BTD

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: ClinGen

BTD and autosomal recessive Biotinidase Deficiency was reported in 1994 by Cole et al. (PMID: 7509806). Profound biotinidase deficiency is defined as less than 10% of mean normal serum enzyme activity; partial biotinidase deficiency is defined as between 10% and 30% of mean normal serumactivity (PMID: 26810761). Patients with Biotinidase deficiency are treated with biotin. At least 200 unique variants (missense, frameshift, nonsense etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data, including an animal model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, BTD is definitively associated with autosomal recessive Biotinidase Deficiency. 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 Hearing Loss Gene Curation Expert Panel in collaboration with the ClinGen General Gene Curation Working Group on 9/25/19.

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0009665

Submitter: PanelApp Australia