Early onset or syndromic epilepsy

Gene: PLA2G6

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 1:13 p.m. | Last Modified: 6 May 2024, 9:22 p.m.

Panel Version: 5.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Sixteen cases of PLA2G6-associated neurodegeneration (PLAN) were examined in PMID: 30340910. Seizures were evident in 5/10 cases with infantile PLAN and in 3/6 cases with childhood PLAN. A total of nine PLA2G6 variants were associated with a phenotype that included seizures.

Created: 17 Oct 2023, 12:03 p.m. | Last Modified: 17 Oct 2023, 12:03 p.m.

Panel Version: 4.120

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 17 Oct 2023, 11:44 a.m. | Last Modified: 17 Oct 2023, 11:44 a.m.

Panel Version: 4.120

Comment on phenotypes: PLA2G6-associated neurodegeneration (PLAN)

Created: 17 Oct 2023, 11:42 a.m. | Last Modified: 17 Oct 2023, 11:42 a.m.

Panel Version: 4.119

Comment on list classification: Although PLA2G6 is Green on the 'Inborn errors of metabolism' panel, have added to the Epilepsy panel as Amber as unclear if seizures are a consistent feature. Requires clinical review (and review of the MOI in PMID:27513994) before promotion to Green.

Created: 7 Nov 2019, 2:09 p.m. | Last Modified: 7 Nov 2019, 2:09 p.m.

Panel Version: 1.403

Comment on mode of inheritance: Selected 'BIALLELIC' inheritance to match the metabolism PanelApp panels (including Inborn errors of metabolism, V1.392), all OMIM disorders and both G2P disorders. However, PMID:27513994 report autosomal dominant inheritance for Familial cortical myoclonic tremor with epilepsy (FCMTE).

Created: 7 Nov 2019, 2:06 p.m. | Last Modified: 7 Nov 2019, 2:06 p.m.

Panel Version: 1.402

PMID:27513994 (Gao et al., 2016) report a family (41 members) which included 6 individuals affected with Familial cortical myoclonic tremor with epilepsy (FCMTE). All 6 individuals had tremors while 5 individuals had seizures. Genomic sequencing was performed on 3 affected and 2 unaffected individuals. A novel missense variant c.475C>T (p.A159T) in PLA2G6 with AD inheritance was identified in this family which segregated with the disease. Note that a variant in SNRNP200 gene also segregated with the disease but is within the untranslated region and the functional effect is unclear.

Created: 7 Nov 2019, 2:02 p.m. | Last Modified: 7 Nov 2019, 2:02 p.m.

Panel Version: 1.401

PMID:30772976. Ma et al., 2019 analyse a Chinese Han pedigree with seizures amongst the phenotype. Compound het variants in PLA2G6 were found (p.A80T and p.D331Y) (full English text not available).

Created: 7 Nov 2019, 2:02 p.m. | Last Modified: 7 Nov 2019, 2:02 p.m.

Panel Version: 1.401

PMID:30340910. Darling et al., 2019 investigated 16 patients from 13 families with PLA2G6-associated neurodegeneration (an autosomal recessive disorder). Epilepsy was observed in 8/16 patients (7 families, 2 patients had been previously reported, Table 1). All patients harboured missense, nonsense and frameshift variants in PLA2G6.

Created: 7 Nov 2019, 2:01 p.m. | Last Modified: 7 Nov 2019, 2:01 p.m.

Panel Version: 1.401

Added to epilepsy panel based on a Green rating on the 'Inborn errors of metabolism panel'- seizures are a reported feature of MIM:256600 and MIM:610217.
Sources: Literature, Other

Created: 7 Nov 2019, 2 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PLA2G6-associated neurodegeneration (PLAN); Familial cortical myoclonic tremor with epilepsy (FCMTE); Infantile neuroaxonal dystrophy 1, 256600; Neurodegeneration with brain iron accumulation 2B, 610217

Publications

• 30340910
• 27513994
• 30772976