D-bifunctional protein deficiency

Summary

D-bifunctional protein deficiency (MONDO:0009855) is a disease caused by HSD17B4 (GenCC Definitive), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include chenodiol, cholic acid, and ursodiol.

At a glance

• Causal gene: HSD17B4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,213
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	d-bifunctional protein deficiency
Mondo ID	MONDO:0009855
OMIM	261515
Orphanet	300
DOID	DOID:0090031
NCIT	C119676
SNOMED CT	238068007
UMLS	C0342870
MedGen	137982
GARD	0004539
Is cancer (heuristic)	no

Also known as: 17-beta-hydroxysteroid dehydrogenase IV deficiency · bifunctional enzyme deficiency · D-bifunctional enzyme deficiency · d-bifunctional protein deficiency · HSD17B4 deficiency · multifunctional enzyme deficiency · peroxisomal multifunctional enzyme (MFE2) deficiency · peroxisomal multifunctional enzyme deficiency · pseudo-Zellweger syndrome

Data availability: 1,213 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › peroxisomal disease › peroxisomal single enzyme/protein defect › disorder of peroxisomal beta oxidation › d-bifunctional protein deficiency

Related subtypes (4): peroxisomal acyl-CoA oxidase deficiency, sterol carrier protein 2 deficiency, alpha-methylacyl-CoA racemase deficiency, acyl-CoA binding domain containing protein 5 deficiency

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

600 retrieved; paginated sample, class counts are floors:

310 likely benign, 123 uncertain significance, 72 likely pathogenic, 31 pathogenic, 20 benign, 19 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027412	NM_000414.4(HSD17B4):c.652G>T (p.Val218Leu)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066269	NM_000414.4(HSD17B4):c.280+2T>C	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070670	NM_000414.4(HSD17B4):c.911C>G (p.Ser304Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1071247	NM_000414.4(HSD17B4):c.1499del (p.Asn500fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1071457	NM_000414.4(HSD17B4):c.1921G>T (p.Glu641Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1074898	NM_000414.4(HSD17B4):c.1951G>T (p.Glu651Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1075507	NC_000005.9:g.(?118865579)(118867109_?)del	HSD17B4	Pathogenic	criteria provided, single submitter
1075802	NM_000414.4(HSD17B4):c.421C>T (p.Gln141Ter)	HSD17B4	Pathogenic	criteria provided, multiple submitters, no conflicts
1252039	NM_000414.4(HSD17B4):c.302+3delinsTGTTGTGATTTTTTAGTGAATTGTGTATTTTAGTGATGTGTGTATAATTTTTTTAAAAAGTATATACTTTCCTCCTTTTACCCTATACAACATTGATTT	HSD17B4	Pathogenic	no assertion criteria provided
1324546	NM_000414.4(HSD17B4):c.302+1G>A	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324548	NM_000414.4(HSD17B4):c.1383_1384del (p.Phe462fs)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333681	NM_000414.4(HSD17B4):c.1984del (p.Ala662fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1353412	NM_000414.4(HSD17B4):c.1235_1236del (p.Glu412fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1357638	NM_000414.4(HSD17B4):c.682G>T (p.Glu228Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1371276	NM_000414.4(HSD17B4):c.439del (p.Ile147fs)	HSD17B4	Pathogenic	criteria provided, single submitter
137617	NM_000414.4(HSD17B4):c.1547T>C (p.Ile516Thr)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404290	NM_000414.4(HSD17B4):c.590_597dup (p.Met200fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1416308	NM_000414.4(HSD17B4):c.1708G>T (p.Gly570Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1423489	NM_000414.4(HSD17B4):c.1480_1481insGA (p.Thr494fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1441941	NM_000414.4(HSD17B4):c.1233dup (p.Glu412fs)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448621	NM_000414.4(HSD17B4):c.1954_1970del (p.Trp652fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1452066	NM_000414.4(HSD17B4):c.1230C>G (p.Tyr410Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1453246	NM_000414.4(HSD17B4):c.657del (p.Pro220fs)	HSD17B4	Pathogenic	criteria provided, single submitter
1454962	NM_000414.4(HSD17B4):c.740T>G (p.Leu247Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1458501	NM_000414.4(HSD17B4):c.605dup (p.Thr203fs)	HSD17B4	Pathogenic	criteria provided, multiple submitters, no conflicts
1459060	NM_000414.4(HSD17B4):c.728G>A (p.Trp243Ter)	HSD17B4	Pathogenic	criteria provided, single submitter
1459623	NM_000414.4(HSD17B4):c.58+1G>T	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460126	NM_000414.4(HSD17B4):c.698dup (p.Asn233fs)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994245	NM_000414.4(HSD17B4):c.1986del (p.Lys663fs)	HSD17B4	Pathogenic	criteria provided, single submitter
2013219	NM_000414.4(HSD17B4):c.1956G>A (p.Trp652Ter)	HSD17B4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
HSD17B4	Definitive	Autosomal recessive	d-bifunctional protein deficiency	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSD17B4	Orphanet:300	Bifunctional enzyme deficiency
HSD17B4	Orphanet:642945	Perrault syndrome type 1
HSD17B4	Orphanet:642976	Perrault syndrome 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
HSD17B4	HGNC:5213	ENSG00000133835	P51659	Peroxisomal multifunctional enzyme type 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSD17B4	Peroxisomal multifunctional enzyme type 2	Bifunctional enzyme acting on the peroxisomal fatty acid beta-oxidation pathway.

