SPG4 frequency is 33.3% in Central Chinese HSP families with 7 novel SPAST variants identified

BackgroundMutations in the SPAST gene cause autosomal dominant hereditary spastic paraplegia (HSP) type 4 (SPG4), which is the most common type of HSP with variable frequencies in different ethnic backgrounds. The clinical and genetic characteristics of SPG4 in Central China have not been well documented.MethodsWe screened for SPAST variants by whole exome sequencing in a cohort of 63 unrelated families with HSP from Central China. The clinical manifestations were evaluated.Results21 variants of SPAST were identified in 21 index patients with a frequency of 33.3% (21/63). Seven novel variants were identified, including one missense variant (p.S399W), five frameshift variants (p.Q170Vfs*2, p.S527Vfs*3, p.I605Vfs*17, p.I605Nfs*26, and p.V443Afs*2), and one splicing variant (c.871-1G>A). We also detected four previously reported exon deletions of SPAST. The mean age of disease onset was 34.0 years. Anticipation and variability of disease severity were observed in some autosomal dominant families. Two patients exhibited a complicated phenotype, one of whom presented with hyposmia, which had never been previously reported with SPG4.ConclusionSPG4 is the most common type of HSP in our cohort. Complicated phenotype, although rare, can also be observed in SPG4 patients. The hyposmia might be a new phenotype associated with SPG4. The SPAST rearrangement is common and should be considered during genetic analysis. The novel SPAST variants identified in this study expand the mutational spectrum.