Whole-exome sequencing analysis to identify novel potential pathogenetic NPC1 mutations in two Chinese families with Niemann–Pick disease type C

Background Niemann–Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, affecting the nervous system and the internal organs. It is characterized by the presence of foam cells in bone marrow, liver, and spleen biopsies. Although many mutations in NPC1 have been identified to be related to disease onset, the relationship between genotype and phenotype remains unclear. To elucidate the genetic heterogeneity of NPC, we described the clinical manifestations and possible genetic pathogenesis of two patients from unrelated families with NPC. Methods DNA was extracted from the peripheral blood of the two patients and their families and from healthy individuals. Whole-exome sequencing followed by Sanger sequencing was performed to verify the mutations identified in their families. Results We identified four mutations in NPC1 in the two patients from different families: c.1290delC (p.F431Lfs*18)/c.2807G > A(p.G936D) in family A and c.3604_3605insA (p.I1202Nfs*56)/c.881 + 3A > G in family B from their parents. Bioinformatics analysis predicted these mutations to be deleterious, suggesting that mutations in exons are highly conservative. The patient in family A presented with a developmental delay that was different from the typical symptoms of developmental regression in family B. Conclusion Our study identified three novel mutations and one known mutation in NPC1 and evaluated their pathogenicity, enriching the NPC1 mutation and phenotype spectrum and providing a new basis for the genetic and prenatal diagnosis of this disease.