MELAS syndrome

Summary

MELAS syndrome (MONDO:0010789) is a disease (an umbrella term covering 10 Mondo subtypes) with 34 cohort genes and 28 clinical trials. The dominant Reactome pathway is Mitochondrial translation termination (10 cohort genes). Top therapeutic interventions include glycerin, idebenone, and triglycerides, medium-chain.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 34
• ClinVar variants: 604
• Phenotypes (HPO): 87
• Clinical trials: 28

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.6	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.18	Japan	Validated
Point prevalence	1-9 / 100 000	1.63	Finland	Validated
Point prevalence	>1 / 1000	236	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

87 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000726	Dementia	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002076	Migraine	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002401	Stroke-like episode	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003200	Ragged-red muscle fibers	Very frequent (80-99%)
HP:0008316	Abnormal mitochondria in muscle tissue	Very frequent (80-99%)
HP:0012429	Aplasia/Hypoplasia of the cerebral white matter	Very frequent (80-99%)
HP:0012766	Widened cerebral subarachnoid space	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000709	Psychosis	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002135	Basal ganglia calcification	Frequent (30-79%)
HP:0002331	Recurrent paroxysmal headache	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002490	Increased CSF lactate	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007159	Fluctuations in consciousness	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0010794	Impaired visuospatial constructive cognition	Frequent (30-79%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0000097	Focal segmental glomerulosclerosis	Occasional (5-29%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0000114	Proximal tubulopathy	Occasional (5-29%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0000590	Progressive external ophthalmoplegia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001045	Vitiligo	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	MELAS syndrome
Mondo ID	MONDO:0010789
MeSH	D017241
OMIM	540000
Orphanet	550
DOID	DOID:3687
ICD-10-CM	E88.41
NCIT	C84885
SNOMED CT	39925003
UMLS	C0162671
MedGen	56485
GARD	0007009
MedDRA	10053872
Is cancer (heuristic)	no

Also known as: MELAS · MELAS syndrome · mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes · mitochondrial encephalomyopathy, lactic acidosis and stroke · mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes · mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes · mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

Data availability: 604 ClinVar variants · 6 GenCC gene-disease records · 22 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › MELAS syndrome

Related subtypes (1183): Neu-Laxova syndrome, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, syndromic intellectual disability, abdominal obesity-metabolic syndrome, fibrogenesis imperfecta ossium, Fanconi renotubular syndrome, palindromic rheumatism, hepatorenal syndrome, Potter sequence, vertebral artery insufficiency, sick sinus syndrome, Tietze syndrome, toxic shock syndrome, capillary leak syndrome, dumping syndrome, FG syndrome, basilar artery insufficiency, long QT syndrome, Treacher-Collins syndrome, superior mesenteric artery syndrome, disappearing bone disease, Brown-Sequard syndrome, Froelich syndrome, diffuse infiltrative lymphocytosis syndrome, Capgras syndrome, compartment syndrome, central sleep apnea syndrome, irritable bowel syndrome, nephrotic syndrome, myalgic encephalomeyelitis/chronic fatigue syndrome, acute coronary syndrome, fibromyalgia, substance withdrawal syndrome, acute chest syndrome, Barre-Lieou syndrome, cauda equina syndrome, Kluver-Bucy syndrome, Miller Fisher syndrome, persian gulf syndrome, Reye syndrome, thoracic outlet syndrome, Waterhouse-Friderichsen syndrome, Wissler syndrome, acute respiratory distress syndrome, Achenbach syndrome, miliaria, anterior spinal artery syndrome, burning mouth syndrome, dry eye syndrome, empty sella syndrome, euthyroid sick syndrome, lateral medullary syndrome, subclavian steal syndrome, tarsal tunnel syndrome, tethered spinal cord syndrome, branchio-oto-renal syndrome, prune belly syndrome, Achard syndrome, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, Finnish type amyloidosis, Angelman syndrome, aniridia-absent patella syndrome, ankyloblepharon filiforme adnatum-cleft palate syndrome, Townes-Brocks syndrome, obstructive sleep apnea syndrome, Lown-Ganong-Levine syndrome, Behcet disease, brachydactyly-arterial hypertension