HSD17B4

Chr 5AR

hydroxysteroid 17-beta dehydrogenase 4

Also known as: DBP, MFE-2, MFP-2, MPF-2, PRLTS1, SDR8C1

NCBI Gene: 3295ENSG00000133835UniProt: P51659

The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

Primary Disease Associations & Inheritance

D-bifunctional protein deficiencyMIM #261515
AR
Perrault syndrome 1MIM #233400
AR
1538
ClinVar variants
55
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HSD17B4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 Pathogenic / Likely Pathogenic· 186 VUS of 1538 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.74LOEUF
pLI 0.000
Z-score 2.91
OE 0.53 (0.38–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.28Z-score
OE missense 1.04 (0.96–1.13)
426 obs / 410.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.53 (0.38–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.96–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 23 / 43.8Missense obs/exp: 426 / 410.3Syn Z: -0.98

ClinVar Variant Classifications

1538 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic35
VUS186
Likely Benign222
Benign6
Conflicting5
20
Pathogenic
35
Likely Pathogenic
186
VUS
222
Likely Benign
6
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
2
11
0
20
Likely Pathogenic
24
5
6
0
35
VUS
2
160
16
8
186
Likely Benign
0
6
152
64
222
Benign
0
0
6
0
6
Conflicting
—5
Total3317319172474

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HSD17B4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HSD17B4-related D-bifunctional protein deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

D-bifunctional protein deficiency

MIM #261515

Molecular basis of disorder known

Autosomal recessive

Perrault syndrome 1

MIM #233400

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.
De Michele G et al.·Cerebellum
2024Review
Rapid whole-genome sequencing identifies a homozygous novel variant, His540Arg, in HSD17B4 resulting in D-bifunctional protein deficiency disorder diagnosis.
Savage L et al.·Cold Spring Harb Mol Case Stud
2020Functional
Exome sequencing reveals pathogenic mutations in the LARS2 and HSD17B4 genes associated with Perrault syndrome and D-bifunctional protein deficiency in Moroccan families.
Idyahia A et al.·Mol Biol Rep
2024Functional
New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.
Faridi R et al.·Hum Genet
2022Review
Expanding the genotypic spectrum of Perrault syndrome.
Demain LA et al.·Clin Genet
2017
Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency.
Lieber DS et al.·BMC Med Genet
2014Case report
Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.
Yamashita S et al.·Sci Rep
2020
Examining the role of mitochondrial genetic variation in nicotine dependence.
Giannoulis SV et al.·Psychiatry Res
2022Meta-analysis
Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series.
Gagnon C et al.·Horm Res Paediatr
2023Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
One novel HSD17B4 mutation in association with D-bifunctional protein deficiency: a case report and literature review.
Xiong L et al.·Front Pediatr
2025🔓 Open AccessReview
Case Report: D-bifunctional protein deficiency caused by novel compound heterozygote HSD17B4 variants in a neonate in China.
Liu H et al.·Front Genet
2025🔓 Open AccessFunctional
D-Bifunctional Protein Deficiency Type III: Two Turkish Cases and a Novel HSD17B4 Gene Variant.
Erdal AE et al.·Mol Syndromol
2026Cohort
HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA.
Bae JE et al.·Nat Commun
2025🔓 Open Access
DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma.
Zhang Z et al.·Drug Resist Updat
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools