Early onset or syndromic epilepsy

Gene: NPRL2

Comment on publications: PMID:34965576 describes conditional knockout mouse model of NPRL2-related epilepsy.

Created: 10 Feb 2023, 6:05 p.m. | Last Modified: 10 Feb 2023, 6:05 p.m.

Panel Version: 3.40

As a result of watchlist tag audit the watchlist tag was removed from NPRL2- this is now a green gene with sufficient evidence/review

Created: 13 Jan 2020, 1:55 p.m. | Last Modified: 13 Jan 2020, 1:55 p.m.

Panel Version: 2.0

Green List (high evidence)

AD FFEVF2 - Ricos et al, 2016 (26505888) 10 patients from 5 unrelated families (family 1: 2 aff had the variant - proband and dad, Family 2 (proband and unaff daughter, aff mother not tested) & 3 (proband and unaff mother): 1 aff and 1 unaff had the variants, Family 4: 1 aff had the variant, Family 5: 2 aff and 1 unaff had the variant (on pedigree proband, aff mother aff grandmother and poss aff aunt, aff cousin had the variant and an unaff aunt also had it) - identifed 5 diff het variants, 2 truncating and 3 missense and there is evidence of incomplete penetrance. Weckhuysen et al, 2016 (27173016) - 2 sisters from a non-consang family both had epilepsy (presenting in childhood in one and teens in the other) also had a paternal family history of nonspecific seizures - het fs variant identified in the two sisters which were also carried by an unaff sister and father a distant paternal relative with an unspecified epilepsy had the variant as well. Baldassari et al 2019 (30093711) - identified 3 more variants in this gene one which had been prev reported by Ricos et al - Arg34* - 2 they classed as pathogenic and a missense as a VUS. The Arg348 variant was inherited from an aff father and no segregation analuysis was done for the other two variants. Perruca et al, 2017 (28199897) - female patient identified with a likely pathogenic missense variant - variant was also identifed in her unaff mother and her aff maternal uncle. Also has two untested nieces with unclassified epilepsy.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

I don't know

No further comment to add; happy with Amber rating for the moment as there are reports of several unaffected carriers which will make any variant difficult to interpret.

Created: 23 Aug 2019, 10:07 a.m. | Last Modified: 23 Aug 2019, 10:07 a.m.

Panel Version: 1.256

I don't know

Some evidence. PMID 26505888 reported disease causing mutations in 10 patients from 5 families with focal epilepsy with variable foci-2.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy familial focal with variable foci 2, 617116

Publications

• 26505888

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases to support gene:disease association, although unaffected carriers/incomplete penetrance may make variant interpretation difficult. Promoted from Amber to Green with the option to review on subsequent versions.

Created: 25 Nov 2019, 8:20 p.m. | Last Modified: 25 Nov 2019, 8:20 p.m.

Panel Version: 1.426

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

NPRL2 re-reviewed for curation of GMS epilepsy panel: Sufficient cases for inclusion but variants in unaffected family members (explained by the authors as incomplete penetrance). Other members of the complex, NPRL3 and DEPDC5, are Green on the panel. Since the last curation there has been a Green review by Deb Pal (Kings College London): PMID:30093711 (2019) note 3 further probands with epilepsy (including 1 with infantile spasm and unclear effect on the protein). They also note incomplete penetrance for variants in their cohort of 73 patients (covering DEPDC5 + NPRL2 + NPRL3 genes which all form the GATOR1 complex together). Awaiting clinical review for final gene rating.

Created: 13 Aug 2019, 3:49 p.m. | Last Modified: 13 Aug 2019, 3:49 p.m.

Panel Version: 1.213

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

PMID:30093711. Baldassari et al 2019 report clinical data for 73 previously unreported probands, including 3 with NPRL2 variants. 1 (Czech) patient had sleep-related hypermotor epilepsy, 1 (UK) patient had frontal lobe epilepsy, and 1 (Italian) patient had infantile spasms. The authors also note reduced penetrance for variants in the overall cohort.

Created: 9 Jul 2019, 12:22 p.m. | Last Modified: 9 Jul 2019, 12:22 p.m.

Panel Version: 1.139

Green List (high evidence)

Amplexa CHE-114 epilepsy panel

Created: 21 Feb 2019, 2:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilepsy; intellectual disability; focal cortical dysplasia

Publications

• 30093711

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: At this time, as there are many unaffected family members with the variants identified in affected patients, Arianna Tucci (Genomics England Clinical Team) agrees that it is best to keep this gene amber for now, due to lack of enough evidence for a monogenic role of this gene in epilepsy.

Created: 11 Dec 2018, 10:05 a.m.

Comment on list classification: Knockout mice do not seem to have a seizure phenotype: http://www.informatics.jax.org/marker/phenotypes/MGI:1914482

Created: 11 Dec 2018, 10:03 a.m.

Comment on list classification: Four families reported (see publications), however the same variants were identified in unaffected family members, with the publications stating this is due to incomplete penetrance.

Created: 11 Dec 2018, 9:38 a.m.

Green List (high evidence)

Multiple individuals from unrelated families reported with variants in this gene.

Created: 17 Aug 2018, 11:01 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, familial focal, with variable foci 2, MIM#617116

Publications

• 26505888
• 27173016

Variants in this GENE are reported as part of current diagnostic practice