Importance of the biochemical investigations for the functional characterization of a NPC1 variant identified by exome sequencing

• Published in: American journal of medical genetics. Part A 2024-08, Vol.194 (8), p.e63595-n/a
• Main Authors: Almenabawy, Nihal, Hung, Clara, Sosova, Iveta, Mercimek‐Andrews, Saadet
• Format: Article
• Language: English
• Subjects: biomarker; Cholesterol; developmental delay; Diagnosis; Endosomes; Exome Sequencing; Genotype & phenotype; Humans; Infant; Intracellular Signaling Peptides and Proteins - genetics; Lysosomal storage diseases; Male; Microencephaly; Mutation - genetics; Niemann-Pick C1 Protein - genetics; Niemann-Pick disease; Niemann-Pick Disease, Type C - diagnosis; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Disease, Type C - pathology; Niemann–Pick type C; Npc1 protein; oxysterol; Phenotype; Phenotypes; Protein transport; Sphingomyelin; Whole genome sequencing
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63595

Niemann–Pick disease type C (NPC) is one of the lysosomal storage disorders. It is caused by biallelic pathogenic variants in NPC1 or NPC2, which results in a defective cholesterol trafficking inside the late endosome and lysosome. There is a high clinical variability in the age of presentation and the phenotype of this disorder making the diagnosis challenging. Here, we report a patient with an infantile onset global developmental delay, microcephaly and dysmorphic features, homozygous for c.3560C>T (p.A1187V) variant in NPC1. His plasma oxysterol levels were normal on two occasions. His lyso‐sphingomyelin‐509 (lyso‐SM 509) and urinary bile acid levels were normal. Based on the phenotype and biochemical features, the diagnosis of NPC was excluded in this patient. We emphasize the importance of functional characterization in the classification of novel variants to prevent a misdiagnosis. Matching the phenotype and biochemical evidence with the molecular genomic tests is crucial for the confirmation of genetic diagnoses.