SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

Area of Science:

• Genetics
• Biochemistry
• Rare Diseases

Background:

• Niemann-Pick Types A and B (NPA/B) are autosomal recessive lysosomal storage disorders.
• These diseases result from deficient acid sphingomyelinase (ASM) activity due to mutations in the SMPD1 gene.

Purpose of the Study:

• To provide a comprehensive review of reported and newly identified SMPD1 variants.
• To establish genotype/phenotype correlations for NPA/B diseases.
• To create a locus-specific database for SMPD1 variants.

Main Methods:

• Literature review and variant compilation.
• In silico prediction of variant effects on ASM protein function and mRNA splicing.
• Creation of a locus-specific database (http://www.inpdr.org/genes).

Main Results:

• Cataloged 417 SMPD1 variants, with 185 found in NPA/B patients.
• Identified missense (65.4%) and frameshift (19%) as common mutation types.
• The p.R610del mutation is frequently reported and linked to an attenuated NP-B phenotype.

Conclusions:

• Updated variant information and genotype/phenotype correlations are crucial for NPA/B diagnosis.
• The developed database facilitates access to comprehensive SMPD1 variant data.
• This resource aids genetic counseling for families affected by NPA/B.