Two Novel Variants in PI4KA in a Family Presenting With Hereditary Spastic Paraparesis: A Case Report

Jevin M Parmar; Elyshia L McNamara; Phillipa J Lamont; Kishore R Kumar; Audrey Rick; Marion Stoll; Pak Leng Cheong; Gianina Ravenscroft

doi:10.1212/NXG.0000000000200152

Two Novel Variants in PI4KA in a Family Presenting With Hereditary Spastic Paraparesis: A Case Report

Neurol Genet. 2024 Apr 25;10(3):e200152. doi: 10.1212/NXG.0000000000200152. eCollection 2024 Jun.

Authors

Jevin M Parmar¹, Elyshia L McNamara¹, Phillipa J Lamont¹, Kishore R Kumar¹, Audrey Rick¹, Marion Stoll¹, Pak Leng Cheong¹, Gianina Ravenscroft¹

Affiliation

¹ From the Rare Disease Genetics and Functional Genomics Group (J.M.P., E.L.M., A.R., G.R.), Centre for Medical Research, University of Western Australia; Harry Perkins Institute of Medical Research (J.M.P., E.L.M., A.R., G.R.), Nedlands; Royal Perth Hospital (P.J.L.); Sydney Medical School (K.R.K., P.L.C.), Faculty of Medicine and Health, University of Sydney, Camperdown; Garvan Institute of Medical Research (K.R.K.), Darlinghurst; Molecular Medicine Laboratory (K.R.K., M.S., P.L.C.), Concord Repatriation General Hospital, NSW Health Pathology; Department of Neurology (K.R.K.), Concord Repatriation General Hospital; and School of Medical Sciences (M.S.), University of Sydney, Camperdown, Australia.

Abstract

Objectives: To report novel biallelic PI4KA variants in a family presenting with pure hereditary spastic paraparesis.

Methods: Two affected sisters presented with unsolved hereditary spastic paraparesis and underwent clinical and imaging assessments. This was followed by short-read next-generation sequencing.

Results: Analysis of next-generation sequencing data uncovered compound heterozygous variants in PI4KA (NM_058004.4: c.[3883C>A];[5785A>C]; p.[(His1295Asn);(Thr1929Pro)]. Using ACMG guidelines, both variants were classified as likely pathogenic.

Discussion: Here, next-generation sequencing revealed 2 novel compound heterozygous variants in the phosphatidylinositol 4-kinase alpha gene (PI4KA) in 2 sisters presenting with progressive pure hereditary spastic paraparesis. Pathogenic variants in PI4KA have previously been associated with a spectrum of disorders including autosomal recessive perisylvian polymicrogyria, with cerebellar hypoplasia, arthrogryposis, and pure spastic paraplegia. The cases presented in this study expand the phenotypic spectrum associated with PI4KA variants and contribute new likely pathogenic variants for testing in patients with otherwise unsolved hereditary spastic paraparesis.