Details

Autor(en) / Beteiligte

• Guatibonza Moreno, Pilar
• Pardo, Luba M
• Pereira, Catarina
• Schroeder, Sabine
• Vagiri, Deepthi
• Almeida, Ligia S
• Juaristi, Carlos
• Hosny, Heba
• Loh, Clarice C Y
• Leubauer, Anika
• Torres Morales, Galina
• Oppermann, Sebastian
• Iurașcu, Marius-Ionuț
• Fischer, Steffen
• Steinicke, Tara-Marisa
• Viceconte, Nikenza
• Cozma, Claudia
• Kandaswamy, Krishna Kumar
• Pinto Basto, Jorge
• Böttcher, Tobias
• Bauer, Peter
• Bertoli-Avella, Aida

Titel

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Ist Teil von

• European journal of human genetics : EJHG, 2023-10, Vol.31 (10), p.1108-1116

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients' clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype-phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0-64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype-phenotype relationships for "frequent" NPC1 variants.