Expanding the repertoire of loss-of-function variants in HACE1 causing complex spastic paraplegia: literature review and recommendations on clinical management.

backgroundHACE1 encodes a HECT domain and ankyrin repeat containing protein regulating several small GTPases. This protein is involved in several important functions, such as cell division, protein ubiquitination, and localization. Biallelic variants in HACE1 have been implicated in spastic paraplegia and psychomotor retardation with or without seizures (MIM: 616756). Previously, 32 patients of various ethnicities have been reported with different types of variants; loss-of-function (LoF), missense, and indels.

resultsHere, we studied five unrelated families of diverse ethnicities with eight cases of 4.5 years to 31 years of age. Our cases presented global developmental delay, dysarthria, intellectual disability, limb spasticity, and seizures. Exome sequencing identified biallelic/ compound heterozygous loss-of-function variants in HACE1 in all families (Family A: HACE1 (NM_020771.4): c.2628-1G > C p.(Ile877Tyrfs*58); Family B and C: c.1396 C > T p.(Gln466*); Family D: c.2242 C > T p.(Arg748*)/c.152 C > G p.(Ser51*); Family E: c.355G > T p.(Glu119*)). All variants co-segregated with the phenotype in respective families and are classified as pathogenic by the ACMG criteria.

conclusionThis study adds eight new cases of HACE1 related spastic paraplegia from five unrelated families to the literature, bringing the total to 40 cases from 22 families. By integrating clinical data from our cohort with the published reports, we defined the phenotypic spectrum linked to HACE1 disruption, noting key overlaps and variability, and highlighted gaps in reporting clinical features. It also provides clinical management recommendations and calls for standardized phenotypic documentation to strengthen genotype-phenotype correlations.