Mosaic brain disorders - deep sequencing

Gene: NPRL3

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 3, OMIM:617118

Publications

• PMID: 30093711
• 31625153

Green List (high evidence)

Comment on list classification: Following further consultation with the requesting specialist team (Thomas Cullup) and the Genomics England clinical team (Helen Brittain) it has been agreed that the rating of this gene can be upgraded from Amber to Green in view of two instances of reported somatically acquired variants in NPRL3 including:

- Niestroj et al., 2019: c.682_683dup 4.5% VAF (patient 3)
- Chung et al., 2023 - c.924+2T>C 20% VAF (supp table 3a)

Multiple germline cases have also been reported; however, other panels such as R87 and R59 would be more cost-effective for detecting these variants than a deep sequencing approach.

Created: 16 Oct 2023, 11:41 a.m. | Last Modified: 16 Oct 2023, 11:41 a.m.

Panel Version: 0.138

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, 12:38 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, 5:37 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