Genetically transitional disease: a new concept in genomic medicine

Yao, Qingping; Gorevic, Peter D.; Shen, Bo; Gibson, Greg

doi:10.1016/j.tig.2022.11.002

Cited by 23 publications

(13 citation statements)

References 83 publications

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“…In these diseases a mutation is necessary, but not sufficient to cause disease. [ 37 ] We believe that further genetic profiling will be useful in the context of an autoinflammatory disease gene panel to cover both high and low penetrance variants. This may be necessary to identify genetic variants associated with SAIDs in a subgroup of DM or ADM patients.…”

Section: Discussionmentioning

confidence: 99%

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

Sharmeen,

Christopher-Stine,

Salvemini

et al. 2024

Rheumatology and Immunology Research

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Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.

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Section: Discussionmentioning

confidence: 99%

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

Sharmeen,

Christopher-Stine,

Salvemini

et al. 2024

Rheumatology and Immunology Research

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“…In this regard, it is pertinent to cite the examples of the abovementioned PKD1 p.Arg3277Cys and MECP2 p.Pro399Leu variants, both of which should theoretically have been filtered out by reference to the maximum allele frequency expected for a typical pathogenic variant in these disorders. As such, "predisposing' variants, which can potentially include any type of variant (e.g., missense, intronic, regulatory), may not only account for a significant fraction of the unexplained cases of both monogenic and oligogenic disease [100][101][102][103] but may also be relevant to the "missing heritability" problem in complex disease [104,105].…”

Section: Discussionmentioning

confidence: 99%

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

Chen

Masson

Zou

et al. 2023

Preprint

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Background:One shortcoming of employing the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)-recommended five-category variant classification scheme (″pathogenic″, ″likely pathogenic″, ″uncertain significance″, ″likely benign″ and ″benign″) in medical genetics lies in the schemeprime or minutes inherent inability to deal properly with variants that fall midway between ″pathogenic″ and ″benign″. Employing chronic pancreatitis as a disease model, and focusing on the four most studied chronic pancreatitis-related genes, we recently expanded the five-category ACMG/AMP scheme into a seven-category variant classification system. With the addition of two new classificatory categories, ″predisposing″ and ″likely predisposing″, our seven-category system promises to provide improved classification for the entire spectrum of variants in any disease-causing gene. The applicability and practical utility of our seven-category variant classification system however remains to be demonstrated in other disease/gene contexts, and this has been the aim of the current analysis.Results:We have sought to demonstrate the potential universality of pathological variants that could be ascribed the new variant terminology (′predisposing′) by trialing it across three Mendelian disease contexts (i.e., autosomal dominant, autosomal recessive and X-linked). To this end, we firstly employed illustrative genes/variants characteristic of these three contexts. On the basis of our own knowledge and expertise, we identified a series of variants that fitted well with our ″predisposing″ category, including ″hypomorphic″ variants in thePKD1gene and ″variants of varying clinical consequence″ in theCFTRgene. These examples, followed by reasonable extrapolations, enabled us to infer the widespread occurrence of ″predisposing″ variants in disease-causing genes. Such ″predisposing″ variants are likely to contribute significantly to the complexity of human genetic disease and may account not only for a considerable proportion of the unexplained cases of monogenic and oligogenic disease but also for much of the ″missing heritability″ characteristic of complex disease.Conclusion:Employing an evidence-based approach together with reasonable extrapolations, we demonstrate both the applicability and utility of our seven-category variant classification system for disease-causing genes. The recognition of the new ″predisposing″ category not only has immediate implications for variant detection and interpretation but should also have important consequences for reproductive genetic counseling.

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“…Autoinflammatory diseases are monogenic, polygenic, or genetically transitional diseases mediated by abnormal innate immunity with some genetic overlapping with CD. 86,87 There are 2 reported cases of CARP with oral ulcers, intermittent fevers, polyarthralgia, migratory oligoarthritis, pericarditis, or papular rash. Genetic testing in both cases revealed mutations of the NOD2/CARD15 gene, including the IVS 8+158 (JW1), which are commonly detected among patients with NOD2-associated autoinflammatory disease.…”

Section: Autoinflammatory Disorders and Pouchmentioning

confidence: 99%

Management of Primary Sclerosing Cholangitis and Extraintestinal Disorders in Patients With Ileal Pouches: A Systematic Review

Shen,

Yao,

Scherl

2024

Diseases of the Colon &Amp; Rectum

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BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis improves the quality of life in patients with ulcerative colitis by the removal of diseased large bowel and preservation of the natural route of defecation. Although the surgery may improve preexisting extraintestinal manifestations in the joint, skin, and eyes, extraintestinal manifestations, particularly primary sclerosing cholangitis can persist after colectomy. OBJECTIVES: A systemic review of diagnosis and treatment of liver, joint, skin, and eye manifestations in patients with restorative proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis DATA SOURCES: PubMed, Google Scholar, and Cochrane database. STUDY SELECTION: Relevant articles on primary sclerosing cholangitis and extraintestinal manifestations in ileal pouches published between Jan 2001 and July 2023 in English were included based on Preferred Reporting Items For Systemic Review and Meta-Analysis guidelines. INTERVENTION: Diagnosis and treatment of primary sclerosing cholangitis and extraintestinal manifestations in patients with restorative proctocolectomy and ileal pouch-anal anastomosis were included. MAIN OUTCOME MEASURES: Association between primary sclerosing cholangitis, extraintestinal manifestations, and inflammatory disorders of the pouch and their management. RESULTS: The presence of primary sclerosing cholangitis and extraintestinal manifestations is associated with pouchitis, particularly chronic pouchitis. Primary sclerosing cholangitis is associated with both chronic pouchitis and enteritis, and possible pouch neoplasia. However, disease severity and disease course of primary sclerosing cholangitis and pouchitis do not appear to parallel. Despite that oral vancomycin or budesonide have been used to treat primary sclerosing cholangitis-associated pouchitis, their impact on the disease course of primary sclerosing cholangitis is not known. Biological therapy for chronic inflammatory disorders of the pouch may be also beneficial for the concurrent extraintestinal manifestations of the joints, skin, and eyes. However, studies on the correlation between the severity of inflammatory pouch disorders and the severity of joint, skin, and eye diseases are lacking. LIMITATIONS: This is a qualitative, not quantitative review of case series and case reports. CONCLUSIONS: Primary sclerosing cholangitis and extraintestinal manifestations of the joints, skin, and eyes appear to be associated with inflammatory disorders of the ileal pouch. While the treatment of pouchitis does not seem to affect the disease course of primary sclerosing cholangitis, effective therapy of inflammatory pouch disorders, particularly with biologics, likely benefits concurrent disorders of the joints, skin, and eyes. See 20-minute symposium video.

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Genetically transitional disease: a new concept in genomic medicine

Cited by 23 publications

References 83 publications

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

Management of Primary Sclerosing Cholangitis and Extraintestinal Disorders in Patients With Ileal Pouches: A Systematic Review

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