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

Abstract

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 Importantly, 73 P/LP variants were previously unpublished.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.

Fig. 1. Geographical origin and type of variants.

A Geographical origin of 602 NPC1 patients (B) and coding effect of the 830 P/LP variants detected. C Most frequent variants in this cohort and distribution according to geographical origin (red color - LoF variants, orange - variants located in the middle luminal NPC1 domain, blue - other missense variants).

Fig. 2. Biomarker PPCS levels (ng/ml) and age at diagnosis, type of NPC1 variants, and region of origin.

A Patients with LoF variants have significantly higher biomarker results compared to patients with missense or conservative changes, and with variants with unknown effect. B Patients with earlier age at diagnosis present significantly higher biomarker values. C Patients from Africa, Asia, and the Middle East have significantly higher biomarker values compared to patients from Europe and Latin America. D Biomarker levels in patients with the most frequent variants detected in this cohort. Patients with variants p.P1007A, p.A1035V, and p.S954L had significantly lower biomarker levels compared to patients with variants p.R1186H and p.I1061T.

Fig. 3. Genotype to phenotype associations with the most frequent variants and LoF variants in this cohort.

A Significant genotype to phenotype associations for the most frequent variants. B Significant genotype to phenotype associations with LoF variants detected. HPO terms, age at diagnosis, and biomarker levels are represented by black, blue, and turquoise lines, respectively. The thickness of the lines represents the strength of the association. All associations are statistically significant after correction for multiple testing.