The relationship between BAAT and bile acid CoA:amino acid N-acyltransferase deficiency (also referred to as familial hypecholanemia in the literature), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of March, 2022. BAAT encodes a liver enzyme that is involved in the final step of bile acid synthesis, the conjugation of mature bile acids to glycine and taurine. This facilitates intestinal absorption of fats and fat-soluble vitamins. Patients with BAAT mutations show increased levels of unconjugated bile acids in the serum, urine and bile. They present with itching and fat malabsorption.
BAAT was first reported in relation to autosomal recessive familial hypecholanemia in 2003 (Carlton et al, PMID: 12704386). The condition is also caused by mutations in genes other than BAAT. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (5.1 points): At least 10 patients in 4 publications have been reported with homozygous missense or nonsense variants (PMID: 12704386,10655068, 22783059, 23415802). The mechanism is expected to be homozygous loss of function. The variant segregated with disease in 5 additional family members.
Summary of experimental data (2.5 points): This gene-disease association is supported by a mouse model originally developed by the IMPC project and later shown to recapitulate the biochemical deficiency (PMID: 21677750, PMID: 36243101). The enzyme is highly expressed in peroxisomes in hepatocytes (PMID: 17256745) and has a role in conjugating bile acids (PMID: 12810727).
In summary, there is moderate level of evidence to support the gene-disease relationship of BAAT and bile acid CoA:amino acid N-acyltransferase deficiency. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP on Apr 9, 2022. It was reevaluated on May 3, 2024. As a result of this reevaluation, the classification did not change.
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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