Mosaic brain disorders - deep sequencing

Gene: NPRL2

Green List (high evidence)

One of the three subunits in the GATOR1 complex which is a negative regulator of the mTOR pathway. Loss of function variants in GATOR1 lead to enhanced mTOR pathway activation. Linked publication shows 4 individuals with FCD IIA harbouring somatic NPRL2 variants. This paper has come out of Paris Brain Institute.

Created: 1 Oct 2025, 12:58 p.m. | Last Modified: 1 Oct 2025, 12:58 p.m.

Panel Version: 0.148

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
FCDII

Publications

• PMID: 37149062

The rating of this gene has been updated to Amber and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 8:53 a.m. | Last Modified: 11 Oct 2023, 8:53 a.m.

Panel Version: 0.133

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Focal cortical dysplasia; Epilepsy, familial focal, with variable foci 2, OMIM:617116

Publications

• PMID: 30093711
• 31625153

I don't know

Comment on list classification: Following further consultation with the requesting specialist team (Thomas Cullup) it has been agreed that the rating of this gene can remain as Amber to allow the providing GLH to analyse and report on it if they feel it is appropriate for their cases. This would facilitate further gathering of data which could potentially support future promotion to green.

Evidence for inclusion: the NPRL2 protein forms the GATOR1 complex along with NPRL3 and DEPDC5 (green rated).

Created: 16 Oct 2023, 11:35 a.m. | Last Modified: 16 Oct 2023, 11:35 a.m.

Panel Version: 0.137

Comment on list classification: This gene causes focal epilepsy which can be associated with structural brain abnormalities in some patients. Although the clinical phenotype is within scope of this panel, I could not find any evidence in literature suggesting pertinence of mosaic variants and therefore rating this gene Amber.

Created: 22 Dec 2022, 4:25 p.m. | Last Modified: 2 Oct 2023, 12:48 p.m.

Panel Version: 0.131

I don't know

The rating of this gene has been updated to Amber and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 5:26 p.m. | Last Modified: 1 Feb 2023, 5:36 p.m.

Panel Version: 0.93

Review submitted on behalf of Dr Lara Menzies, Dr Wendy Jones, Dr Amy McTague. Mode of inheritance: AD. Publications: Baldassari and Baulac 2019 Genetics in Medicine, Iffand et al 2019 Epilepsia. Mechanism: LOF (MTOR pathway). Penetrance: variable penetrance.

Created: 21 Dec 2022, 12:16 p.m. | Last Modified: 21 Dec 2022, 12:16 p.m.

Panel Version: 0.2

Phenotypes
Epilepsy and cortical dysplasia