The relationship between ABCD3 and congenital bile acid synthesis defect 5 (ABCD3 congenital bile acid synthesis defect), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2022. ABCD3 encodes an ATP-binding cassette transporter involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs (also called peroxisomal membrane protein 70, PMP70). Some of the phenotypes associated with ABCD3 congenital bile acid synthesis defect or include hepatomegaly, jaundice and increased plasma bile acid intermediates and VLCFAs.
ABCD3 was first reported in relation to autosomal recessive congenital bile acid synthesis defect in 2015. (Ferdinandusse et al, PMID: 25168382). This is the only report of a genetic defect in ABCD3 identified in a human patient. Earlier, ABCD3 was associated with peroxisome biogenesis as mutations were identified in the ABCD3 gene in patients with Zellweger syndrome. However, it was later shown that a PEX1 defect was the underlying cause of peroxisome biogenesis disorder in those patients (PMID: 25168382).
Summary of Case Level Data (1 point): A homozygous deletion variant has been reported in 1 proband in 1 publication (PMID: 25168382), wherein a truncated protein product is shown to be made. The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (4 points): This gene-disease association is supported by a mouse models that recapitulate some of the human disease phenotype (PMIDs 25168382, 34564857) and protein interactions with ABCD1 (PMID: 10551832) and PEX19 (PMID: 16344115).
In summary, there is limited evidence to support the gene-disease relationship of ABCD3 and congenital bile acid synthesis defect 5. 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 GCEP on April 27, 2022. It was reevaluated on June 6, 2025 (SOP v 10). No new evidence was added and 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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