Perrault syndrome

Summary

Perrault syndrome (MONDO:0017312) is a disease (an umbrella term covering 7 Mondo subtypes) caused by HSD17B4 (GenCC Definitive), with 8 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HSD17B4 (GenCC Definitive)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 984
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		124	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Very frequent (80-99%)
HP:0000013	Hypoplasia of the uterus	Frequent (30-79%)
HP:0000786	Primary amenorrhea	Frequent (30-79%)
HP:0008209	Premature ovarian insufficiency	Frequent (30-79%)
HP:0010464	Streak ovary	Frequent (30-79%)
HP:0000027	Azoospermia	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000813	Bicornuate uterus	Occasional (5-29%)
HP:0000869	Secondary amenorrhea	Occasional (5-29%)
HP:0000876	Oligomenorrhea	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0001519	Disproportionate tall stature	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Perrault syndrome
Mondo ID	MONDO:0017312
OMIM	233400
Orphanet	2855
DOID	DOID:0050857
ICD-11	256968598
SNOMED CT	93466004
UMLS	C0685838
MedGen	151934
GARD	0002542
NORD	2031
Is cancer (heuristic)	no

Also known as: gonadal dysgenesis, XX type, with deafness · Perrault syndrome · XX gonodal dysgenesis-deafness syndrome

Data availability: 984 ClinVar variants · 9 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 7 Mondo subtypes.

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

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (7): Perrault syndrome 1, 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

600 retrieved; paginated sample, class counts are floors:

375 likely benign, 117 uncertain significance, 29 pathogenic, 21 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 17 likely pathogenic, 13 benign, 8 benign/likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
208286	NM_012208.4(HARS2):c.1102G>T (p.Val368Leu)	HARS2	Pathogenic/Likely pathogenic	no assertion criteria provided
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
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
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
2025376	NM_000414.4(HSD17B4):c.715-1G>A	HSD17B4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 47 · Orphanet: 23 · 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
CLPP	Definitive	Autosomal recessive	Perrault syndrome 3	4
HSD17B4	Definitive	Autosomal recessive	Perrault syndrome	9
TWNK	Definitive	Autosomal recessive	Perrault syndrome 5	10
HARS2	Strong	Autosomal recessive	Perrault syndrome 2	4
LARS2	Strong	Autosomal recessive	Perrault syndrome 4	6
ERAL1	Moderate	Autosomal recessive	Perrault syndrome 6	3
PEX6	Limited	Autosomal recessive	Perrault syndrome	10
SGO2	Limited	Autosomal recessive	Perrault syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
LARS2	Orphanet:528091	Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
LARS2	Orphanet:642945	Perrault syndrome type 1
LARS2	Orphanet:642976	Perrault syndrome type 2
CLPP	Orphanet:642945	Perrault syndrome type 1
CLPP	Orphanet:642976	Perrault syndrome type 2
ERAL1	Orphanet:642945	Perrault syndrome type 1
ERAL1	Orphanet:642976	Perrault syndrome type 2
HARS2	Orphanet:642945	Perrault syndrome type 1
HARS2	Orphanet:642976	Perrault syndrome type 2
HSD17B4	Orphanet:300	Bifunctional enzyme deficiency
HSD17B4	Orphanet:642945	Perrault syndrome type 1
HSD17B4	Orphanet:642976	Perrault syndrome type 2
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome

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
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	gencc,clinvar
LARS2	HGNC:17095	ENSG00000011376	Q15031	Leucine–tRNA ligase, mitochondrial	gencc,clinvar
CLPP	HGNC:2084	ENSG00000125656	Q16740	ATP-dependent Clp protease proteolytic subunit, mitochondrial	gencc,clinvar
ERAL1	HGNC:3424	ENSG00000132591	O75616	GTPase Era, mitochondrial	gencc,clinvar
HARS2	HGNC:4817	ENSG00000112855	P49590	Histidine–tRNA ligase, mitochondrial	gencc,clinvar
HSD17B4	HGNC:5213	ENSG00000133835	P51659	Peroxisomal multifunctional enzyme type 2	gencc,clinvar
SGO2	HGNC:30812	ENSG00000163535	Q562F6	Shugoshin 2	gencc
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
LARS2	Leucine–tRNA ligase, mitochondrial	Catalyzes the attachment of leucine to its cognate tRNA.
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.
ERAL1	GTPase Era, mitochondrial	Probable GTPase that plays a role in the mitochondrial ribosomal small subunit assembly.
HARS2	Histidine–tRNA ligase, mitochondrial	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
HSD17B4	Peroxisomal multifunctional enzyme type 2	Bifunctional enzyme acting on the peroxisomal fatty acid beta-oxidation pathway.
SGO2	Shugoshin 2	Cooperates with PPP2CA to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.

Protein-family classification

Druggable: 6 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.75

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)	6	9.0×	2e-05
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
LARS2	Enzyme (other)	yes	6.1.1.4	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Leu-tRNA-ligase
CLPP	Enzyme (other)	yes	3.4.21.92	ClpP, ClpP_Ser_AS, ClpP/TepA
ERAL1	Other/Unknown	no		Small_GTP-bd, GTPase_Era-like, GTP-bd
HARS2	Enzyme (other)	yes	6.1.1.21	Anticodon-bd, HisRS/HisZ, aa-tRNA-synth_II
HSD17B4	Enzyme (other)	yes	4.2.1.119	SDR_fam, MaoC-like_dom, SCP2_sterol-bd_dom
SGO2	Other/Unknown	no		Shugoshin1/2
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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
gastrocnemius	2
oocyte	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
adrenal tissue	1
ventricular zone	1
hindlimb stylopod muscle	1
cerebellar cortex	1
left lobe of thyroid gland	1
right lobe of liver	1
right lobe of thyroid gland	1
secondary oocyte	1
sperm	1
body of pancreas	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
LARS2	285	ubiquitous	yes	ventricular zone, oocyte, adrenal tissue
CLPP	287	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, mucosa of transverse colon
ERAL1	256	ubiquitous	marker	mucosa of transverse colon, right hemisphere of cerebellum, cerebellar hemisphere
HARS2	272	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
HSD17B4	295	ubiquitous	marker	right lobe of thyroid gland, right lobe of liver, left lobe of thyroid gland
SGO2	225	ubiquitous	marker	oocyte, secondary oocyte, sperm
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPP	5,157
LARS2	3,406
HARS2	2,703
PEX6	2,620
HSD17B4	2,471
ERAL1	2,294
TWNK	1,390
SGO2	1,321