syndrome, brachydactyly type A2, fibular aplasia-ectrodactyly syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, Sillence syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, dilated cardiomyopathy 1A, cat-eye syndrome, cerebrocostomandibular syndrome, Alagille syndrome, autosomal dominant chondrodysplasia punctata, cleidocranial dysplasia 1, cleidorhizomelic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Cri-du-chat syndrome, autosomal dominant deafness - onychodystrophy syndrome, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, Duane retraction syndrome, 3-M syndrome, dyschondrosteosis-nephritis syndrome, hereditary benign intraepithelial dyskeratosis, encephalopathy, recurrent, of childhood, Camurati-Engelmann disease, Felty syndrome, chromosome 16p12.1 deletion syndrome, 520kb, Frasier syndrome, Gamstorp-Wohlfart syndrome, Tourette syndrome, glaucoma-sleep apnea syndrome, renal cysts and diabetes syndrome, hypotrichosis-lymphedema-telangiectasia syndrome (grouping), GMS syndrome, gray platelet syndrome, hand-foot-genital syndrome, facial hemiatrophy, Bencze syndrome, alpha thalassemia-intellectual disability syndrome type 1, Gilbert syndrome, mullerian duct anomalies-limb anomalies syndrome, hypoparathyroidism-deafness-renal disease syndrome, chromosome 18p deletion syndrome, Pallister-Hall syndrome, ichthyosis-cheek-eyebrow syndrome, Jacobsen syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, palmoplantar keratoderma-esophageal carcinoma syndrome, Kleine-Levin syndrome, angioosteohypertrophic syndrome, congenital laryngeal web, Lenz-Majewski hyperostotic dwarfism, Noonan syndrome with multiple lentigines, lymphedema-cerebral arteriovenous anomaly syndrome, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, yellow nail syndrome, lymphedema-distichiasis syndrome, Nager acrofacial dysostosis, jaw-winking syndrome, Marfan syndrome, Melkersson-Rosenthal syndrome, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, microgastria-limb reduction defect syndrome, Mobius syndrome, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, nail-patella syndrome, Schilbach-Rott syndrome, syndromic orbital border hypoplasia, Buschke-Ollendorff syndrome, nasopalpebral lipoma-coloboma syndrome, Perry syndrome, Poland syndrome, polydactyly-myopia syndrome, Greig cephalopolysyndactyly syndrome, Prader-Willi syndrome, Guttmacher syndrome, Currarino triad, Hutchinson-Gilford progeria syndrome, progeria-short stature-pigmented nevi syndrome, Liddle syndrome, exfoliation syndrome, ptosis-strabismus-ectopic pupils syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, radial ray hypoplasia-choanal atresia syndrome, Roussy-Levy syndrome, Silver-Russell syndrome, Ruvalcaba syndrome, oculodental syndrome, Rutherfurd type, aplasia of lacrimal and salivary glands, scalp defects-postaxial polydactyly syndrome, ulnar-mammary syndrome, septooptic dysplasia, Czeizel-Losonci syndrome, polycystic ovary syndrome, stiff-person syndrome, syndactyly-polydactyly-ear lobe syndrome, HELLP syndrome, double uterus-hemivagina-renal agenesis syndrome, VACTERL/vater association, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, ptosis-vocal cord paralysis syndrome, Freeman-Sheldon syndrome, Williams syndrome, Denys-Drash syndrome, Wolf-Hirschhorn syndrome, ablepharon macrostomia syndrome, acrocallosal syndrome, PAGOD syndrome, alopecia - intellectual disability syndrome, mitochondrial DNA depletion syndrome 4a, Alstrom syndrome, aniridia-cerebellar ataxia-intellectual disability syndrome, aniridia-renal agenesis-psychomotor retardation syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, fetal akinesia deformation sequence, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, Bloom syndrome, Elsahy-Waters syndrome, campomelia, Cumming type, camptomelic syndrome, long-limb type, congenital cataract-ichthyosis syndrome, colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, hepatic fibrosis-renal cysts-intellectual disability syndrome, Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome, CHARGE syndrome, Aagenaes syndrome, infantile choroidocerebral calcification syndrome, Yunis-Varon syndrome, corneal dystrophy-perceptive deafness syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Crigler-Najjar syndrome, cataract-nephropathy-encephalopathy syndrome, Fraser syndrome, cystic fibrosis-gastritis-megaloblastic anemia syndrome, cystinuria, DOORS syndrome, high myopia-sensorineural deafness syndrome, dermochondrocorneal dystrophy, nephrogenic diabetes insipidus-intracranial calcification syndrome, diverticulosis of bowel, hernia, and retinal detachment, Dyggve-Melchior-Clausen disease, cerebellar ataxia, intellectual disability, and dysequilibrium, ectrodactyly-polydactyly