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Likely inborn error of metabolism v8.94 ACOX2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ACOX2.
Likely inborn error of metabolism v8.94 ACOX2 Achchuthan Shanmugasundram reviewed gene: ACOX2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Likely inborn error of metabolism v8.93 ACOX2 Achchuthan Shanmugasundram Source NHS GMS was added to ACOX2.
Source Expert Review Green was added to ACOX2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v8.64 ACOX2 Achchuthan Shanmugasundram Classified gene: ACOX2 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.64 ACOX2 Achchuthan Shanmugasundram Gene: acox2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.63 ACOX2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ACOX2.
Likely inborn error of metabolism v8.63 ACOX2 Achchuthan Shanmugasundram Publications for gene: ACOX2 were set to 27647924; 27884763; 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.; to: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. The association is supported by a mouse model, where Acox2 knockout resulted in elevated hepatic transaminases, liver fibrosis and hepatic inflammation.
Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska commented on gene: ACOX2: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 29287774, 33340570, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.


PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.


PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 29287774, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.


This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.


This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Sources: Other, ClinGen; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 2928777435395098
Likely inborn error of metabolism v8.60 ACOX2 Ida Ertmanska gene: ACOX2 was added
gene: ACOX2 was added to Likely inborn error of metabolism. Sources: Other,ClinGen
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763; 35395098
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6, OMIM:617308
Review for gene: ACOX2 was set to GREEN
Added comment: The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Sources: Other, ClinGen