Intra-cohort edges

A	B	Sources
CLPP	ERAL1	string_interaction
ERAL1	LARS2	string_interaction
ERAL1	TWNK	string_interaction
HARS2	LARS2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLPP	Q16740	29
HSD17B4	P51659	7
TWNK	Q96RR1	2
ERAL1	O75616	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LARS2	Q15031	90.57
HARS2	P49590	88.44
PEX6	Q13608	69.87
SGO2	Q562F6	42.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 8 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial tRNA aminoacylation	2	129.8×	0.003	LARS2, HARS2
tRNA Aminoacylation	2	71.4×	0.006	LARS2, HARS2
Peroxisomal protein import	2	43.3×	0.011	HSD17B4, PEX6
Mitochondrial protein degradation	2	28.6×	0.018	TWNK, CLPP
TYSND1 cleaves peroxisomal proteins	1	178.4×	0.031	HSD17B4
Beta-oxidation of pristanoyl-CoA	1	142.8×	0.031	HSD17B4
Strand-asynchronous mitochondrial DNA replication	1	142.8×	0.031	TWNK
Translation	2	15.5×	0.031	LARS2, HARS2
Beta-oxidation of very long chain fatty acids	1	109.8×	0.035	HSD17B4
alpha-linolenic acid (ALA) metabolism	1	89.2×	0.039	HSD17B4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	57.1×	0.055	HSD17B4
Transcriptional activation of mitochondrial biogenesis	1	25.5×	0.107	TWNK
Amplification of signal from the kinetochores	1	24.6×	0.107	SGO2
Mitotic Spindle Checkpoint	1	19.8×	0.123	SGO2
Mitochondrial translation initiation	1	15.9×	0.130	ERAL1
Mitochondrial translation elongation	1	15.9×	0.130	ERAL1
Mitochondrial ribosome-associated quality control	1	15.3×	0.130	ERAL1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	14.6×	0.130	SGO2
Mitochondrial translation termination	1	13.7×	0.130	ERAL1
Mitotic Metaphase and Anaphase	1	12.1×	0.130	SGO2
Mitotic Anaphase	1	12.1×	0.130	SGO2
EML4 and NUDC in mitotic spindle formation	1	11.6×	0.130	SGO2
Cell Cycle Checkpoints	1	11.1×	0.130	SGO2
Resolution of Sister Chromatid Cohesion	1	10.8×	0.130	SGO2
RHO GTPases Activate Formins	1	9.7×	0.138	SGO2
Mitotic Prometaphase	1	8.7×	0.144	SGO2
RHO GTPase Effectors	1	8.5×	0.144	SGO2
M Phase	1	8.2×	0.144	SGO2
Separation of Sister Chromatids	1	7.6×	0.150	SGO2
Metabolism of proteins	2	3.1×	0.154	LARS2, HARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA aminoacylation for protein translation	2	210.7×	0.001	LARS2, HARS2
histidyl-tRNA aminoacylation	1	1053.2×	0.008	HARS2
leucyl-tRNA aminoacylation	1	1053.2×	0.008	LARS2
very long-chain fatty-acyl-CoA metabolic process	1	1053.2×	0.008	HSD17B4
mitochondrial translation	2	43.4×	0.008	LARS2, HARS2
medium-chain fatty-acyl-CoA metabolic process	1	702.2×	0.009	HSD17B4
protein import into peroxisome matrix, translocation	1	526.6×	0.011	PEX6
protein unfolding	1	421.3×	0.012	PEX6
mitochondrial transcription	1	300.9×	0.012	TWNK
protein import into peroxisome matrix, receptor recycling	1	300.9×	0.012	PEX6
meiotic sister chromatid cohesion	1	300.9×	0.012	SGO2
mitochondrial small ribosomal subunit assembly	1	263.3×	0.012	ERAL1
protein targeting to peroxisome	1	210.7×	0.012	PEX6
mitochondrial DNA replication	1	191.5×	0.012	TWNK
mitochondrial protein catabolic process	1	191.5×	0.012	CLPP
fatty acid derivative biosynthetic process	1	191.5×	0.012	HSD17B4
ribosomal small subunit assembly	1	175.5×	0.012	ERAL1
protein import into peroxisome matrix	1	175.5×	0.012	PEX6
protein hexamerization	1	175.5×	0.012	TWNK
fatty acid beta-oxidation using acyl-CoA oxidase	1	140.4×	0.014	HSD17B4
Sertoli cell development	1	140.4×	0.014	HSD17B4
membrane protein proteolysis	1	131.7×	0.014	CLPP
androgen metabolic process	1	110.9×	0.015	HSD17B4
alpha-linolenic acid metabolic process	1	110.9×	0.015	HSD17B4
peroxisome organization	1	100.3×	0.015	PEX6
very long-chain fatty acid metabolic process	1	95.8×	0.015	HSD17B4
protein quality control for misfolded or incompletely synthesized proteins	1	95.8×	0.015	CLPP
unsaturated fatty acid biosynthetic process	1	81.0×	0.018	HSD17B4
estrogen metabolic process	1	78.0×	0.018	HSD17B4
DNA-templated DNA replication	1	70.2×	0.019	TWNK

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
TWNK	0	0
LARS2	0	0
ERAL1	0	0
HARS2	0	0
HSD17B4	0	0
SGO2	0	0
PEX6	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): 6.

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

Symbol	Assays	Type breakdown
CLPP	96	Binding:96
HSD17B4	11	Binding:10, Functional:1
LARS2	1	ADMET:1
ERAL1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
LARS2	6.1.1.4	leucine-tRNA ligase
CLPP	3.4.21.92	Endopeptidase Clp
HARS2	6.1.1.21	histidine-tRNA ligase
HSD17B4	4.2.1.119	enoyl-CoA hydratase 2
PEX6	3.6.4.7	peroxisome-assembly ATPase

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	TWNK, HSD17B4
D	Druggable family + AlphaFold only, no drug	3	LARS2, HARS2, PEX6
E	Difficult family or no structure, no drug	2	ERAL1, SGO2

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)
TWNK	0	—
LARS2	1	—
ERAL1	1	—
HARS2	0	—
HSD17B4	11	—
SGO2	0	—
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.