syndrome, Bonnemann-Meinecke-Reich syndrome, epidermolysis bullosa simplex 5B, with muscular dystrophy, Wolcott-Rallison syndrome, ermine phenotype, eyebrow duplication-syndactyly syndrome, Fanconi-like syndrome, gingival fibromatosis-facial dysmorphism syndrome, frontofacionasal dysplasia, Fryns syndrome, German syndrome, Bernard-Soulier syndrome, triple-A syndrome, Grubben-de Cock-Borghgraef syndrome, mullerian derivatives-lymphangiectasia-polydactyly syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Hirschsprung disease-nail hypoplasia-dysmorphism syndrome, Holzgreve-Wagner-Rehder syndrome, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, growth delay-hydrocephaly-lung hypoplasia syndrome, Dubin-Johnson syndrome, ornithine translocase deficiency, acrofrontofacionasal dysostosis 2, hypertrichotic osteochondrodysplasia Cantu type, hypergonadotropic hypogonadism-cataract syndrome, primary hypergonadotropic hypogonadism-partial alopecia syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Bamforth-Lazarus syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, ichthyosis-intellectual disability-dwarfism-renal impairment syndrome, Vici syndrome, channelopathy-associated congenital insensitivity to pain, autosomal recessive, Joubert syndrome with oculorenal defect, oculocerebrofacial syndrome, Kaufman type, Landau-Kleffner syndrome, laryngo-onycho-cutaneous syndrome, Laurence-Moon syndrome, Donohue syndrome, Miller-Dieker lissencephaly syndrome, Marinesco-Sjogren syndrome, Frank-Ter Haar syndrome, Mietens syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, microcephalic primordial dwarfism, Toriello type, Say-Barber-Miller syndrome, microcephaly and chorioretinopathy 1, Galloway-Mowat syndrome, microtia with meatal atresia and conductive deafness, mucopolysaccharidosis type 6, mulibrey nanism, lethal multiple pterygium syndrome, lethal congenital contracture syndrome 1, Schwartz-Jampel syndrome, Nathalie syndrome, nephronophthisis 1, nephropathy - deafness - hyperparathyroidism syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, Netherton syndrome, Norman-Roberts syndrome, cloacal exstrophy, ichthyosis-oral and digital anomalies syndrome, Primrose syndrome, familial osteodysplasia, Anderson type, multicentric osteolysis, nodulosis, and arthropathy, osteopenia-intellectual disability-sparse hair syndrome, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, Parana hard-skin syndrome, PEHO syndrome, Imerslund-Grasbeck syndrome, Peters plus syndrome, pili torti-developmental delay-neurological abnormalities syndrome, Rabson-Mendenhall syndrome, postaxial acrofacial dysostosis, Gitelman syndrome, Wiedemann-Rautenstrauch syndrome, Acrootoocular syndrome, holoprosencephaly-postaxial polydactyly syndrome, autosomal recessive multiple pterygium syndrome, Perlman syndrome, retinitis pigmentosa-intellectual disability-deafness-hypogenitalism syndrome, EEC syndrome, SHORT syndrome, Sjogren syndrome, spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome, corneal-cerebellar syndrome, spastic ataxia-corneal dystrophy syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, familial infantile bilateral striatal necrosis, subaortic stenosis-short stature syndrome, thrombocytopenia-absent radius syndrome, thyrocerebrorenal syndrome, Pendred syndrome, VACTERL with hydrocephalus, Weaver syndrome, Werner syndrome, Wernicke-Korsakoff syndrome, wooly hair-hypotrichosis-everted lower lip-outstanding ears syndrome, de Sanctis-Cacchione syndrome, corpus callosum agenesis-abnormal genitalia syndrome, Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, X-linked lissencephaly with abnormal genitalia, X-linked myotubular myopathy-abnormal genitalia syndrome, Christianson syndrome, Armfield syndrome, Lesch-Nyhan syndrome, Atkin-Flaitz syndrome, alpha-thalassemia-myelodysplastic syndrome, deafness-intellectual disability, Martin-Probst type syndrome, fragile X-associated tremor/ataxia syndrome, fragile X syndrome, syndactyly-telecanthus-anogenital and renal malformations syndrome, X-linked dominant chondrodysplasia, Chassaing-Lacombe type, X-linked central congenital hypothyroidism with late-onset testicular enlargement, Meester-Loeys syndrome, Arts syndrome, X-linked mandibulofacial dysostosis, Abruzzo-Erickson syndrome, Aicardi syndrome, craniofrontonasal syndrome, deafness-hypogonadism syndrome, X-linked corneal dermoid, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, hydrocephaly-cerebellar agenesis syndrome, keratosis follicularis-dwarfism-cerebral atrophy syndrome, laryngeal abductor paralysis-intellectual disability syndrome, oculocerebrorenal syndrome, Menkes disease, paraplegia-intellectual disability-hyperkeratosis syndrome, mucopolysaccharidosis type 2, orofaciodigital