Congenital bile acid synthesis defect 2

Summary

Congenital bile acid synthesis defect 2 (MONDO:0009339) is a disease caused by AKR1D1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: AKR1D1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 120
• Phenotypes (HPO): 27
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0002904	Hyperbilirubinemia	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0200084	Giant cell hepatitis	Very frequent (80-99%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001978	Extramedullary hematopoiesis	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002570	Steatorrhea	Frequent (30-79%)
HP:0002630	Fat malabsorption	Frequent (30-79%)
HP:0002908	Conjugated hyperbilirubinemia	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0003256	Abnormality of the coagulation cascade	Frequent (30-79%)
HP:0003645	Prolonged partial thromboplastin time	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0030984	Abnormal serum bile acid concentration	Frequent (30-79%)
HP:0040319	Dark urine	Frequent (30-79%)
HP:0100513	Low levels of vitamin E	Frequent (30-79%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0002748	Rickets	Occasional (5-29%)
HP:0011040	Abnormality of the intrahepatic bile duct	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital bile acid synthesis defect 2
Mondo ID	MONDO:0009339
MeSH	C535443
OMIM	235555
Orphanet	79303
DOID	DOID:0111069
UMLS	C1856127
MedGen	383840
GARD	0010045
Is cancer (heuristic)	no

Also known as: AKR1D1 congenital bile acid synthesis defect · BASD2 · bile acid synthesis defect, congenital, 2 · bile acid synthesis defect, congenital, type 2 · CBAS2 · cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency · congenital bile acid synthesis defect caused by mutation in AKR1D1 · congenital bile acid synthesis defect type 2 · congenital bile acid synthesis defect, type 2

Data availability: 120 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › steroid inherited metabolic disorder › congenital bile acid synthesis defect › congenital bile acid synthesis defect 2

Related subtypes (5): congenital bile acid synthesis defect 4, congenital bile acid synthesis defect 1, congenital bile acid synthesis defect 3, congenital bile acid synthesis defect 5, congenital bile acid synthesis defect 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

120 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 20 benign, 10 likely benign, 7 conflicting classifications of pathogenicity, 7 likely pathogenic, 5 pathogenic/likely pathogenic, 5 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064451	NM_005989.4(AKR1D1):c.797G>A (p.Arg266Gln)	AKR1D1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070635	NM_005989.4(AKR1D1):c.148C>T (p.Arg50Ter)	AKR1D1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293811	NM_005989.4(AKR1D1):c.238del (p.Glu80fs)	AKR1D1	Pathogenic	criteria provided, single submitter
4525818	NM_005989.4(AKR1D1):c.580-13T>A	AKR1D1	Pathogenic	criteria provided, single submitter
5375	AKR1D1, 1-BP DEL, 511T	AKR1D1	Pathogenic	no assertion criteria provided
5376	NM_005989.4(AKR1D1):c.316C>T (p.Leu106Phe)	AKR1D1	Pathogenic	no assertion criteria provided
5378	NM_005989.4(AKR1D1):c.781C>T (p.Arg261Cys)	AKR1D1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
595370	NM_005989.4(AKR1D1):c.583G>T (p.Glu195Ter)	AKR1D1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915290	NM_005989.4(AKR1D1):c.267G>A (p.Trp89Ter)	AKR1D1	Pathogenic	criteria provided, single submitter
915331	NM_005989.4(AKR1D1):c.796C>T (p.Arg266Ter)	AKR1D1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323872	NM_005989.4(AKR1D1):c.864del (p.Ser290fs)	AKR1D1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910216	NM_005989.4(AKR1D1):c.919C>T (p.Arg307Cys)	AKR1D1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3362334	NM_005989.4(AKR1D1):c.141_142del (p.Gly48fs)	AKR1D1	Likely pathogenic	criteria provided, single submitter
3594299	NM_005989.4(AKR1D1):c.174_175del (p.Tyr58_Gln59delinsTer)	AKR1D1	Likely pathogenic	criteria provided, single submitter
4081100	NM_005989.4(AKR1D1):c.261+2T>C	AKR1D1	Likely pathogenic	criteria provided, single submitter
4535962	NM_005989.4(AKR1D1):c.158A>G (p.Asp53Gly)	AKR1D1	Likely pathogenic	criteria provided, single submitter
800839	NM_005989.4(AKR1D1):c.940T>C (p.Trp314Arg)	AKR1D1	Likely pathogenic	criteria provided, single submitter
1030985	NM_005989.4(AKR1D1):c.509A>G (p.Asn170Ser)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499336	NM_005989.4(AKR1D1):c.242A>T (p.Asp81Val)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5374	NM_005989.4(AKR1D1):c.593C>T (p.Pro198Leu)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5377	NM_005989.4(AKR1D1):c.398C>G (p.Pro133Arg)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594766	NM_005989.4(AKR1D1):c.332T>C (p.Leu111Pro)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908393	NM_005989.4(AKR1D1):c.782G>A (p.Arg261His)	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911442	NM_005989.4(AKR1D1):c.*537T>C	AKR1D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030986	NM_005989.4(AKR1D1):c.647T>C (p.Ile216Thr)	AKR1D1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030987	NM_005989.4(AKR1D1):c.675T>A (p.Ser225Arg)	AKR1D1	Uncertain significance	criteria provided, single submitter
1946862	NM_005989.4(AKR1D1):c.157G>A (p.Asp53Asn)	AKR1D1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438957	NM_005989.4(AKR1D1):c.66_71del (p.Leu23_Gly24del)	AKR1D1	Uncertain significance	criteria provided, single submitter
2585007	NM_005989.4(AKR1D1):c.949C>T (p.His317Tyr)	AKR1D1	Uncertain significance	criteria provided, single submitter
289546	NM_005989.4(AKR1D1):c.380C>T (p.Pro127Leu)	AKR1D1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AKR1D1	Definitive	Autosomal recessive	congenital bile acid synthesis defect 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKR1D1	Orphanet:79303	Congenital bile acid synthesis defect type 2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AKR1D1	HGNC:388	ENSG00000122787	P51857	Aldo-keto reductase family 1 member D1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKR1D1	Aldo-keto reductase family 1 member D1	Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKR1D1	Enzyme (other)	yes	1.3.1.3	Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
primordial germ cell in gonad	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKR1D1	85	tissue_specific	marker	liver, right lobe of liver, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKR1D1	1,544

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AKR1D1	P51857	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	878.5×	0.004	AKR1D1
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	761.3×	0.004	AKR1D1
Bile acid and bile salt metabolism	1	496.5×	0.004	AKR1D1
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.004	AKR1D1
Synthesis of bile acids and bile salts	1	407.9×	0.004	AKR1D1
Metabolism of steroids	1	137.6×	0.010	AKR1D1
Metabolism of lipids	1	31.6×	0.036	AKR1D1
Metabolism	1	11.6×	0.086	AKR1D1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bile acid catabolic process	1	8426.0×	7e-04	AKR1D1
C21-steroid hormone metabolic process	1	3370.4×	9e-04	AKR1D1
cholesterol catabolic process	1	1872.4×	0.001	AKR1D1
androgen metabolic process	1	887.0×	0.002	AKR1D1
bile acid biosynthetic process	1	624.1×	0.002	AKR1D1
digestion	1	624.1×	0.002	AKR1D1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AKR1D1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AKR1D1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKR1D1	1.3.1.3	DELTA4-3-oxosteroid 5beta-reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AKR1D1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AKR1D1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns