{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:03:05Z","timestamp":1780473785344,"version":"3.54.1"},"reference-count":14,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003810","name":"Hospital de Cl\u00ednicas de Porto Alegre","doi-asserted-by":"publisher","award":["2011\u20100477;2022\u20100206"],"award-info":[{"award-number":["2011\u20100477;2022\u20100206"]}],"id":[{"id":"10.13039\/501100003810","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>LYSET<\/jats:italic>\n                    gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose\u20106\u2010phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal dysplasia with coarse facies, distended abdomen, short stature, and severe physical disability. In a diagnostic odyssey, we report a female patient, born in 2008, daughter of consanguineous parents, with hand contractures and a typical facial appearance since 5\u2009months old. She was clinically diagnosed at 2\u2009years old with contractures and severe dysplasia. Systolic murmur, thickening of mitral and aortic valves, and tricuspid regurgitation were observed. Nine enzymes showed increased levels in plasma, and seven showed decreased levels in fibroblasts. Abnormal sialic acid profile and GAGs (glycosaminoglycans) were detected in urine. No variants were identified during more than a decade of investigation. A whole\u2010genome analysis identified the homozygous nonsense variant NM_001098621.4:c.112C&gt;T (p.Gln38Ter) in the\n                    <jats:italic>LYSET<\/jats:italic>\n                    gene. The patient had not been diagnosed before due to the recent association of the gene with the lysosomal hydrolase labeling pathway. She died in 2018 from respiratory causes. The discovery of the relationship between the\n                    <jats:italic>LYSET<\/jats:italic>\n                    gene and lysosomal biogenesis was determinative of the diagnostic conclusion. Cases of dysostosis multiplex can be highly challenging due to the rarity of the disease and its clinical similarity to mucopolysaccharidosis (MPS) and mucolipidosis II\/III (MLII\/III). This is the first western report of a challenging case of an extensive diagnostic odyssey and demonstrates that the\n                    <jats:italic>LYSET<\/jats:italic>\n                    gene must be considered in the differential diagnosis when M6P\u2010labeled lysosomal enzymes are altered.\n                  <\/jats:p>","DOI":"10.1111\/cge.70165","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T07:11:35Z","timestamp":1773990695000},"page":"125-130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Diagnostic Odyssey of a Biochemically Confirmed Case of\n                    <scp>ML II<\/scp>\n                    : The First Western Patient With\n                    <scp>LYSET<\/scp>\n                    Deficiency"],"prefix":"10.1111","volume":"110","author":[{"given":"Fernanda","family":"Sperb\u2010Ludwig","sequence":"first","affiliation":[{"name":"BRAIN Laboratory Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Genetics Department Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taciane","family":"Alegra","sequence":"additional","affiliation":[{"name":"Children's Health Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Martinello","family":"da Rosa","sequence":"additional","affiliation":[{"name":"BRAIN Laboratory Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Genetics Department Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataniel Floriano","family":"Ludwig","sequence":"additional","affiliation":[{"name":"BRAIN Laboratory Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Genetics Department Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata Voltolini","family":"Velho","sequence":"additional","affiliation":[{"name":"Department of Gynecology Charit\u00e9 With Center of Oncological Surgery Endometriosis Research Charit\u00e9, Campus Virchow\u2010Klinikum  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-6687","authenticated-orcid":false,"given":"Ida Vanessa Doederlein","family":"Schwartz","sequence":"additional","affiliation":[{"name":"BRAIN Laboratory Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre Brazil"},{"name":"Postgraduate Program in Genetics and Molecular Biology, Genetics Department Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"},{"name":"Medical Genetics Service Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24139"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2167376"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemeta\/loac039"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33025-1"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1590\/2326-4594-jiems-2020-0029"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.07.011"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-019-0508-0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-020-01151-5"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rare.2024.100022"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1697605"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4063"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70155"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01285-9"}],"container-title":["Clinical 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