To report a novel SPAST/SPG4 splice-site mutation in a family with dominant hereditary spastic paraplegia (HSP).

A 46 year-old man presented with gait and balance difficulties over 15 years. Neurological examination revealed spastic paraparesis, brisk patellar and ankles reflexes, and Babinski responses. Mild ankle eversion weakness and diminished distal vibratory sensation was noted. Gait was scissoring. Family history was notable for a father that developed similar symptoms age 45, and a cousin who developed imbalance in her 20s followed by urinary and bowel dysfunction, anosmia, ageusia, and sensorineural hearing loss.

We suspected HSP and pursued genetic testing for autosomal dominant forms. Using next-generation sequencing we looked for sequence changes and exonic deletions/duplications in 12 genes associated with HSP. DNA from the proband’s blood and family members’ saliva was subjected to hybridization capture and sequenced.

We identified a variant in the SPAST gene [exon-13, c.1536G>A, heterozygous], affecting codon-512 of the SPAST mRNA. This variant was not present in population databases. The mutation fell at the last nucleotide of exon-13, which is part of the consensus splice site. A novel pathogenic mutation was suspected since nucleotide substitutions within the consensus splice site are a common cause of aberrant splicing, and since a different variant affecting this nucleotide (c.1536G>C) was previously determined to be pathogenic. Saliva from the patient’s sister and father’s affected cousin was tested and demonstrated the identical variant in the affected cousin, but not the unaffected sister.

We report a family with HSP and a novel mutation in SPG4/SPAST gene.  Genetic confirmation obviated the need for additional invasive and costly diagnostics, and helped with patient care and counseling. More than 80 genes and many more mutations have been associated with HSP, so next-generation sequencing panels should be considered first-line in the right clinical scenario.