A novel SPAST gene splicing variant (c.1617-2A>C) in a heterozygous carrier with hereditary spastic paraplegia

TL;DR

A new genetic variant in the SPAST gene is linked to hereditary spastic paraplegia in a family, suggesting it may cause the disease.

Contribution

A novel SPAST gene splicing variant (c.1617-2A>C) is identified as pathogenic in autosomal dominant HSP.

Findings

The c.1617-2A>C variant disrupts RNA splicing and is classified as a null variant.

The variant was found in a heterozygous carrier with clinical features of SPG4.

The study supports the pathogenicity of the novel SPAST gene variant.

Abstract

Hereditary spastic paraplegia (HSP) is a group of genetically heterogenous neurodegenerative disorders characterized by progressive spasticity and weakness of lower limbs. We report a novel splicing variant (c.1617-2A>C) of the SPAST gene in a heterozygous carrier from an Italian family with autosomal dominant HSP. The case study describes a pure form of spastic paraparesis with the cardinal clinical features of SPG4. The novel variant affects a canonical splice site and is likely to disrupt RNA splicing. We conclude that the c.1617-2A>C substitution is a null variant, which could be classified as pathogenic; its penetrance should be further investigated.

•Hereditary spastic paraplegia (HSP) denotes a group of clinically and genetically heterogeneous neurodegenerative disorders; the identification of the underlying pathogenic variant is crucial.•The case study presents a 59-years-old woman with progressive spasticity and weakness of lower limbs; family history was suggestive for HSP.•Genetic analysis demonstrated a novel heterozygous variant (c.1617-2A>C) of the SPAST gene, which was predicted to disrupt RNA splicing.•Based on clinical and molecular findings, the c.1617-2A>C substitution could be classified as a pathogenic null variant associated with SPG4.

Hereditary spastic paraplegia (HSP) denotes a group of clinically and genetically heterogeneous neurodegenerative disorders; the identification of the underlying pathogenic variant is crucial.

The case study presents a 59-years-old woman with progressive spasticity and weakness of lower limbs; family history was suggestive for HSP.

Genetic analysis demonstrated a novel heterozygous variant (c.1617-2A>C) of the SPAST gene, which was predicted to disrupt RNA splicing.

Based on clinical and molecular findings, the c.1617-2A>C substitution could be classified as a pathogenic null variant associated with SPG4.

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