CEP85L was first reported in relation to autosomal dominant lissencephaly spectrum disorder (MONDO:0018838) in 2020 (Tsai et al., PMID: 32097630, Kodani et al., 32097629). The phenotypic spectrum includes developmental delay and seizures. Brain imaging shows features consistent with neuronal migration defects, including posterior-predominant lissencephaly, pachygyria, agyria, and subcortical band heterotopia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND/OR inheritance pattern AND/OR phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity lissencephaly spectrum disorder (MONDO:0018838), AD. 17 variants (start codon, nonsense, splice and missense) that have been reported in 17 probands in 3 publications (PMID: 32097630, 32097629, 4440382) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function, and possibly dominant negative. This gene-disease relationship is also supported by experimental evidence, including animal models, and in vitro human stable cell lines (PMID: 32097630, 32097629). Mouse embryonic neuronal electroporation assays indicate reduced neuronal migration after shRNA knockdown of CEP85L. Human stable cell models (U2-OS) indicate reduced wound healing after siRNA knockdown of CEP85L. In summary, there is definitive evidence supporting the relationship between CEP85L and autosomal dominant lissencephaly spectrum disorder (MONDO:0018838). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen brain malformations GCEP on the meeting date 9/24/2024, (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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