Submission Details

FRRS1L was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 by two groups (Madeo et al., PMID: 27236917; Shaheen et al. PMID: 27239025). Typical phenotypes of individuals affected with FRRS1L-related DEE include severe intractable seizures, global developmental delay, regression, hypotonia, and movement disorders such as choreoathetosis. Eleven homozygous variants (missense and truncations) reported in 11 probands in eight publications are included in this curation (PMIDs: 27236917, 27239025, 28675162, 30525197, 31130284, 33584793, 35815844, 36703223). While a founder variant from Saudi Arabia, NM_014334.4 c.808C>T p.Gln270* (CA10575812), was found in the homozygous state in affected individuals from at least four families in three publications (PMID: 27239025, 27236917, 31054490), only one of the probands was included in the scoring as the level of relatedness between these two families is unclear (PMID: 27239025). Other variants segregated with disease in two different families resulting in a total LOD score of 5.86. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a knockout mouse model that showed spontaneous seizures (PMID: 30692144). In summary, there is definitive evidence supporting the relationship between FRRS1L and autosomal recessive DEE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by ClinGen Epilepsy GCEP on the meeting date, September 17, 2024 (SOP version 11).