Submission Details

The relationship between BCAT2 and hypervalinemia and hyperleucine-isoleucinemia, an autosomal recessive disorder of branched chain amino acid metabolism, was evaluated using the ClinGen Clinical Validity Framework as of July 9, 2020. There are three branched chain amino acids (BCAAs) – leucine, isoleucine, and valine. A branched-chain amino acid transferase (BCAT), which is pyridoxine-dependent, carries out the first step of BCAA metabolism, using alpha-ketoglutarate to form branched chain alpha-keto acids. There are two isoforms of BCAT; BCAT1 (also known as BCATc) is cytosolic and expressed mainly in neurons, while BCAT2 (also known as BCATm) is mitochondrial and expressed in most tissues. The next step in branched chain amino acid metabolism is carried out by branched chain alpha-ketoacid dehydrogenase (BCKD), which is deficient in patients with Maple Syrup Urine disease, a condition characterized by elevated BCAA’s and branched chain keto-acids and allo-isoleucine. The relationship between BCAT2 and hypervalinemia and hyperleucine-isoleucinemia is supported by case-level and experimental evidence. Biallelic variants in BCAT2 were first reported in 2015 in a single patient with hypervalinemia and hyperleucine-isoleucinemia (Wang et al, 25653144). A further 6 patients have been reported since then, including an affected mother and daughter (Navarette et al, 2019, PMID 30626930; Knerr et al, 2019, PMID 31177572). To our knowledge, no other patients with this disorder and variants in BCAT2 have been reported in the literature. Nine unique variants (missense, inframe deletion, frameshift, and nonsense) in 6 probands from these three publications were curated; 6.25 points were given for genetic evidence. Note that that phenotype curated for was elevated leucine, valine, and isoleucine. The clinical findings of the reported patients include various neurological findings, including developmental delay in some of the patients. This could be due to ascertainment bias, and further studies are needed to assess the clinical features associated with this condition. Experimental evidence supporting this gene-disease relationship includes the function of BCAT2, which is consistent with the biochemical findings in patients (Ichihara et al, 1966, PMID 5943594; Bledsoe et al, 1997, PMID 9165094; Ananieva et al, 2017, PMID 27886623; Brosnan et al, 2006, PMID 16365084), functional alteration studies showing altered branched chain amino acid metabolism in cells from patients with BCAT2 variants (Knerr et al, 2019), and the findings in an ENU-generated mouse model (Wu et al, 2004, PMID 14755340) and a knock-out mouse. Additional experimental evidence is available but the maximum score (6 points) was given. In summary, BCAT2 is definitively associated with hypervalinemia and hyperleucine-isoleucinemia. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.