syndrome I, otopalatodigital syndrome type 1, Pallister-W syndrome, Rett syndrome, SCARF syndrome, Simpson-Golabi-Behmel syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, trigonocephaly-short stature-developmental delay syndrome, ulnar hypoplasia-split foot syndrome, van den Bosch syndrome, Wildervanck syndrome, Kearns-Sayre syndrome, MERRF syndrome, Pearson syndrome, proximal tubulopathy-diabetes mellitus-cerebellar ataxia syndrome, pancreatic hypoplasia-diabetes-congenital heart disease syndrome, chondrodysplasia-pseudohermaphroditism syndrome, Qazi Markouizos syndrome, familial developmental dysphasia, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, CODAS syndrome, lethal hemolytic anemia-genital anomalies syndrome, HEC syndrome, anophthalmia plus syndrome, infundibulopelvic stenosis-multicystic kidney syndrome, Ayme-Gripp syndrome, dilated cardiomyopathy 1E, diaphragmatic defect-limb deficiency-skull defect syndrome, skeletal dysplasia-epilepsy-short stature syndrome, Potocki-Shaffer syndrome, amelia cleft lip palate hydrocephalus iris coloboma, human HOXA1 syndromes, dyssegmental dysplasia-glaucoma syndrome, lung agenesis-heart defect-thumb anomalies syndrome, tetrasomy 12p, chromosome 18q deletion syndrome, lymphedema-atrial septal defects-facial changes syndrome, infantile convulsions and choreoathetosis, RHYNS syndrome, Pierre Robin sequence with pectus excavatum and rib and scapular anomalies, colobomatous macrophthalmia-microcornea syndrome, Marshall-Smith syndrome, distal monosomy 13q, MPI-congenital disorder of glycosylation, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radioulnar synostosis-microcephaly-scoliosis syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, complex regional pain syndrome type 1, temtamy preaxial brachydactyly syndrome, Diamond-Blackfan anemia 2, genitopatellar syndrome, Phelan-McDermid syndrome, hypotonia-cystinuria syndrome, DNA ligase IV deficiency, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Duane-radial ray syndrome, psoriatic arthritis, neonatal ichthyosis-sclerosing cholangitis syndrome, skin fragility-woolly hair-palmoplantar keratoderma syndrome, tubulointerstitial nephritis and uveitis syndrome, caudal duplication, sweet syndrome, ichthyosis prematurity syndrome, Meacham syndrome, BNAR syndrome, PCWH syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, MEDNIK syndrome, Cerebrorenodigital syndrome, fetal valproate syndrome, Goldberg-Shprintzen syndrome, Al-Gazali syndrome, CEDNIK syndrome, osteosclerosis-ichthyosis-premature ovarian failure syndrome, cortical dysplasia-focal epilepsy syndrome, DK1-congenital disorder of glycosylation, Potocki-Lupski syndrome, Pitt-Hopkins syndrome, XFE progeroid syndrome, deafness-infertility syndrome, COG1-congenital disorder of glycosylation, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome, mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria, ANE syndrome, CLOVES syndrome, Hirschsprung disease-ganglioneuroblastoma syndrome, parkinsonism-dystonia, infantile, alpha 1-antitrypsin deficiency, COG5-congenital disorder of glycosylation, chromosome 13q14 deletion syndrome, deafness-lymphedema-leukemia syndrome, microcephaly-capillary malformation syndrome, EDICT syndrome, peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, IMAGe syndrome, short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome, microcephalic primordial dwarfism, Alazami type, intellectual disability-strabismus syndrome, estrogen resistance syndrome, Hartsfield-Bixler-Demyer syndrome, severe dermatitis-multiple allergies-metabolic wasting syndrome, alacrima, achalasia, and intellectual disability syndrome, familial episodic pain syndrome with predominantly lower limb involvement, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, polyendocrine-polyneuropathy syndrome, chronic atrial and intestinal dysrhythmia, motor developmental delay due to 14q32.2 paternally expressed gene defect, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, epilepsy with myoclonic atonic seizures, short stature, microcephaly, and endocrine dysfunction, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, PMP22-RAI1 contiguous gene duplication syndrome, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, Luscan-Lumish syndrome, even-plus syndrome, MIRAGE syndrome, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, intellectual disability-epilepsy-extrapyramidal syndrome, 48,XXYY syndrome, FRAXF syndrome, complex hereditary spastic paraplegia, aniridia-ptosis-intellectual disability-familial obesity syndrome, aniridia - intellectual disability syndrome, ankyloblepharon filiforme-imperforate anus syndrome, pentasomy X, Bardet-Biedl syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, Bartter syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, ataxia-photosensitivity-short stature syndrome, Brugada syndrome, Feingold syndrome, cardiomyopathy-cataract-hip spine disease syndrome, cataract - microcornea syndrome, autism-facial port-wine stain syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, syndromic craniosynostosis, drug rash with eosinophilia and systemic symptoms, multicentric reticulohistiocytosis, hereditary sensory and autonomic neuropathy with deafness and global delay, craniofacial microsomia, ring chromosome 10, Coffin-Siris syndrome, corpus callosum agenesis-double urinary collecting system syndrome, short rib-polydactyly syndrome, oromandibular-limb anomalies syndrome, hemophagocytic syndrome, cataract-glaucoma syndrome, diencephalic syndrome, hypereosinophilic syndrome, distal trisomy 14q, intellectual disability-cataracts-kyphosis syndrome, progressive familial intrahepatic cholestasis, thoraco-abdominal enteric duplication, oculomaxillofacial dysostosis, growth hormone insensitivity syndrome, syndromic dyslipidemia, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, eosinophilic granulomatosis with polyangiitis, axial mesodermal dysplasia spectrum, fetal hydantoin syndrome, vitamin K-antagonist embryofetopathy, fetal alcohol syndrome, methimazole embryofetopathy, Evans syndrome, Cornelia de Lange syndrome, cleft lip-retinopathy syndrome, cleft lip/palate-deafness-sacral lipoma syndrome, Crandall syndrome, syndromic microphthalmia, Cole-Carpenter syndrome, myotonic syndrome, Guillain-Barre syndrome, atypical hemolytic-uremic syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, nodular neuronal heterotopia, Hirschsprung disease-type D brachydactyly syndrome, holoprosencephaly, hydrocephalus-obesity-hypogonadism syndrome, hydrocephalus-blue sclerae-nephropathy syndrome, xeroderma pigmentosum-Cockayne syndrome complex, Joubert syndrome with ocular defect, hypogonadism-mitral valve prolapse-intellectual disability syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, hypotrichosis-intellectual disability, Lopes type, congenital ichthyosis-microcephalus-tetraplegia syndrome, Hughes-Stovin syndrome, heart-hand syndrome, ptosis-upper ocular movement limitation-absence of lacrimal punctum syndrome, syndromic agammaglobulinemia, isotretinoin syndrome, microcornea-posterior megalolenticonus-persistent fetal vasculature-coloboma syndrome, Kabuki syndrome, Kenny-Caffey syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, Kousseff syndrome, limb body wall complex, Lennox-Gastaut syndrome, Lowe-Kohn-Cohen syndrome, macrocephaly-short stature-paraplegia syndrome, primary ciliary dyskinesia, familial intestinal malrotation-facial anomalies syndrome, primary hypertrophic osteoarthropathy, Melhem-Fahl syndrome, lower limb deficiency-hypospadias syndrome, 8p23.1 microdeletion syndrome, sickle cell-beta-thalassemia disease syndrome, sickle cell-hemoglobin c disease syndrome, sickle cell-hemoglobin d disease syndrome, sickle cell-hemoglobin E disease syndrome, hereditary persistence of fetal hemoglobin-sickle cell disease syndrome, microcephaly-brain defect-spasticity-hypernatremia syndrome, microcephaly-microcornea syndrome, Seemanova type, Meier-Gorlin syndrome, Mikati-Najjar-Sahli syndrome, shoulder and girdle defects-familial intellectual disability syndrome, myopathy-growth delay-intellectual disability-hypospadias syndrome, Fuchs heterochromic iridocyclitis, microcephalic osteodysplastic primordial dwarfism types I and III, osteochondrodysplatic nanism-deafness-retinitis pigmentosa syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, oculo-skeletal-renal syndrome, olivopontocerebellar atrophy-deafness syndrome, Opitz G/BBB syndrome, imperforate oropharynx-costo vetebral anomalies syndrome, Bruck syndrome, osteoporosis-macrocephaly-blindness-joint hyperlaxity syndrome, calciphylaxis, recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome, X-linked ichthyosis syndrome, autoimmune polyendocrinopathy, renal caliceal diverticuli-deafness syndrome, tempi syndrome, syndromic oculocutaneous albinism, short stature-deafness-neutrophil dysfunction-dysmorphism syndrome, congenital varicella syndrome, polyneuropathy-intellectual disability-acromicria-premature menopause syndrome, celiac trunk compression syndrome, hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome, fetal cytomegalovirus syndrome, Reunion island Larsen syndrome, 46,XX disorder of sex development-anorectal anomalies syndrome, mitochondrial neurogastrointestinal encephalomyopathy, Baraitser-Winter cerebrofrontofacial syndrome, mirror polydactyly-vertebral segmentation-limbs defects syndrome, intellectual disability-hypotonia-skin hyperpigmentation