EPM_CSNK1E ?

[Macayla-weiner]

Article Akshay sent: Akçimen, 2025

Present EPM in CSNK1E in one case with a CGG expansion in exon 1 of chr22:38317282-38317375 with incomplete penetrance. "The longest expanded allele as CGGn = 745 in the proband, CGGn = 131 in the unaffected mother, CGGn = 8 in the unaffected father, and CGGn = 980 in the unaffected sibling." Proband age onset 10 yr, sibling had the expansion but no phenotype.

[hdashnow]

See also two additional cases in:
LaFlamme 2024
Note: some caveats that it may be seen in unaffected individuals.

See, also in gnomAD: https://gnomad.broadinstitute.org/short-tandem-repeat/CSNK1E?dataset=gnomad_r3

[Macayla-weiner]

With that article, age of onset is pediatric signaling at DEE rather than EPM. It's actually one of the citations in Akshay's article and they explain why they do not believe the two are studying the same disease.

[hdashnow]

Questions arising:
The Akçimen paper suggested the phenotype was sufficiently different from LaFlamme to be a different disease:

The proband in our study exhibited a different phenotype compared with the previously reported three cases, who were diagnosed between 9 months and 4–5 years of age and presented with developmental and epileptic encephalopathy (DEE). Although the proband in this report and the previously described cases shared a common feature of epileptic disorders, there were significant differences in the age of disease onset, phenotype spectrum, and severity.41 Unlike the previously reported cases, our proband did not exhibit developmental abnormalities and presented with a phenotype suggestive of EPM rather than DEE.

Do we think this is phenotypic expansion/expressivity, or do we think these are truly different diseases?

What about the penetrance concerns mentioned in both papers?

[Macayla-weiner]

Christy LaFlamme also shared the following articles that study expansions in CSNK1E: Garg 2020, Jadhav 2024, and Chen 2018

[Macayla-weiner]

Issues we're having: seemingly the same motif at nearly the exact same coordinates with similar symptoms. Articles say that due to the differences in symptoms and ages of onset, DEE and EPM are not related. However we do not find this entirely convincing and think it possible that this is an expressivity or phenotypic spectrum and/or that the hypermethylation causes changes in onset, severity, etc.