Novel PLA2G6 Pathogenic Variants in Chinese Patients With PLA2G6-Associated Neurodegeneration

Abstract

BackgroundPLA2G6-associated neurodegeneration (PLAN) is a heterogeneous group of neurodegenerative diseases caused by biallelic PLA2G6 mutations, covering diseases such as infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). The study aims to report the clinical and genetic features of a series of PLAN patients.MethodsThe clinical and radiological findings of five Chinese patients from three families were collected. Whole-exome next generation sequencing (NGS) was applied to identify the genetic causes. Co-segregation analysis of the detected candidate variants were performed in their families. The pathogenicity of identified novel variants was predicted by in silico analysis.ResultsNGS revealed compound heterozygous variants of PLA2G6 gene in all five patients. There were six PLA2G6 variants identified, including two known variants (c.116G>A, c.238G>A) and four novel variants (c.2120dupA, c.2071C>G, c.967G>A, c1534T>A). ACMG predicts c.2120dupA to be pathogenic, c.2071C>G and c.1534T>A to be likely pathogenic, and c1534T>A to be of uncertain significance. Clinically, four patients fell into the diagnosis of ANAD, and 1 into the diagnosis of AREP. Brain imaging revealed cerebellar atrophy, iron deposition in bilateral globus pallidus, and substantia nigra in three cases.ConclusionsFour novel pathogenic variants were discovered and the pathogenic variant spectrum of the PLA2G6 gene was expanded.

Case Report: A case of PLA2G6 gene-related early-onset Parkinson's disease and review of literature

“…In the ClinVar database, the pathogenicity of this variant is classified as pathogenic, and the corresponding disease is EOPD (Shen et al, 2019). Another variant site, c.1427 + 1G > A, is reported to be related to the INAD phenotype (Wan et al, 2022) the reports of the EOPD phenotype have been scarce. Previous investigations showed that the clinical symptoms of EOPD patients caused by only c.991G > T mutation were relatively mild with typical PD symptoms, no dystonia, and relatively slow disease progression (more than 10 years).…”

Molecular genetics of neuropsychiatric illness: some musings

“…PLA2G6-related parkinsonism shows a fairly distinct phenotype of young onset parkinsonism/dystonia, gait/balance, and/or psychiatric/ cognitive symptoms (Magrinelli et al, 2022). Several population-specific mutations in PLA2G6 have been reported to cause Infantile neuroaxonal dystrophy and autosomal recessive Parkinsonism (Hanna Al-Shaikh et al, 2022;Wan Y et al, 2022). PLA2G6 gene-associated neurodegenerative disorders resulting from homozygous c. 2222G > A (p.Arg741Gln) mutation has been described in two cases having variable neuropsychiatric phenotypic and imaging findings from our centre (Sakhardande et al, 2021).…”