syndrome, congenital hereditary facial paralysis-variable hearing loss syndrome, intellectual disability-microcephaly-phalangeal-facial abnormalities syndrome, Mayer-Rokitansky-Kuster-Hauser syndrome, developmental and speech delay due to SOX5 deficiency, Spigelian hernia-cryptorchidism syndrome, autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome, severe neonatal hypotonia-seizures-encephalopathy syndrome due to 5q31.3 microdeletion, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, X-linked spasticity-intellectual disability-epilepsy syndrome, spina bifida-hypospadias syndrome, hantavirus pulmonary syndrome, white matter hypoplasia-corpus callosum agenesis-intellectual disability syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, hearing loss-familial salivary gland insensitivity to aldosterone syndrome, multiple synostoses syndrome, central nervous system calcification-deafness-tubular acidosis-anemia syndrome, multiple paragangliomas associated with polycythemia, syngnathia multiple anomalies, Takayasu arteritis, severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, hypotrichosis-deafness syndrome, thalidomide embryopathy, trisomy X, trisomy 13, trisomy 18, umbilical cord ulceration-intestinal atresia syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, infantile spasms, Wolfram syndrome, epidermal nevus syndrome, digital anomalies-intellectual disability-short stature syndrome, intellectual disability-obesity-brain malformations-facial dysmorphism syndrome, Erdheim-Chester disease, Stevens-Johnson syndrome, CADDS, finger hyperphalangy - toe anomalies - severe pectus excavatum syndrome, ataxia - telangiectasia variant, growth retardation-mild developmental delay-chronic hepatitis syndrome, primary microcephaly-mild intellectual disability-young-onset diabetes syndrome, ferro-cerebro-cutaneous syndrome, dystonia-aphonia syndrome, microcephaly-complex motor and sensory axonal neuropathy syndrome, X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, intrauterine growth restriction-short stature-early adult-onset diabetes syndrome, pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa, familial chylomicronemia syndrome, caudal regression-sirenomelia spectrum, visceral heterotaxy, Holmes-Adie syndrome, microcephalic primordial dwarfism due to RTTN deficiency, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, Kallmann syndrome, Caroli syndrome, X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability, microlissencephaly-micromelia syndrome, branchiootic syndrome, Plummer-Vinson syndrome, Cushing syndrome, McCune-Albright syndrome, Meckel syndrome, SUNCT syndrome, mucopolysaccharidosis type 3, mucopolysaccharidosis type 4, congenital myasthenic syndrome, Loeys-Dietz syndrome, Alport syndrome, schisis association, Tolosa-Hunt syndrome, iridocorneal endothelial syndrome, Noonan syndrome, short fifth metacarpals-insulin resistance syndrome, progressive supranuclear palsy, benign exophthalmos syndrome, Sandifer syndrome, global developmental delay-osteopenia-ectodermal defect syndrome, tubular renal disease-cardiomyopathy syndrome, angioosteohypotrophic syndrome, 6q terminal deletion syndrome, Axenfeld-Rieger syndrome, peroxisome biogenesis disorder, ectodermal dysplasia syndrome, Seckel syndrome, Sotos syndrome, Stickler syndrome, pelvis syndrome, Susac syndrome, ischio-vertebral syndrome, BRESEK syndrome, Turner syndrome, Usher syndrome, obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome, CREST syndrome, Sheehan syndrome, polymyalgia rheumatica, autoinflammatory syndrome, neuroleptic malignant syndrome, pituitary stalk interruption syndrome, monosomy 13q34, ring chromosome 13, 48,XXXY syndrome, 49,XXXXY syndrome, hereditary continuous muscle fiber activity, Eisenmenger syndrome, Robinow syndrome, Ehlers-Danlos syndrome, hypoplastic right heart syndrome, shone complex, 48,XYYY syndrome, subcortical band heterotopia, complex regional pain syndrome type 2, faciodigitogenital syndrome, neoplastic syndrome, paraneoplastic syndrome, post-infectious syndrome, Achard-Thiers syndrome, acral dysostosis dyserythropoiesis syndrome, agnathia-microstomia-synotia, Aksu von Stockhausen syndrome, Aloi Tomasini Isaia syndrome, temporomandibular joint dysfunction syndrome, Apert-like polydactyly syndrome, arakawa syndrome 2, arena syndrome, Arnold stickler bourne syndrome, baetz-greenwalt syndrome, bagatelle Cassidy syndrome, baker Vinters syndrome, bobble-head doll syndrome, Boerhaave syndrome, Cantu Sanchez-Corona Fragoso syndrome, Cantu Sanchez-Corona Hernandez syndrome, carbon baby syndrome, Carnevale hernandez castillo syndrome, Cartwright Nelson Fryns syndrome, Charles bonnet syndrome, Parinaud syndrome, corticobasal degeneration disorder, hair