Perrault syndrome 1

Summary

Perrault syndrome 1 (MONDO:0009300) is a disease caused by HSD17B4 (GenCC Strong), with 8 cohort genes.

At a glance

• Causal gene: HSD17B4 (GenCC Strong)
• Cohort genes: 8
• ClinVar variants: 185

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Perrault syndrome 1
Mondo ID	MONDO:0009300
OMIM	233400
Orphanet	642945
UMLS	C4551721
MedGen	1640257
GARD	0024656
Is cancer (heuristic)	no

Also known as: HSD17B4 Perrault syndrome · Perrault syndrome 1 · Perrault syndrome caused by mutation in HSD17B4 · Perrault syndrome type 1 · PRLTS1

Data availability: 185 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › Perrault syndrome › Perrault syndrome 1

Related subtypes (6): Perrault syndrome 3, Perrault syndrome 2, Perrault syndrome 4, Perrault syndrome 5, Perrault syndrome 6, Perrault syndrome 7

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

185 retrieved; paginated sample, class counts are floors:

50 likely pathogenic, 45 uncertain significance, 32 conflicting classifications of pathogenicity, 20 benign, 18 pathogenic/likely pathogenic, 10 pathogenic, 8 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579749	NM_006012.4(CLPP):c.383_399dup (p.Asp134fs)	CLPP	Pathogenic	criteria provided, single submitter
2683851	NM_004632.4(DAP3):c.1174G>A (p.Glu392Lys)	DAP3	Pathogenic/Likely pathogenic	no assertion criteria provided
2683852	NM_004632.4(DAP3):c.1184G>A (p.Cys395Tyr)	DAP3	Pathogenic/Likely pathogenic	no assertion criteria provided
2683853	NC_000001.11:g.(155747068_155747546)_(155611487_155611965)del	DAP3	Pathogenic	no assertion criteria provided
1332755	NM_000138.5:c.(1468+1_1469-1)_(1837+1_1838-1)del	FBN1	Pathogenic	criteria provided, single submitter
1027412	NM_000414.4(HSD17B4):c.652G>T (p.Val218Leu)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075802	NM_000414.4(HSD17B4):c.421C>T (p.Gln141Ter)	HSD17B4	Pathogenic	criteria provided, multiple submitters, no conflicts
137617	NM_000414.4(HSD17B4):c.1547T>C (p.Ile516Thr)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458501	NM_000414.4(HSD17B4):c.605dup (p.Thr203fs)	HSD17B4	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1685886	NM_000414.4(HSD17B4):c.532C>T (p.Leu178Phe)	HSD17B4	Pathogenic	criteria provided, single submitter
3064205	NM_000414.4(HSD17B4):c.1545C>G (p.His515Gln)	HSD17B4	Pathogenic	criteria provided, single submitter
371008	NM_000414.4(HSD17B4):c.1717_1718del (p.Leu573fs)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371366	NM_000414.4(HSD17B4):c.742C>T (p.Arg248Cys)	HSD17B4	Pathogenic	criteria provided, multiple submitters, no conflicts
371607	NM_000414.4(HSD17B4):c.67C>T (p.Arg23Ter)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495866	NM_000414.4(HSD17B4):c.1516C>T (p.Arg506Cys)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504023	NM_000414.4(HSD17B4):c.936_937del (p.His312_Thr313insTer)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554817	NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555830	NM_000414.4(HSD17B4):c.2116C>T (p.Gln706Ter)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632857	NM_000414.4(HSD17B4):c.868+1del	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
655256	NM_000414.4(HSD17B4):c.1704T>A (p.Tyr568Ter)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7656	NM_000414.4(HSD17B4):c.1369A>T (p.Asn457Tyr)	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691723	NM_004927.4(MRPL49):c.262C>T (p.Arg88Cys)	MRPL49	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691724	NM_004927.4(MRPL49):c.263G>A (p.Arg88His)	MRPL49	Pathogenic	criteria provided, single submitter
2691725	NM_004927.4(MRPL49):c.275A>C (p.His92Pro)	MRPL49	Pathogenic/Likely pathogenic	no assertion criteria provided
2691726	NM_004927.4(MRPL49):c.125_126del (p.Val42fs)	MRPL49	Pathogenic	criteria provided, single submitter
638208	NM_014672.4(PRORP):c.1454C>T (p.Ala485Val)	PRORP	Pathogenic/Likely pathogenic	no assertion criteria provided
3385343	NC_000001.11:g.(155641696_155642174)_(155747546_155777277)del	DAP3	Likely pathogenic	no assertion criteria provided
1332757	NM_000138.5(FBN1):c.1867T>A (p.Cys623Ser)	FBN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 18 · 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	Perrault syndrome	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
PRORP	Orphanet:642945	Perrault syndrome type 1
PRORP	Orphanet:642976	Perrault syndrome type 2
CLPP	Orphanet:642945	Perrault syndrome type 1
CLPP	Orphanet:642976	Perrault syndrome type 2
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HSD17B4	HGNC:5213	ENSG00000133835	P51659	Peroxisomal multifunctional enzyme type 2	gencc,clinvar
MRPL49	HGNC:1176	ENSG00000149792	Q13405	Large ribosomal subunit protein mL49	clinvar
PRORP	HGNC:19958	ENSG00000100890	O15091	Mitochondrial ribonuclease P catalytic subunit	clinvar
CLPP	HGNC:2084	ENSG00000125656	Q16740	ATP-dependent Clp protease proteolytic subunit, mitochondrial	clinvar
GPN2	HGNC:25513	ENSG00000142751	Q9H9Y4	GPN-loop GTPase 2	clinvar
DAP3	HGNC:2673	ENSG00000132676	P51398	Small ribosomal subunit protein mS29	clinvar
DLGAP3	HGNC:30368	ENSG00000116544	O95886	Disks large-associated protein 3	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	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.
PRORP	Mitochondrial ribonuclease P catalytic subunit	Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5’-ends.
CLPP	ATP-dependent Clp protease proteolytic subunit, mitochondrial	Protease component of the ClpXP complex that cleaves peptides and various proteins in an ATP-dependent process.
GPN2	GPN-loop GTPase 2	Small GTPase involved in the correct assembly of RNA polymerase RNA polymerase II and III (RNAPII and RNAPIII) complexes, ensuring their proper nuclear import.
DAP3	Small ribosomal subunit protein mS29	As a component of the mitochondrial small ribosomal subunit, it plays a role in the translation of mitochondrial mRNAs.
DLGAP3	Disks large-associated protein 3	May play a role in the molecular organization of synapses and neuronal cell signaling.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.38

