HSD17B4

protein-coding

hydroxysteroid 17-beta dehydrogenase 4, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

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]

MANE transcript

NM_000414.4

Inheritance

ClinVar variants

P:295U:390B:349

Top phenotype

Perrault syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr5:119,452,465-119,637,199

External References & Databases

Ensembl (ENSG00000133835)

Transcript & Mutation Effects

hg38 • Region Span ~184.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Perrault syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009300

Submitter: Labcorp Genetics (formerly Invitae)

d-bifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: Ambry Genetics

d-bifunctional protein deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: PanelApp Australia

Perrault syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009300

Submitter: PanelApp Australia

d-bifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: Natera

d-bifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: G2P

d-bifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: Myriad Women's Health

d-bifunctional protein deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: Labcorp Genetics (formerly Invitae)

d-bifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009855

Submitter: ClinGen

HSD17B4 was first reported in relation to autosomal recessive d-bifunctional protein deficiency in 1997 (Suzuki et al., PMID: 9345094). At least 14 unique variants (missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 14.5 points. Variants in this gene have been reported in at least 10 probands in 9 publications (PMIDs: 30396834, 11992265, 24553428, 23181892, 11743515, 20673864, 9345094, 9482850, 9915948). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by animal models and functional assays. In summary, HSD17B4 is definitively associated with autosomal recessive d-bifunctional protein deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability among the following disease entities: (1) D-bifunctional protein deficiency (MIM: 261515) and (2) Perrault syndrome 1 (MIM: 233400). Therefore, all of the disease entities have been lumped into one disease entity, d-bifunctional protein deficiency.

Perrault syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017312

Submitter: ClinGen

The HSD17B4 gene has been associated with autosomal recessive Perrault syndrome using the ClinGen Clinical Validity Framework as of 1/10/2018. This association was made using case-level data only. At least 19 missense, nonsense, frameshift variants and splice-site variants have been reported in humans. HSD17B4 was first associated with this disease in humans as early as 2010 (Pierce et al.). Association was scored in at least 7 probands in 6 publications (20673864, 23181892, 24553428, 24602372, 28830375, 27790638). Perrault syndrome is characterized by ovarian dysgenesis in females and often azoospermia in males, as well as childhood to adult onset sensorineural hearing loss and ataxia. More severe types of DBP deficiency occur which cause severe phenotypes and infant mortality. That is outside the scope of this curation, but is important to note. Very little experimental evidence exists for HSD17B4 and Perrault syndrome. In summary, HSD17B4 is definitively associated with autosomal recessive Perrault syndrome.

Clinical Genomic Database (CGD)

Perrault syndrome 1AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Obstetric

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: The condition may be clinically recognizable in females, and the exact onset of hearing loss is unclear, but evidence suggests a prelingual onset

Refs: 4061497; 2868085; 2882519; 2921319; 2122104; 1357231; 8147505; 8279468; 9482850; 9915948; 10400999; 11992265; 11743515; 15216544; 16385454; 20673864; 23181892; 24553428

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HSD17B4 variants in ClinVar

11 Conditions Cataloged

Bifunctional peroxisomal enzyme deficiencyTotal: 1191

Perrault syndromeTotal: 945

not providedTotal: 296

HSD17B4-related disorderTotal: 146

Perrault syndrome 1Total: 124

Inborn genetic diseasesTotal: 112

not specifiedTotal: 100

Isolated cerebellar hypoplasia/agenesisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000414.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	13 clinvar	321 clinvar	2 clinvar	337
missense	7 clinvar	49 clinvar	359 clinvar	22 clinvar	4 clinvar	441
nonsense	24 clinvar	26 clinvar				50
start loss		4 clinvar				4
frameshift	29 clinvar	80 clinvar	5 clinvar			114
splice donor/acceptor (+/-2bp)	5 clinvar	70 clinvar	13 clinvar			88
Total	65	230	390	343	6	1034

Highest pathogenic variant AF is 0.00032841007

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000414.4	RefSeq	NP_000405.1	24	MANE Select
ENST00000510025.7	Ensembl	ENSP00000424940.3	24	MANE Select
NM_001199291.3	RefSeq	NP_001186220.1	25	Standard
NM_001199292.2	RefSeq	NP_001186221.1	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hsd17b4	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

hsd17b4

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis
Congenital Bile Acid Synthesis Defect Type II

Biological Process

very long-chain fatty acid metabolic process
osteoblast differentiation
protein targeting to peroxisome
fatty acid beta-oxidation
bile acid biosynthetic process

Molecular Function

3-hydroxyacyl-CoA dehydrogenase activity
signaling receptor binding
long-chain-enoyl-CoA hydratase activity
isomerase activity
3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA hydratase activity

Cellular Component

peroxisome
peroxisomal membrane
peroxisomal matrix
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000504811
Coding exons: 25
Length: 184757
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.275	426	410	1.04	0.0000209	4954
Missense (PolyPhen)		106	134.69	0.78699		1640
Synonymous	-0.977	149	135	1.11	0.00000670	1453
Loss of Function	2.91	23	43.8	0.526	0.00000186	591

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00023	0.00022	rare
South Asian	0.00029	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Bifunctional enzyme acting on the peroxisomal beta- oxidation pathway for fatty acids. Catalyzes the formation of 3- ketoacyl-CoA intermediates from both straight-chain and 2-methyl- branched-chain fatty acids. {ECO:0000269|PubMed:8902629, ECO:0000269|PubMed:9089413}.;
Disease: DISEASE: Perrault syndrome 1 (PRLTS1) [MIM:233400]: A sex- influenced disorder characterized by sensorineural deafness in both males and females and ovarian dysgenesis in females. Some patients also have neurologic manifestations, including mild mental retardation and cerebellar and peripheral nervous system involvement. {ECO:0000269|PubMed:20673864}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.497

Intolerance Scores

LoFtool: 0.233
RVIS EVS: 0.27
RVIS percentile EVS: 70.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.853

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High