defect with photosensitivity and intellectual disability syndrome, AIDS dysmorphic syndrome, congenital acardia, acute lymphoblastic leukemia congenital sporadic aniridia, aglossia and situs inversus, agyria pachygyria polymicrogyria, agyria-pachygyria type 1, Ahumada Del Castillo syndrome, alopecia congenita keratosis palmoplantaris, alpha-mannosidosis type 1, aluminosis, Mauriac syndrome, ankle defects short stature, ankyloblepharon filiforme imperforate anus, annular constricting bands, anophthalmia cleft palate micrognathia, anophthalmia esophageal atresia cryptorchidism, anotia facial palsy cardiac defect, aortic dissection lentiginosis, childhood aortic valve stenosis, arthrogryposis IUGR thoracic dystrophy, arthrogryposis multiplex congenita CNS calcification, arthrogryposis spinal muscular atrophy, asternia, atlanto-axial fusion, atrophoderma of Pierini and Pasini, Barnicoat Baraitser syndrome, Basedow’s coma, BD syndrome, Beardwell syndrome, bhaskar jagannathan syndrome, bidirectional tachycardia, bilirubin induced brain injury in the newborn, blepharo naso facial syndrome van Maldergem type, bone dysplasia corpus callosum agenesis, brachydactyly absence of distal phalanges, brachydactyly anonychia, brachydactyly small stature face anomalies, brachydactyly tibial hypoplasia, brittle bone syndrome lethal type, bronchiectasis oligospermia, Brunsting-Perry syndrome, bruyn scheltens syndrome, burn goodship syndrome, camptodactyly joint contractures and facial skeletal dysplasia, camptodactyly vertebral fusion, Cantu Sanchez-Corona Garcia-Cruz syndrome, cardiac hydatid cysts with intracavitary expansion, cardioencephalomyopathy, cardiofacial syndrome short limbs, cardiomelic syndrome stratton Koehler type, cardiomyopathy and deafness due to tRNA lysine gene mutation, cardiomyopathy diabetes deafness, cardiomyopathy hypogonadism collagenoma syndrome, cardiomyopathy hypogonadism metabolic anomalies, cardiomyopathy spherocytosis, carpo tarsal osteolysis recessive, autosomal dominant cataract, cataract skeletal anomalies, cennamo gangemi syndrome, cerebellar agenesis, cerebello-olivary atrophy, cerebral calcification cerebellar hypoplasia, cerebral calcifications opalescent teeth phosphaturia, oculo digital syndrome, chondrodysplasia, choreoacanthocytosis amyotrophic, chorioretinopathy dominant form microcephaly, Christian Demyer Franken syndrome, Christian Johnson angenieta syndrome, chromosome 3 duplication syndrome, chronic demyelinizing neuropathy with IgM monoclonal, ciliary dyskinesia-bronchiectasis, circumscribed cutaneous aplasia of the vertex, circumscribed disseminated keratosis Jadassohn lew type, cleft lip and palate malrotation cardiopathy, cleft lip and/or palate with mucous cysts of lower, cleft lip palate dysmorphism kumar type, cleft lip palate intellectual disability corneal opacity, cleft lip palate oligodontia syndactyly pili torti, cleft lip palate pituitary deficiency, cleft lip palate-tetraphocomelia, cleft lower lip cleft lateral canthi chorioretinal, cleft palate cardiac defect ectrodactyly, cleft palate colobomata radial synostosis deafness, cleft palate heart disease polydactyly absent tibia, cleft tongue, coarse face hypotonia constipation, Cohen Lockood Wyborney syndrome, type 2 collagenopathy, Collins-Sakati syndrome, coloboma porencephaly hydronephrosis, colobomata unilobar lung heart defect, colonic malakoplakia, Colver Steer Godman syndrome, Combarros Calleja Leno syndrome, complement receptor deficiency, congenital absence of the sternocleidomastoid muscle, congenital amputation, congenital aneurysms of the great vessels, congenital articular rigidity, congenital benign spinal muscular atrophy dominant, congenital cardiovascular shunt, congenital contractures, congenital craniosynostosis maternal hyperthyroiditis, congenital cystic eye, congenital heart disease ptosis hypodontia craniostosis, congenital heart disease radio ulnar synostosis intellectual disability, congenital mumps, congenital stenosis of cervical medullary canal, Dennis-Fairhurst-Moore syndrome, congenital unilateral pulmonary hypoplasia, congenital vagal hyperreflexivity, Cormier Rustin Munnich syndrome, corneal crystals myopathy neuropathy, corneal dystrophy ichthyosis microcephaly intellectual disability, corneal dystrophy pigmentary anomaly malabsorption, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cortada Koussef Matsumoto syndrome, Cortes Lacassie syndrome, craniofacial and skeletal defects, craniofacial dysostosis arthrogryposis progeroid appearance, craniofrontonasal syndrome Teebi type, craniostenosis with congenital heart disease intellectual disability, crawfurd syndrome, cutis gyratum acanthosis nigricans craniosynostosis, cutis laxa