Early onset or syndromic epilepsy

Gene: PRICKLE1

I don't know

The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 10:58 a.m. | Last Modified: 26 Sep 2024, 10:58 a.m.

Panel Version: 6.6

Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified to date in Genomics England's Clinical Variant Archive (CVA) dataset are UNCLASSIFIED.

Created: 23 Jan 2024, 5:08 p.m. | Last Modified: 23 Jan 2024, 5:13 p.m.

Panel Version: 4.151

Publications

• 30564977
• 30345727
• 21276947
• 26727662
• 29790814
• 31875159
• 31035234
• 15634728
• 15642921
• 16376507
• 18976727
• 20301774

Green List (high evidence)

Both AR and AD variants reported (PMID: 21276947 - for AD). AR progressive myoclonic epilepsy 1B (EPM1B). Affected members of the families reported by Berkovic et al, 2005 (consang Israeli-Arab family - 8 affecteds), Straussberg et al, 2005 (consang Israeli-Arab family - 3 affected sibs) and El Shanti et al, 2006 (consang Jordanian family - 4 affected sibs) - same hom variant R104Q - suggests founder effect. Tao et al 2001 - 2 diff het variants R114H and Y472H in 2 unrelated patients with myoclonic epilepsy. The authours suggest both hom and het variants result in seizures suggesting a dosge effect. No functional work done. Bosoi et al, 2011 - 7 rare missense het variants associated with individuals with neural tube defects.

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

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epilepsy progressive myoclonic, 612437

Publications

• 21276947
• 21276947

I don't know

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: John Taylor and Helen Lord. Suggested gene rating: Green.

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

Panel Version: 1.189

Comment on mode of inheritance: Updated MOI from biallelic to BOTH monoallelic and biallelic based on PMID:21276947. Tao et al. 2011 sequenced PRICKLE1 (and PRICKLE2) in 88 unrelated patients with myoclonus epilepsy and found two patients with heterozygous missense mutations in PRICKLE1: p.Arg144His and p.Tyr472His. The variants were not found in control data sets. The authors therefore suggest that the heterozygous PRICKLE1 variants are also associated with myoclonus epilepsy.

Created: 11 Jul 2019, 8:32 a.m. | Last Modified: 11 Jul 2019, 8:32 a.m.

Panel Version: 1.152

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants identified in unrelated cases.

Created: 16 Oct 2018, 3:37 p.m.

Multiple individuals from unrelated families described with bi-allelic variants in this gene and a seizure disorder.

Created: 19 Aug 2018, 11:36 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epilepsy, progressive myoclonic 1B, MIM#612437

Publications

• 18976727
• 21276947

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

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)