Heterozygous variants in AP4S1 are not associated with a neurological phenotype

Abstract

Biallelic loss-of-function variants in AP4S1 cause childhood-onset hereditary spastic paraplegia. A recent report suggested that heterozygous AP4S1 variants lead to a syndrome of lower limb spasticity and dysregulation of sphincter function. We critically evaluate this claim against clinical observations in 28 heterozygous carriers of the same AP4S1 variant (NM_007077.3: c.289C>T, p.Arg97Ter). In these 14 males and 14 females (mean age: 37.6 ± 4.9 years [SD], range: 30–50 years), we ascertain no increased prevalence of neurological manifestations. Alternative causes should be considered when evaluating patients with heterozygous AP4S1 variants and neurological symptoms, as misattribution of pathogenicity can impact clinical care and genetic counseling.