Genetic analysis of two heterozygous SMPD1 variants in a pediatric Niemann-Pick disease patient

Background Niemann-Pick disease (NPD), also known as acid sphingomyelinase deficiency, represents a group of rare genetic disorders first described in 1914. SMPD1 is a crucial gene in this disease, which encodes the enzyme sphingomyelinase essential for the breakdown of sphingomyelin, a component of cell membranes. Mutations in the SMPD1 gene disrupt this enzymatic activity, leading to the accumulation of sphingomyelin in lysosomes. Methods We investigated a a child diagnosed with Niemann-Pick disease and his parents. Whole exome sequencing, in silico analysis, minigene constructs, transfection, RT-PCR were used to analyze the genotype and mutations of the proband and his parents. Results Whole exome sequencing revealed that the proband had compound heterozygous mutations in the SMPD1 gene: c.1497_1498GT > AC and c.1486 + 5G > C, inherited from his father and mother, respectively. The c.1486 + 5G > C mutation resulted in the loss of exon 5, seriously affecting the protein function. This mutation was classified as pathogenic or suspected pathogenic based on HGMD data and ACMG guidelines. Conclusion This study identified two heterozygous pathogenic SMPD1 variants (c.1497_1498GT > AC and c.1486 + 5G > C) in a pediatric patient with Niemann-Pick disease. The SMPD1 gene splicing site mutation c.1486 + 5G > C leads to the deletion of exon 5, significantly impacting protein function. These new findings expand the variant spectrum of SMPD1 mutations causing NPD and contribute to a better understanding of the genetic basis of the disease.