The relationship between NDUFB11 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 20, 2022. NDUFB11 encodes an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFB11 was first reported in relation to X-linked mitochondrial disease in 2015 (PMID: 25772934). While various names have been given to the constellation of features seen in those with NDUFB11-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFB11 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants, comprising four nonsense and frameshift variants, three missense variants, and one in-frame deletion, in 13 probands across seven publications (PMIDs: 25772934, 25921236, 26741492, 27488349, 28050600, 27102574, 30423443). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.
Of note, NDUFB11 pathogenic variants were initially reported in individuals with linear skin defects, failure to thrive, developmental delay, and histiocytoid cardiomyopathy. Subsequent publications have shown expansion of the phenotypic spectrum, ranging from isolated cardiomyopathy to multisystemic disorders including cardiomyopathy, optic atrophy, myopathy, short stature, and hearing impairment. The recurrent in-frame deletion, c.276_278del (p.Phe93del) has been reported in at least five probands (PMIDs: 27488349, 27102574) with a unique presentation of sideroblastic anemia with or without some of the multisystemic features described above. Loss-of-function is implicated as the mechanism of disease. This gene-disease association is also supported by the known biochemical function, rescue in a cell culture model, and animal models (PMIDs: 27509854, 25921236, 26741492, 27488349, 27102574). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached.
In summary, NDUFB11 is definitively associated with X-linked mitochondrial disease. This has been repeatedly demonstrated and has been upheld over time. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 20, 2022 (SOP Version 8).
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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