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)
HSD17B4	Enzyme (other)	yes	4.2.1.119	SDR_fam, MaoC-like_dom, SCP2_sterol-bd_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
left lobe of thyroid gland	1
right lobe of liver	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSD17B4	295	ubiquitous	marker	right lobe of thyroid gland, right lobe of liver, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSD17B4	2,471

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSD17B4	P51659	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
TYSND1 cleaves peroxisomal proteins	1	1427.5×	0.002	HSD17B4
Beta-oxidation of pristanoyl-CoA	1	1142.0×	0.002	HSD17B4
Beta-oxidation of very long chain fatty acids	1	878.5×	0.002	HSD17B4
alpha-linolenic acid (ALA) metabolism	1	713.8×	0.002	HSD17B4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.003	HSD17B4
Peroxisomal protein import	1	173.0×	0.006	HSD17B4

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
very long-chain fatty-acyl-CoA metabolic process	1	8426.0×	0.001	HSD17B4
medium-chain fatty-acyl-CoA metabolic process	1	5617.3×	0.001	HSD17B4
fatty acid derivative biosynthetic process	1	1532.0×	0.002	HSD17B4
fatty acid beta-oxidation using acyl-CoA oxidase	1	1123.5×	0.002	HSD17B4
Sertoli cell development	1	1123.5×	0.002	HSD17B4
androgen metabolic process	1	887.0×	0.002	HSD17B4
alpha-linolenic acid metabolic process	1	887.0×	0.002	HSD17B4
very long-chain fatty acid metabolic process	1	766.0×	0.002	HSD17B4
unsaturated fatty acid biosynthetic process	1	648.1×	0.002	HSD17B4
estrogen metabolic process	1	624.1×	0.002	HSD17B4
long-chain fatty acid biosynthetic process	1	443.5×	0.003	HSD17B4
fatty acid beta-oxidation	1	374.5×	0.003	HSD17B4
osteoblast differentiation	1	121.2×	0.008	HSD17B4

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
HSD17B4	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
HSD17B4	11	Binding:10, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD17B4	4.2.1.119	enoyl-CoA hydratase 2

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	HSD17B4
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)
HSD17B4	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
NCT00004442	Not specified	TERMINATED	Study of Bile Acids in Patients With Peroxisomal Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHENODIOL	4	1
CHOLIC ACID	4	1
URSODIOL	4	1