The relationship between CLPB and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The CLPB gene has a function in mitochondrial protein disaggregation, but the disease mechanism is currently somewhat unclear.
The CLPB gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2015 (PMIDs: 25597511, 25597510). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Many other cases have been reported with CLPB-related disease, however brain imaging was not performed or was not consistent with Leigh syndrome spectrum. 3-methylglutaconic aciduria is a common finding in individuals with CLPB-related disease.
This curation included three unique variants identified in three unrelated cases from two publications (PMIDs: 25597511, 25597510). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by animal models (PMIDs: 25597510, 25650066).
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 June 8, 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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