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)	3	4.5×	0.047
Other/Unknown	5	1.1×	0.496

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
MRPL49	Other/Unknown	no		Ribosomal_mL49
PRORP	Enzyme (other)	yes	3.1.26.5	TPR-like_helical_dom_sf, PRORP_C, MRPP3_PIN_dom
CLPP	Enzyme (other)	yes	3.4.21.92	ClpP, ClpP_Ser_AS, ClpP/TepA
GPN2	Other/Unknown	no		Gpn, P-loop_NTPase, Gpn2
DAP3	Other/Unknown	no		Ribosomal_mS29_met, Ribosomal_mS29, P-loop_NTPase
DLGAP3	Other/Unknown	no		SAPAP
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

6 cohort genes 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	3
left lobe of thyroid gland	1
right lobe of liver	1
right lobe of thyroid gland	1
pancreatic ductal cell	1
right adrenal gland	1
right adrenal gland cortex	1
primordial germ cell in gonad	1
rectum	1
gastrocnemius	1
hindlimb stylopod muscle	1
left adrenal gland	1
stromal cell of endometrium	1
adrenal tissue	1
body of pancreas	1
colonic epithelium	1
anterior cingulate cortex	1
nucleus accumbens	1
right frontal lobe	1
decidua	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
MRPL49	300	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, pancreatic ductal cell
PRORP	177	ubiquitous	yes	primordial germ cell in gonad, rectum, mucosa of transverse colon
CLPP	287	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, mucosa of transverse colon
GPN2	252	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, left adrenal gland
DAP3	294	ubiquitous	marker	body of pancreas, adrenal tissue, colonic epithelium
DLGAP3	150	broad	yes	right frontal lobe, anterior cingulate cortex, nucleus accumbens
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPP	5,157
FBN1	3,640
DAP3	3,504
HSD17B4	2,471
GPN2	2,208
MRPL49	1,897
PRORP	1,894
DLGAP3	1,613

