Submission Details

PLA2G6, the gene encoding phospholipase A2 group VI, was first reported in relation to autosomal recessive PLA2G6-associated neurodegeneration (PLAN) in 2006 (Morgan et al., PMID: 16783378). PLAN is a continuum of three phenotypes with overlapping clinical and radiological features: (1) infantile neuronal dystrophy (INAD) or NBIA2A (OMIM: 256600), (2) atypical neuronal dystrophy (ANAD) with childhood-onset or NBIA2B (OMIM: 610217), (3) adult-onset dystonia-parkinsonism form named PARK14 (OMIM: 612953), to possibly a certain subtype of hereditary spastic paraplegia (HSP) (Deng et al. 2023. PMID: 37236368). INAD, or NBIA2A, usually begins between ages six months and three years with rapid progression, characterized by psychomotor regression or delay, hypotonia, progressive spastic tetraparesis, and visual impairment. Many affected children do not survive beyond their first decade. ANAD, or NBIA2B, shows more phenotypic variability than INAD and may present in early childhood but can be as late as the end of the second decade. The presenting signs may be speech delay, gait instability, ataxia, postural instability, dystonia, spasticity, and cognitive decline with autistic features. Strabismus, nystagmus, and optic atrophy are common. PARK14, or PLA2G6-related dystonia-parkinsonism, has a variable age of onset, but most individuals present gait disturbance or neuropsychiatric changes and develop dystonia and parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) in their late teens to early twenties. Cerebellar atrophy is a typical radiological sign which correlates with the severity of the phenotype. Another common feature, iron accumulation within the globus pallidum and substantia nigra are variable and does not correlate with the severity of the phenotype (Gregory et al. GeneReviews, PMID: 20301718, https://www.ncbi.nlm.nih.gov/books/NBK1675/).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern AND pathological phenotypes. Therefore, the following disease entities have been lumped into one disease entity: NBIA2A (OMIM: 256600), NBIA2B (OMIM: 610217), autosomal recessive Parkinson disease 14 (OMIM: 612953), to possibly a certain subtype of hereditary spastic paraplegia (HSP).

To date, 217 pathogenic or likely pathogenic variants in PLA2G6 (OMIM: 603604) including missense or nonsense variants, splicing variants, small insertions/deletions, multi-exon deletion, and copy number variations have been submitted to ClinVar. This curation includes 13 variants from 10 probands in one publication (Morgan et al. 2006. PMID: 16783378). These variants (missense, in-frame indel, nonsense, frameshift) have also been reported in other probands in 26 publications (PMIDs: 28097321, 18799783, 22934738, 19138334, 29859652, 20619503, 29395073, 18359254, 24745848, 33101984, 32860008, 20886109, 25164370, 29482223, 24108619, 20619503, 29915382, 30772976, 34622992, 31548400, 28097321, 17033970, 24628589, 28714225, 34272103, 27196560). More evidence is available in the literature, but the maximum score for genetic evidence (12 points.) has been reached. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence. This includes the biochemical function of the gene product, which is consistent with the features observed in human patients. PLA2G6 encodes a calcium-independent group VI phospholipase A2, iPLA2β, which localizes to the neuronal mitochondria and endosomal and lysosomal membranes. In the nervous system, iPLA2β may be involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation (Zhou et al. 2016. PMID: 26755131; Malley et al. 2018. PMID: 29472584; Deng et al, 2023, PMID: 37236368). In addition, non-human animal models Knock out mice, Drosophila) recapitulate the clinical and histopathological features of the disease (Malik et al. 2008. PMID: 18202189; Beck et al. 2008. PMID: 21813701; Zhao et al. 2011. PMID: 22046428) and a *Drosophila *model (Lin et al. 2018. PMID: 29909971) (Experimental evidence – 6 points).

In summary, there is definitive evidence supporting the relationship between PLA2G6 and PLA2G6-associated neurodegeneration (PLAN), an autosomal recessive disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases Gene Curation Expert Panel on March 21, 2024 (SOP v10).