Intrafamilial phenotypic discordance in Niemann–Pick disease type C with novel compound heterozygous NPC1 variants: a case report with literature review

Abstract Introduction Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration. Its marked clinical variability complicates genotype–phenotype correlations, making the reporting of novel variants important. The present report describes a case of NPC associated with novel compound heterozygous (CH) variants in the NPC1 gene with intrafamilial phenotypic heterogeneity. Case presentation A 20-month-old girl presented with delayed walking. She had a history of prolonged neonatal jaundice. Family history was notable for a male sibling who had been genetically diagnosed with NPC and died in infancy. Physical examination revealed hepatosplenomegaly. Laboratory investigations revealed microcytic anemia, thrombocytopenia, elevated aspartate aminotransferase, and hypertriglyceridemia. Abdominal ultrasonography demonstrated hepatosplenomegaly. Whole exome sequencing identified novel variants of uncertain significance (VUS) in the NPC1 gene (c.3422T > A (p. Val1141Asp) and c.2870G > C (p. Cys957Ser) in trans configuration) with predicted deleterious effects. The same variants were previously detected in a deceased sibling, supporting segregation within the family. A probable diagnosis of Niemann–Pick disease type C (NPC) was made based on clinical features, family history, and identification of compound heterozygous NPC1 variants in trans configuration. Definitive confirmation was limited by the absence of NPC-specific biomarker testing. The patient is currently under regular follow-up, and genetic counseling has been provided to the parents. Literature review In a review of 10 NPC cases, six patients (60.0%) were male, with ages ranged from the neonatal period to 67 years. Clinical manifestations varied according to the age at onset of neurological symptoms. Genetic analysis identified CH variants in the NPC1 gene, including novel variants in 20% of cases. Conclusions The identification of novel NPC1 variants may expand the mutational spectrum of NPC. More importantly, this case illustrates the classical intrafamilial phenotypic discordance in NPC between a perinatal rapidly fatal form in one sibling and an early infantile neurological form in the propositus — a clinically significant pattern that remains underrecognized.