Study Identifies Novel SMPD1 Variants in Patients With ASMD in India

Researchers found 18 novel and 21 known variants of SMPD1 with disease-causing potential, providing data that may be helpful in prenatal diagnosis of acid sphingomyelinase deficiency in India.

The rare lysosomal storage disorder acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease (NPD), is caused by variants in the SMPD1 gene, but the full spectrum of variants in different populations is not yet known. A recent study assessed variations in SMPD1 to provide deeper understanding of variants with disease-causing potential in Indian patients.

Identifying such variants is a crucial aspect of early, accurate ASMD diagnosis in pediatric patients affected by the most severe phenotypes. The SMPD1 variations that cause ASMD lead to a range of manifestations involving the spleen, lungs, liver, bone marrow, and neurovisceral symptoms in NPD type A—the most severe form, which tends to be fatal by 3 years of age. NPD type B is chronic, typically does not include the neurovisceral manifestations present in type A, and patients may live to early adulthood. There are no approved disease-modifying therapies for ASMD.

The study recruited 40 pediatric patients (and their family members when possible) to conduct molecular genetic studies of the SMPD1 gene based on enzyme assay results for acid sphingomyelinase (ASM). Normal ASM levels were defined as 9.5-58 nmol/hr/mg of protein, and patients in the study showed levels ranging from 0 to 3.8 nmol/h/mg.

Overall, researchers identified 39 variants—18 novel and 21 known variants of SMPD1. Variants were interpreted based on American College of Medical Genetics and Genomics & Association for Molecular Pathology (ACMG/AMP) criteria. The variants included 26 single nucleotide substitutions, 5 deletions, 3 duplications, and 2 insertion-deletions.

Several variants generated prematurely truncated ASM protein and led to neurovisceral ASMD, or NPD type A. Variants with single nucleotide deletions or duplications typically produced truncated proteins due to frameshift, the authors reported. Genotype-phenotype correlations identified in the study suggest that a selection of missense variants may cause NPD type A.

All of the variants identified in the study showed reduced ASM activity, meaning they have disease causing potential and add to data relevant to prenatal diagnosis of ASMD. However, even patients with the same mutations experienced a range of symptoms and varied disease severity. Therefore, more studies are needed to expand the variant spectrum and to establish genotype‐phenotype correlation for all the variants.

Despite the small study size, the selection of variants identified sheds light on potentially predictive mutations in an underrepresented community in global genome studies. The authors noted that India encompasses approximately 17% of the world’s population and has diverse, anthropologically distinct populations across the country.

“Our study has widened the spectrum of pathogenic variations in SMPD1 in the Indian population,” the authors concluded. “In silico and in vitro functional characterization of variants helped in proper classification of pathogenic variants. The knowledge of the spectrum of variations and their impact on protein will be helpful in prenatal diagnosis and improved genetic counseling of families with NPD.”


Deshpande DD, Gupta SK, Sarma AS, et al. Functional characterization of novel variants in SMPD1 in Indian patients with acid sphingomyelinase deficiency. Hum Mutat. Published online July 17, 2021. doi:10.1002/humu.24263

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