PRICKLE1

Inheritance Pattern: AR

Disease ID:MONDO:0012904

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009698

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0020074

Submitter: ClinGen

*PRICKLE1* was first reported in relation to autosomal recessive progressive myoclonic epilepsy (PME) in 2008 when Bassuk et al. studied 3 large consanguineous Middle Eastern pedigrees with autosomal recessive PME without variants in *CSTB*, another gene associated with Unverricht-Lundborg syndrome (PMID: 18976727). These families were all found to have an identical homozygous p.Arg104Gln variant. Later in 2018, Mastrangelo M et al. identified another proband with a similar phenotypic presentation and the homozygous p.Ala274Thr variant (PMID: 30345727). Additional probands were identified in the literature; however, they were not scored based on atypical phenotypes not consistent with PME and the high minor allele frequency of the variants detected (PMID: 30564977, 37593999). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities: autosomal recessive progressive myoclonic epilepsy (PME) and autosomal dominant epilepsy. The split curation for autosomal dominant epilepsy has been curated separately. Experimental evidence identified in the literature was not scored as it did not provide sufficient evidence supporting the gene-disease relationship. In summary, there is limited evidence to support the relationship between *PRICKLE1* and autosomal recessive progressive myoclonus epilepsy (PME). This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 1, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from Progressive Myoclonic Epilepsy to Epilepsy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. ** PRICKLE1 was reported in relation to autosomal dominant progressive myoclonic epilepsy (PME) in 2019 by Algahtani et al (PMID: 31035234). However, the phenotype described, presence of unaffected carriers, and allele frequency of the variant identified were not consistent with AD PME. Additional probands in whom a heterozygous PRICKLE1 variant was identified had epileptic phenotypes inconsistent with PME (21276947, 31875159, 29790814). No case-level evidence supports this gene-disease relationship. Of note, one case of a de novo variant in PRICKLE1 causing autosomal dominant complex neurodevelopmental disorder, including a seizure phenotype, has been reported (29790814). PRICKLE1 has also been assessed for autosomal recessive progressive myoclonic epilepsy by the ClinGen Epilepsy Expert Panel and found to have a Limited classification. In summary, there is convincing evidence disputing the relationship between PRICKLE1 and autosomal dominant epilepsy. More evidence is needed to either support or refute the role PRICKLE1 plays in this disease. This classification was approved by the ClinGen Epilepsy Expert Panel on 9/1/2020.

Inheritance Pattern: AR

Disease ID:MONDO:0012904

Submitter: Labcorp Genetics (formerly Invitae)