RESUMEN
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.
RESUMEN
The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5'-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele and is present on all major haplotypes. This common sequence variation is present nearly exclusively on nonpathogenic alleles with fewer than 30 GAA-pure triplets and is associated with enhanced stability of the repeat locus upon intergenerational transmission and increased Fiber-seq chromatin accessibility.