{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:00:34Z","timestamp":1782943234596,"version":"3.54.5"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Alexion Pharma Canada"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Med"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                <jats:title>Abstract<\/jats:title>\n                <jats:p>Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Complement and coagulation gene variants have been associated with aHUS susceptibility. We assessed the diagnostic yield of a next-generation sequencing (NGS) panel in a large cohort of Canadian patients with suspected aHUS. Molecular testing was performed on peripheral blood DNA samples from 167 patients, collected between May 2019 and December 2021, using a clinically validated NGS pipeline. Coding exons with 20 base pairs of flanking intronic regions for 21 aHUS-associated or candidate genes were enriched using a custom hybridization protocol. All sequence and copy number variants were assessed and classified following American College of Medical Genetics guidelines. Molecular diagnostic results were reported for four variants in three individuals (1.8%). Twenty-seven variants of unknown significance were identified in 25 (15%) patients, and 34 unique variants in candidate genes were identified in 28 individuals. An illustrative patient case describing two genetic alterations in complement genes is presented, highlighting that variable expressivity and incomplete penetrance must be considered when interpreting genetic data in patients with complement-mediated disease, alongside the potential additive effects of genetic variants on aHUS pathophysiology. In this cohort of patients with suspected aHUS, using clinical pipelines for genetic testing and variant classification, pathogenic\/likely pathogenic variants occurred in a very small percentage of patients. Our results highlight the ongoing challenges in variant classification following NGS panel testing in patients with suspected aHUS, alongside the need for clear testing guidance in the clinical setting.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p>\u2022 Clinical molecular testing for disease associated genes in aHUS is challenging.<\/jats:p>\n                <jats:p>\u2022 Challenges include patient selection criteria, test validation, and interpretation.<\/jats:p>\n                <jats:p>\u2022 Most variants were of uncertain significance (31.7% of patients; VUS + candidates).<\/jats:p>\n                <jats:p>\u2022 Their clinical significance may be elucidated as more evidence becomes available.\u00a0<\/jats:p>\n                <jats:p>\u2022 Low molecular diagnostic rate (1.8%), perhaps due to strict classification criteria.<\/jats:p>\n                <jats:p>\u2022 Case study identified two likely pathogenic variants; one each in\u00a0<jats:italic>MCP\/CD46<\/jats:italic>\u00a0and\u00a0<jats:italic>CFI<\/jats:italic>.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-023-02341-4","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T11:02:51Z","timestamp":1689764571000},"page":"1029-1040","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genotypic analysis of a large cohort of patients with suspected atypical hemolytic uremic syndrome"],"prefix":"10.1007","volume":"101","author":[{"given":"Dervla M.","family":"Connaughton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Bhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Isenring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Mahdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4980-7484","authenticated-orcid":false,"given":"Laila C.","family":"Schenkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"2341_CR1","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1056\/NEJMra0902814","volume":"361","author":"M Noris","year":"2009","unstructured":"Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. 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Informed consent was obtained from the patient described in the case study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Informed consent was obtained from the participants described in the case study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Paul Isenring has received consultancy fees from Alexion, AstraZeneca Rare Disease. Mohammed Mahdi is an employee of Alexion, AstraZeneca Rare Disease, Canada.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}