of SLE.ConclusionThe combined complexity of polymorphisms in the coding regions of ACP5 and SAMHD1 influences the susceptibility to SLE. Alterations in these genes may lead to abnormalities in the type I interferon pathway. Our study extends the spectrum of mutations in the ACP5 and SAMHD1 genes. The identification of these mutations could aid in the diagnosis of SLE with genetic counseling and suggest potential precise treatments for specific pathways.

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Genetic screening of early-onset patients with systemic lupus erythematosus by a targeted next-generation sequencing gene panel

Cited by 21 publications

References 30 publications

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

Complement C1s as a diagnostic marker and therapeutic target: Progress and propective

Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus

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