The relationship between BTD and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 12, 2020. The BTD gene encodes biotinidase, the enzyme responsible for recycling biotin. Biotin is an essential vitamin and coenzyme for four mitochondrial carboxylases necessary for metabolism in humans: acetyl-CoA carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and pyruvate carboxylase.
The BTD gene was first reported in relation to autosomal recessive Leigh syndrome spectrum (LSS) in 2008 (PMID: 18645204). It is important to note, however, that there were many earlier reports of biotinidase deficiency resulting in a phenotype consistent with LSS, however genetic testing was not routinely performed at the time of these early case reports. By the time genetic testing was more widely utilized, biotinidase deficiency had been adopted into many newborn screening programs and was being treated presymptomatically, therefore preventing manifestation of LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one variant identified in two cases from two publications (PMIDs: 21907891, 18645204), although as stated above there are many other probands in whom LSS was prevented with biotin treatment. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, and animal models (PMIDs: 27977873, 25613900, 21051254).
In summary, there is currently limited evidence to support this gene-disease relationship. However, the expert panel agreed to increase this gene-disease association to moderate, primarily due to the fact that there would be many more cases to score if this was not a treatable condition that is screened for at birth in many countries. 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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