{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:59:30Z","timestamp":1782215970408,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The clinical heterogeneity of type 1 Gaucher disease (GD1) underscores the limited correlation between the GBA1 genotype and phenotype. This study examined GD1 patients from the Spanish Gaucher Disease Registry carrying heterozygous GBA1 genotypes distinct from NM_000157: c.[1226A&gt;G](N370S); [1448T&gt;C](L444P). Among 374 patients with GD1, 195 (52.1%) had alternative heterozygous combinations, including variants corresponding to severe (37.9%) or moderate (42.1%) mutation, whereas only 20% patients harbored mild variants\u2014all of them in combination with N370S. Descriptive statistics and predictive models based on logistic regression and decision trees were applied. Patients carrying N370S with a different L444P variant showed significantly higher rates of advanced bone disease (59.9%) compared to those with homozygous N370S (38.3%) or N370S; L444P (41.0%) (p = 0.002). Decision tree analysis identified the bone marrow burden score (S-MRI) as the strongest predictor of osteopenia\/osteoporosis at diagnosis. Genotype also emerged as a key discriminator for Parkinson\u2019s disease: patients with non-N370S; L444P genotypes showed a markedly higher likelihood of developing Parkinsonism. Overall, GD1 patients with genotypes other than N370S; L444P present more severe phenotypes, particularly with greater skeletal involvement and neurological complications. These findings highlight the importance of genotype stratification and predictive modeling in improving risk assessment and clinical management in GD1.<\/jats:p>","DOI":"10.3390\/ijms262010088","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:33:22Z","timestamp":1760632402000},"page":"10088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Variability and Genotype\u2013Phenotype Correlation in Spanish Patients with Type 1 Gaucher Disease: A Focus on Non-c.[1226A&gt;G]; [1448T&gt;C] Genotypes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7507-9249","authenticated-orcid":false,"given":"Irene","family":"Serrano-Gonzalo","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Department of Biochemistry and Cellular and Molecular Biology, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8306-221X","authenticated-orcid":false,"given":"Francisco","family":"Bauza","sequence":"additional","affiliation":[{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos (BIFI), Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1369-6225","authenticated-orcid":false,"given":"Laura","family":"Lopez de Frutos","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Grupo Espa\u00f1ol de Enfermedades de Dep\u00f3sito Lisosomal de la SEHH (GEEDL), 50006 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4805-4804","authenticated-orcid":false,"given":"Isidro","family":"Arevalo-Vargas","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Department of Biochemistry and Cellular and Molecular Biology, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5682-906X","authenticated-orcid":false,"given":"Mercedes","family":"Roca-Espiau","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1637-7112","authenticated-orcid":false,"given":"Marcio","family":"Andrade-Campos","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Grupo Espa\u00f1ol de Enfermedades de Dep\u00f3sito Lisosomal de la SEHH (GEEDL), 50006 Zaragoza, Spain"},{"name":"Instituto de Investigaci\u00f3n Hospital del Mar, IMIM-Parc Salut Mar, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3090-8787","authenticated-orcid":false,"given":"Esther","family":"Valero-Tena","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Department of Biochemistry and Cellular and Molecular Biology, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Roca-Esteve","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Espa\u00f1ola para el Estudio y Terap\u00e9utica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50006 Zaragoza, Spain"},{"name":"Department of Biochemistry and Cellular and Molecular Biology, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Iniguez","sequence":"additional","affiliation":[{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos (BIFI), Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Fundaci\u00f3n ARAID, 50018 Zaragoza, 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