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Vasculitis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Michelle L. Robinette, Eli Miloslavsky, Zachary S. Wallace
Adult-onset somatic mutations are of particular interest as a potential cause of vasculitis. Using a genotype-first approach, novel somatic myeloid-restricted mutations in UBA1 with high variant allelic frequency have been identified in men with severe adult-onset autoinflammatory syndromes, called the VEXAS syndrome (Table 10.2) (55). Other manifestations include hematologic malignancy and vasculitis typically characterized as PAN or GCA. Mechanistically, UBA1 mutations deregulate ubiquitination, a critical component across cell biology, including innate immune signaling, resulting in increased generation of pro-inflammatory cytokines, cellular stress, and unfolded protein response (UPR) (55). Similar mechanisms are implicated in germline forms of monogenic vasculitis, including DADA2, COPA, and SAVI (65, 66). Somatic mutations have also been recently identified in Sjögren’s syndrome–associated cryoglobulinemic vasculitis, with several lymphoma driver mutations identified in B cell lineages during the transition of benign rheumatoid factor (RF) into pathogenic cryoglobulinemic RF (67).
Co-occurring medical conditions among individuals with ASD-associated disruptive mutations
Published in Children's Health Care, 2020
Evangeline C. Kurtz-Nelson, Jennifer S. Beighley, Caitlin M. Hudac, Jennifer Gerdts, Arianne S. Wallace, Kendra Hoekzema, Evan E. Eichler, Raphael A. Bernier
In the past decade, exome sequencing technologies have identified a number of disruptive mutations in single genes that directly contribute to ASD (Iossifov et al., 2012; O’Roak et al., 2012). De novo mutations in these ASD-risk genes are currently proposed to account for up to 10% of ASD cases (Krumm, O’Roak, Shendure, & Eichler, 2014; Ramaswami & Geschwind, 2018). ASD-risk genes are typically highly conserved and expressed neurologically, and high confidence ASD-risk genes include genes involved in chromatin remodeling (e.g., CHD8), sodium ion channels (e.g., SCN2A), and brain growth and development (e.g., DYRK1A; Krumm et al., 2014). Identification and confirmation of ASD-risk genes has led to a genotype-first approach in ASD research, in which individuals with disruptive mutations in high-confidence risk genes complete clinical phenotyping to inform genotype-phenotype relations (Arnett, Trinh, & Bernier, 2019; Stessman, Bernier, & Eichler, 2014). The genotype-first approach allows for the identification of genetic ASD subtypes with unique clinical profiles and enhances our understanding of how genetic mechanisms contribute to phenotypic heterogeneity in ASD (Arnett et al., 2019; Stessman et al., 2014).
Health-related issues in youth with autism spectrum disorder
Published in Children's Health Care, 2020
Leandra N. Berry, Robin P. Goin-Kochel
For decades, we have known that ASD has strong genetic underpinnings, and thanks to advances in genetic-testing capabilities, there are more than 1,000 genes now believed to be associated with ASD (see www.gene.sfari.org). Understanding more about subgroups of individuals with ASD who share the same genetic mutations can help us to identify other shared medical/neurodevelopmental conditions, which may inform treatment recommendations and/or the development of more personalized interventions. This special issue opens with a manuscript by Kurtz-Nelson and colleagues (this issue) that examines and compares rates of co-occurring medical conditions in individuals with disruptive mutations to ASD risk genes to better elucidate the relationship between these comorbidities and genetic etiologies. In order to establish a sizable cohort of individuals with rare mutations, the authors combined data from two projects using a genotype-first approach to understanding genetic mechanisms in ASD. Specifically, they examined rates of co-occurring medical conditions across a sample of individuals with disruptive mutations to 1 of 18 ASD risk genes compared to a sample of children and adolescents with idiopathic ASD (i.e., no known genetic etiology). Elevated rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were observed, with significant group differences noted. Importantly, these findings may have implications for the medical care of individuals with ASD-associated mutations.
An update on VEXAS syndrome
Published in Expert Review of Clinical Immunology, 2023
The genotype first approach, which led to discovery of VEXAS, demonstrates the power of genetic enquiry when applied to a large cohort of phenotypically well-characterised patients without a definitive diagnosis. The success of such an approach is likely to be replicated when applied to similar cohorts, but the diagnosis of patients presenting with suspected late onset SAID, requires a different approach. For example, it might be necessary to combine deep sequencing of the whole exome (or ideally genome), using DNA obtained from various cellular or tissue locations to identify relevant somatic variants. This approach is currently used in the diagnosis of malignancies. Here, the genomic reference DNA sequence is obtained from skin fibroblasts and used to validate new somatic variants originating from lesional or malignant tissues. The difficulty in translating this approach into the investigation of inflammatory conditions is knowing which cell type or tissue might harbour the somatic variants in the first place. An additional challenge is confirming that such variants are indeed pathogenic. This might require additional functional tests but depending on which genes or biological pathways need to be studied, many of these tests might still need to be developed. Lastly, we might need to develop consensus criteria for the diagnosis of such disorders. These criteria are likely to include a combination of clinical characteristics and genetic findings. Until now, most newly diagnosed VEXAS patients appear to have broadly similar clinical features, but new pathogenic variants in UBA1, which are likely to be reported in the future, might be associated with a different or more restricted phenotype. This has already been suggested for patients harbouring the UBA1 Ser56Phe variant [7].