A novel missense variant in Sterol-sensing domain related to Niemann-Pick type C1: case report and comprehensive analysis.

objectivesThe aim of this paper is to report a novel pathogenic variant (p.Val699Leu) in the Sterol-Sensing Domain in the NPC1 protein encoded by NPC1 gene related to Niemann-Pick disease type C, and to highlight the critical role of this domain in protein function and disease severity .

methodsThe patient underwent genetic consultation to assess family history and gather clinical data through physical examination, laboratory testing, and imaging assessment. Subsequently, genetic analysis was performed, including Exome Sequencing (ES), followed by segregation analysis using Sanger sequencing.

resultsThe patient is a Moroccan infant born from a consanguineous family presenting with progressive neurodevelopmental regression and hepatosplenomegaly. The genetic analysis detected a novel pathogenic variant (NM_000271.5: c.2095G > C; p.Val699Leu) in the NPC1 gene at homozygous state, located within the Sterol-Sensing Domain (SSD). The proband died at age 10 with no targeted therapy was administered due to delayed molecular diagnosis. DISCUSSION: Our report expands the mutational spectrum associated with Niemann-Pick disease type C1 particularly within underrepresented North-African populations, and underscores the Sterol Sensing Domain’s essential role in NPC1 protein function offering insight into variant-specific molecular mechanisms. It also, highlights the importance of early genomic diagnosis in rare neurodegenerative diseases, especially in consanguineous populations.