The relationship between DNM1L and autosomal dominant Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 12, 2020. The DNM1L gene encodes Dynamin 1-like protein, a member of the dynamin superfamily of GTPases. This protein mediates mitochondrial and peroxisomal fission. Defects in DNM1L lead to impaired mitochondrial fission and therefore impaired mitochondrial replication, distribution, transport, and dynamics. DNM1L also has a role in peroxisomal fission.
The DNM1L gene has been reported only once in relation to autosomal dominant Leigh syndrome spectrum, in 2016 (PMID: 27301544). Pathogenic variants in DNM1L, inherited in an autosomal dominant manner, have also been associated with other features ranging from isolated optic atrophy to neonatal or infantile-onset encephalopathy. This gene has also been implicated in autosomal recessive Leigh syndrome spectrum (please see separate curation). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one de novo variant identified in one case in one publication (PMID: 27301544). No segregation data were available. Dominant negative effect is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and expression (PMIDs: 30361041, 18853439).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 12, 2020 (SOP Version 7).
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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