{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T13:24:06Z","timestamp":1775136246588,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BBB-BMD\/6301\/2014"],"award-info":[{"award-number":["PTDC\/BBB-BMD\/6301\/2014"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NORTE2020","award":["NORTE-01-0246-FEDER-000014 DESVENDAR \u201cDEScobrir, VENcer as Doen\u00e7as Raras\u201d"],"award-info":[{"award-number":["NORTE-01-0246-FEDER-000014 DESVENDAR \u201cDEScobrir, VENcer as Doen\u00e7as Raras\u201d"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and\/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.<\/jats:p>","DOI":"10.3390\/ijms21176355","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T22:07:46Z","timestamp":1598998066000},"page":"6355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3726-2851","authenticated-orcid":false,"given":"Marisa","family":"Encarna\u00e7\u00e3o","sequence":"first","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Newborn Screening, Metabolism &amp; Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, 4051-401 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-3622","authenticated-orcid":false,"given":"Maria Francisca","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, 4051-401 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-8488","authenticated-orcid":false,"given":"Lisbeth","family":"Silva","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Newborn Screening, Metabolism &amp; Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"}]},{"given":"Diogo","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"}]},{"given":"Souad","family":"Ouesleti","sequence":"additional","affiliation":[{"name":"Biochemical Service, CHU Farhat Hached, 4000 Sousse, Tunisia"}]},{"given":"Teresa","family":"Campos","sequence":"additional","affiliation":[{"name":"Reference Center for Inherited Metabolic Disorders, University Hospital Centre S. Jo\u00e3o, 4202-451 Porto, Portugal"}]},{"given":"Helena","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hospital Centre, EPE, 4434-502 V.N. Gaia, Portugal"}]},{"given":"Esmeralda","family":"Martins","sequence":"additional","affiliation":[{"name":"Oporto Hospital Centre, University of Porto, 4099-001 Porto, Portugal"}]},{"given":"Maria Teresa","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Reference Center for Inherited Metabolic Disorders, University Hospital Centre S. Jo\u00e3o, 4202-451 Porto, Portugal"}]},{"given":"Laura","family":"Vilarinho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Newborn Screening, Metabolism &amp; Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, 4051-401 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8881-9197","authenticated-orcid":false,"given":"Sandra","family":"Alves","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, 4051-401 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.tins.2011.05.006","article-title":"Clarifying lysosomal storage diseases","volume":"34","author":"Schultz","year":"2011","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nrm1423","article-title":"The cell biology of lysosomal storage disorders","volume":"5","author":"Futerman","year":"2004","journal-title":"Nat. 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