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

Autor: Guatibonza Moreno P; CENTOGENE GmbH, Rostock, Germany., Pardo LM; CENTOGENE GmbH, Rostock, Germany., Pereira C; CENTOGENE GmbH, Rostock, Germany., Schroeder S; CENTOGENE GmbH, Rostock, Germany., Vagiri D; CENTOGENE GmbH, Rostock, Germany., Almeida LS; CENTOGENE GmbH, Rostock, Germany., Juaristi C; CENTOGENE GmbH, Rostock, Germany., Hosny H; CENTOGENE GmbH, Rostock, Germany., Loh CCY; CENTOGENE GmbH, Rostock, Germany., Leubauer A; CENTOGENE GmbH, Rostock, Germany., Torres Morales G; CENTOGENE GmbH, Rostock, Germany., Oppermann S; CENTOGENE GmbH, Rostock, Germany., Iurașcu MI; CENTOGENE GmbH, Rostock, Germany., Fischer S; CENTOGENE GmbH, Rostock, Germany., Steinicke TM; CENTOGENE GmbH, Rostock, Germany., Viceconte N; CENTOGENE GmbH, Rostock, Germany., Cozma C; CENTOGENE GmbH, Rostock, Germany., Kandaswamy KK; CENTOGENE GmbH, Rostock, Germany., Pinto Basto J; CENTOGENE GmbH, Rostock, Germany., Böttcher T; CENTOGENE GmbH, Rostock, Germany., Bauer P; CENTOGENE GmbH, Rostock, Germany. Peter.Bauer@centogene.com.; Univesrity of Rostock, Rostock, Germany. Peter.Bauer@centogene.com., Bertoli-Avella A; CENTOGENE GmbH, Rostock, Germany.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2023 Oct; Vol. 31 (10), pp. 1108-1116. Date of Electronic Publication: 2023 Jul 11.
DOI: 10.1038/s41431-023-01408-7
Abstrakt: 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 Importantly, 73 P/LP variants were previously unpublished.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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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