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL49	Q13405	85
DAP3	P51398	77
CLPP	Q16740	29
FBN1	P35555	11
HSD17B4	P51659	7
PRORP	O15091	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GPN2	Q9H9Y4	84.60
DLGAP3	O95886	50.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation	2	39.3×	0.009	MRPL49, DAP3
Mitochondrial translation initiation	2	36.2×	0.009	MRPL49, DAP3
Mitochondrial translation elongation	2	36.2×	0.009	MRPL49, DAP3
Mitochondrial ribosome-associated quality control	2	35.1×	0.009	MRPL49, DAP3
Mitochondrial translation termination	2	31.4×	0.009	MRPL49, DAP3
tRNA processing in the mitochondrion	1	326.3×	0.014	PRORP
TYSND1 cleaves peroxisomal proteins	1	203.9×	0.017	HSD17B4
rRNA processing in the mitochondrion	1	181.3×	0.017	PRORP
Beta-oxidation of pristanoyl-CoA	1	163.1×	0.017	HSD17B4
tRNA modification in the mitochondrion	1	148.3×	0.017	PRORP
Translation	2	17.7×	0.017	MRPL49, DAP3
Beta-oxidation of very long chain fatty acids	1	125.5×	0.019	HSD17B4
alpha-linolenic acid (ALA) metabolism	1	102.0×	0.021	HSD17B4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	65.3×	0.030	HSD17B4
tRNA processing	1	51.0×	0.035	PRORP
Elastic fibre formation	1	48.0×	0.035	FBN1
TGF-beta receptor signaling activates SMADs	1	46.6×	0.035	FBN1
Molecules associated with elastic fibres	1	44.1×	0.035	FBN1
Neurexins and neuroligins	1	28.1×	0.052	DLGAP3
Peroxisomal protein import	1	24.7×	0.056	HSD17B4
rRNA processing	1	20.9×	0.062	PRORP
Integrin cell surface interactions	1	19.2×	0.065	FBN1
Degradation of the extracellular matrix	1	16.8×	0.070	FBN1
Mitochondrial protein degradation	1	16.3×	0.070	CLPP
Post-translational protein phosphorylation	1	14.3×	0.076	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	12.4×	0.084	FBN1
Metabolism of proteins	2	3.5×	0.108	MRPL49, DAP3
Metabolism of RNA	1	6.0×	0.156	PRORP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 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	1203.7×	0.010	HSD17B4
medium-chain fatty-acyl-CoA metabolic process	1	802.5×	0.010	HSD17B4
post-embryonic eye morphogenesis	1	802.5×	0.010	FBN1
mitochondrial tRNA 5’-end processing	1	802.5×	0.010	PRORP
obsolete sequestering of BMP in extracellular matrix	1	601.9×	0.010	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	601.9×	0.010	FBN1
mitochondrial translation	2	49.6×	0.010	MRPL49, DAP3
negative regulation of osteoclast development	1	481.5×	0.011	FBN1
modification of postsynaptic structure	1	267.5×	0.015	DLGAP3
signaling	1	218.9×	0.015	DLGAP3
mitochondrial protein catabolic process	1	218.9×	0.015	CLPP
embryonic eye morphogenesis	1	218.9×	0.015	FBN1
fatty acid derivative biosynthetic process	1	218.9×	0.015	HSD17B4
tRNA 5’-leader removal	1	185.2×	0.015	PRORP
cellular response to insulin-like growth factor stimulus	1	185.2×	0.015	FBN1
fatty acid beta-oxidation using acyl-CoA oxidase	1	160.5×	0.016	HSD17B4
Sertoli cell development	1	160.5×	0.016	HSD17B4
membrane protein proteolysis	1	150.5×	0.016	CLPP
androgen metabolic process	1	126.7×	0.016	HSD17B4
apoptotic mitochondrial changes	1	126.7×	0.016	DAP3
alpha-linolenic acid metabolic process	1	126.7×	0.016	HSD17B4
very long-chain fatty acid metabolic process	1	109.4×	0.017	HSD17B4
protein quality control for misfolded or incompletely synthesized proteins	1	109.4×	0.017	CLPP
cell adhesion mediated by integrin	1	96.3×	0.018	FBN1
unsaturated fatty acid biosynthetic process	1	92.6×	0.018	HSD17B4
estrogen metabolic process	1	89.2×	0.018	HSD17B4
negative regulation of osteoclast differentiation	1	77.7×	0.020	FBN1
obsolete proteolysis involved in protein catabolic process	1	75.2×	0.020	CLPP
metanephros development	1	73.0×	0.020	FBN1
long-chain fatty acid biosynthetic process	1	63.4×	0.022	HSD17B4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLPP	2	3
HSD17B4	0	0
MRPL49	0	0
PRORP	0	0
GPN2	0	0
DAP3	0	0
DLGAP3	0	0
FBN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DORDAVIPRONE	3	CLPP
ONC-206	1	CLPP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
CLPP	96	Binding:96
HSD17B4	11	Binding:10, Functional:1
DAP3	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD17B4	4.2.1.119	enoyl-CoA hydratase 2
PRORP	3.1.26.5	ribonuclease P
CLPP	3.4.21.92	Endopeptidase Clp

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
DORDAVIPRONE	3	CLPP
ONC-206	1	CLPP

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	1	CLPP
C	Druggable family + PDB, no drug	2	HSD17B4, PRORP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	MRPL49, GPN2, DAP3, DLGAP3, FBN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HSD17B4	11	—
MRPL49	0	—
PRORP	0	—
GPN2	0	—
DAP3	2	—
DLGAP3	0	—
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.