{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:31:45Z","timestamp":1760149905647,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T00:00:00Z","timestamp":1694304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Stiftung f\u00fcr Wissenschaftliche Forschung am Stadtspital Triemli"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G&gt;A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient\u2019s blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics.<\/jats:p>","DOI":"10.3390\/life13091889","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T09:05:17Z","timestamp":1694423117000},"page":"1889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria"],"prefix":"10.3390","volume":"13","author":[{"given":"Adrian","family":"Belosevic","sequence":"first","affiliation":[{"name":"Institute of Laboratory Medicine, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Elisabeth","family":"Minder","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"},{"name":"Swiss Reference Centre for Porphyrias, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8574-9640","authenticated-orcid":false,"given":"Morgan","family":"Gueuning","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"van Breemen","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"},{"name":"Swiss Reference Centre for Porphyrias, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4436-3455","authenticated-orcid":false,"given":"Gian Andri","family":"Thun","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja P.","family":"Mattle-Greminger","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics and Cytometry, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Baumer","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, University of Z\u00fcrich, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth I.","family":"Minder","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"},{"name":"Swiss Reference Centre for Porphyrias, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoye","family":"Schneider-Yin","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"},{"name":"Swiss Reference Centre for Porphyrias, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7272-8824","authenticated-orcid":false,"given":"Jasmin","family":"Barman-Aks\u00f6zen","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"},{"name":"Swiss Reference Centre for Porphyrias, Stadtspital Z\u00fcrich, Triemli, 8063 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1053\/j.gastro.2019.04.050","article-title":"Clinical Guide and Update on Porphyrias","volume":"157","author":"Doss","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1136\/jclinpath-2021-207647","article-title":"Update on the diagnosis and management of the autosomal dominant acute hepatic porphyrias","volume":"75","author":"Stewart","year":"2022","journal-title":"J. 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