Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Summary

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (MONDO:0011835) is a disease caused by POLG (GenCC Definitive), with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: POLG (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 287
• Phenotypes (HPO): 31
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001751	Abnormal vestibular function	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002403	Positive Romberg sign	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003434	Sensory ataxic neuropathy	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0006858	Impaired distal proprioception	Frequent (30-79%)
HP:0007344	Atrophy/Degeneration involving the spinal cord	Frequent (30-79%)
HP:0008619	Bilateral sensorineural hearing impairment	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0025331	Upgaze palsy	Frequent (30-79%)
HP:0031422	Abnormal morphology of the cerebellar cortex	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002578	Gastroparesis	Occasional (5-29%)
HP:0004389	Intestinal pseudo-obstruction	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mondo ID	MONDO:0011835
OMIM	607459, 613832
Orphanet	70595, 402082
DOID	DOID:0111276
UMLS	C1843851
MedGen	375302
GARD	0009998
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic, 5 · epilepsy, progressive myoclonic, type 5 · EPM5 · mitochondrial recessive ataxia syndrome (includes SANDO and SCAE) · PME type 5 · PRICKLE2 progressive myoclonic epilepsy · progressive myoclonic epilepsy caused by mutation in PRICKLE2 · progressive myoclonus epilepsy type 5 · SANDO · sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Data availability: 287 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (1): spinocerebellar ataxia with epilepsy

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

287 retrieved; paginated sample, class counts are floors:

100 uncertain significance, 76 conflicting classifications of pathogenicity, 36 pathogenic/likely pathogenic, 28 likely pathogenic, 20 pathogenic, 12 benign/likely benign, 11 benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163576	NM_002693.3(POLG):c.3104+2_3104+5del	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339608	NM_002693.3(POLG):c.660-2A>G	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341586	NM_002693.3(POLG):c.3601del (p.Ser1201fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13496	NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13497	NM_002693.3(POLG):c.911T>G (p.Leu304Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13499	NM_002693.3(POLG):c.1879C>T (p.Arg627Trp)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13500	NM_002693.3(POLG):c.2794C>T (p.His932Tyr)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13501	NM_002693.3(POLG):c.3151G>C (p.Gly1051Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13502	NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13506	NM_002693.3(POLG):c.2591A>G (p.Asn864Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13507	NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13513	NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13515	NM_002693.3(POLG):c.679C>T (p.Arg227Trp)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1412024	NM_002693.3(POLG):c.624C>A (p.Cys208Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453904	NM_002693.3(POLG):c.3482+2T>C	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455434	NM_002693.3(POLG):c.1457G>A (p.Trp486Ter)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
1458421	NM_002693.3(POLG):c.1575_1578del (p.Met525fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1961036	NM_002693.3(POLG):c.178C>T (p.Gln60Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206523	NM_002693.3(POLG):c.2420G>A (p.Arg807His)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206528	NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
206577	NM_002693.3(POLG):c.428C>T (p.Ala143Val)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206600	NM_002693.3(POLG):c.1716G>A (p.Trp572Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206606	NM_002693.3(POLG):c.1943C>G (p.Pro648Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677947	NM_002693.3(POLG):c.3643+1G>A	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677952	NM_002693.3(POLG):c.3626_3629dup (p.Tyr1210Ter)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677961	NM_002693.3(POLG):c.1356T>G (p.Tyr452Ter)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
279948	NM_002693.3(POLG):c.3014_3057del (p.Val1005fs)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279961	NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279982	NM_002693.3(POLG):c.2419C>T (p.Arg807Cys)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
280017	NM_002693.3(POLG):c.1433+1G>A	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 17 · 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
POLG	Definitive	Autosomal recessive	sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome
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
PRICKLE2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
PRICKLE2	Orphanet:402082	Progressive myoclonic epilepsy type 5
FANCI	Orphanet:84	Fanconi anemia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	gencc,clinvar
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
PRICKLE2	HGNC:20340	ENSG00000163637	Q7Z3G6	Prickle-like protein 2	clinvar
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	clinvar
POLGARF	HGNC:56246	ENSG00000291307	A0A3B3IS91	POLG alternative reading frame	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
PRICKLE2	Prickle-like protein 2	Is involved in the organization and maintenance of axon initial segment (AIS) architecture, likely cooperating with IGSF9B to regulate ANK3/ANKG localization to AIS.
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	2.4×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
PRICKLE2	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
POLGARF	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

3 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)	4
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1
gastrocnemius	1
tendon of biceps brachii	1
cauda epididymis	1
colonic epithelium	1
oviduct epithelium	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
PRICKLE2	233	ubiquitous	marker	oviduct epithelium, cauda epididymis, colonic epithelium
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
POLGARF

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
FANCI	2,312
TWNK	1,390
PRICKLE2	1,151
POLGARF	0

Intra-cohort edges

A	B	Sources
POLG	TWNK	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
FANCI	Q9NVI1	8
TWNK	Q96RR1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRICKLE2	Q7Z3G6	56.41
POLGARF	A0A3B3IS91	40.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	2	761.3×	1e-05	POLG, TWNK
Fanconi Anemia Pathway	1	92.8×	0.021	FANCI
Transcriptional activation of mitochondrial biogenesis	1	68.0×	0.021	TWNK
TP53 Regulates Transcription of DNA Repair Genes	1	60.4×	0.021	FANCI
Mitochondrial protein degradation	1	38.1×	0.026	TWNK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial DNA replication	2	766.0×	3e-05	POLG, TWNK
DNA-templated DNA replication	2	280.9×	1e-04	POLG, TWNK
DNA replication proofreading	1	1404.3×	0.003	POLG
protein localization to axon	1	842.6×	0.004	PRICKLE2
mitochondrial transcription	1	601.9×	0.004	TWNK
protein hexamerization	1	351.1×	0.006	TWNK
base-excision repair, gap-filling	1	280.9×	0.006	POLG
DNA metabolic process	1	263.3×	0.006	POLG
blastocyst formation	1	191.5×	0.008	PRICKLE2
base-excision repair	1	117.0×	0.010	POLG
Wnt signaling pathway, planar cell polarity pathway	1	113.9×	0.010	PRICKLE2
interstrand cross-link repair	1	108.0×	0.010	FANCI
positive regulation of protein ubiquitination	1	53.3×	0.019	FANCI

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4
TWNK	0	0
PRICKLE2	0	0
FANCI	0	0
POLGARF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
FANCI	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TWNK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PRICKLE2, FANCI, POLGARF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TWNK	0	POLG
PRICKLE2	0	—
FANCI	1	—
POLGARF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders