Submission Details

SERPINI1 was first reported in relation to an autosomal dominant condition with progressive psychomotor deterioration and neuroserpin-immunoreactive inclusion body in a large family in 1999 (Davis et al. 1999 PMID: 10517635). The onset of this family was in their 40’s and epilepsy was not present. Later, this family was found to be on the milder spectrum of this condition, because families reported after this initial publication had earlier age of onset (7-30 yo) and epilepsy. Typical phenotypes of these probands were psychomotor deterioration, progressive myoclonus epilepsy, and Periodic Acid-Schiff-positive, diastase resistant, and neuroserpin-immunoreactive inclusion bodies called Collins bodies in the brain. For this reason, SERPINI1 is curated for autosomal dominant progressive myoclonus epilepsy. Seven missense SERPINI1 variants that have been reported in twelve probands in nine publications have been included in this curation. The mechanism of pathogenicity appears to be GOF. Of the twelve reported families, ten had variants with functional studies and/or neuroserpin-immuoreactive inclusion bodies in the brain and were awarded 0.5 pts. Five families received additional 0.5 pts, because the variants were de novo. Four variants were recurrent in nine families, and each received 0.5 pts more. For the large family studied in PMID: 10517635, LOD score of 3.4 was published, resulting in 1 pt for segregation. In total, maximum score for genetic evidence (12 pts) has been reached. There was no scorable experimental evidence for this gene-disease association. In summary, SERPINI1 is definitively associated with autosomal dominant progressive myoclonus epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.