osteoporosis, Davenport-Donlan syndrome, Davis Lafer syndrome, de Hauwere Leroy adriaenssens syndrome, deafness conductive stapedial ear malformation facial palsy, deafness goiter stippled epiphyses, deafness hypospadias metacarpal and metatarsal syndrome, deafness mesenteric diverticula of small bowel neuropathy, deafness peripheral neuropathy arterial disease, deafness progressive cataract autosomal dominant, dermatocardioskeletal syndrome boronne type, dextrocardia with situs inversus, diabetes persistent mullerian ducts, diaphragmatic agenesis radial aplasia omphalocele, diaphragmatic hernia exomphalos corpus callosum agenesis, diaphragmatic hernia upper limb defects, die Smulders droog van dijk syndrome, diomedi bernardi placidi syndrome, diphallus rachischisis imperforate anus, distichiasis heart congenital anomalies, double discordia, double uterus-hemivagina-renal agenesis, Drachtman Weinblatt Sitarz syndrome, Duker-Weiss-Siber syndrome, duodenal atresia tetralogy of fallot, duplication of leg mirror foot, duplication of the thumb unilateral biphalangeal, dupont sellier chochillon syndrome, dwarfism bluish sclerae, dwarfism deafness retinitis pigmentosa, dwarfism lethal type advanced bone age, dwarfism thin bones multiple fractures, dysmorphism cleft palate loose skin, Eagle syndrome, ectrodactyly cardiopathy dysmorphism, Elliott ludman Teebi syndrome, enamel hypoplasia cataract hydrocephaly, encephalocele anencephaly, enchondromatosis dwarfism deafness, Engelhard Yatziv syndrome, enlarged vestibular aqueduct syndrome, epidermal nevus vitamin D resistant rickets, epimetaphyseal dysplasia cataract, epiphyseal dysplasia dysmorphism camptodactyly, esophageal atresia coloboma talipes, extrasystoles short stature hyperpigmentation microcephaly, facial clefting corpus callosum agenesis, facio digito genital syndrome recessive form, facio skeletal genital syndrome rippberger type, familial capillaro-venous leptomeningeal angiomatosis, Dursun syndrome, Faye-Petersen-Ward-Carey syndrome, feigenbaum Bergeron syndrome, Feingold trainer syndrome, fetal brain disruption sequence, fetal enterovirus syndrome, fetal parainfluenza virus type 3 syndrome, fetal phenothiazine syndrome, fibromatosis multiple non ossifying, fibula aplasia complex brachydactyly, fibular hypoplasia scapulo pelvic dysplasia absent, Fitz-Hugh-Curtis syndrome, focal alopecia congenital megalencephaly, focal or multifocal malformations in neuronal migration, foix chavany Marie syndrome, Fontaine farriaux blanckaert syndrome, Fraser Jequier Chen syndrome, Freiberg disease, Friedman Goodman syndrome, frontonasal malformation cloacal exstrophy, frontonasal dysplasia Klippel feil syndrome, frontonasal dysplasia phocomelic upper limbs, Fryns Fabry Remans syndrome, Fryns Smeets Thiry syndrome, Fuchs atrophia gyrata chorioideae et retinae, Fukuda-Miyanomae-Nakata syndrome, Fuqua Berkovitz syndrome, Garret-Tripp syndrome, gas bloat syndrome, Gaucher ichthyosis restrictive dermopathy, gershinibaruch Leibo syndrome, Ghose-Sachdev-Kumar syndrome, gigantism advanced bone age hoarse cry, glossopalatine ankylosis micrognathia ear anomalies, goldstein hutt syndrome, goniodysgenesis intellectual disability short stature, green sandford davison syndrome, grix Blankenship Peterson syndrome, Ho-Kaufman-McAlister syndrome, Jaffer-Beighton syndrome, Judge Misch wright syndrome, Kashani-Strom-Utley syndrome, Kasznica-Carlson-Coppedge syndrome, Katsantoni-Papadakou-Lagoyanni syndrome, Kocher-debre-Semelaigne syndrome, Koone-Rizzo-Elias syndrome, Kozlowski Brown Hardwick syndrome, Kozlowski Ouvrier syndrome, Kozlowski Rafinski Klicharska syndrome, Kozlowski Warren Fisher syndrome, Krauss Herman Holmes syndrome, Krieble Bixler syndrome, Kuster Majewski Hammerstein syndrome, Kuster syndrome, Laugier-Hunziker syndrome, Laurence-Prosser-Rocker syndrome, le Marec-Bracq-Picaud syndrome, levator syndrome, Marinesco-Sjogren-like syndrome, Milner-Khallouf-Gibson syndrome, radio-digito-facial dysplasia, Seckel like syndrome majoor-krakauer type, neonatal aspiration syndrome, muscular fibrosis multifocal obstructed vessels, short stature contractures hypotonia, Alice in Wonderland syndrome, megacystis-microcolon-intestinal hypoperistalsis syndrome, Basilicata-Akhtar syndrome, Liberfarb syndrome, craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome, cardiac, facial, and digital anomalies with developmental delay, fibrosis, neurodegeneration, and cerebral angiomatosis, Duane anomaly-myopathy-scoliosis syndrome, congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, acute radiation syndrome, monoclonal mast cell activation syndrome, oculocerebrodental syndrome, syndromic congenital sodium diarrhea, congenital brachyesophagus-intrathoracic stomach-vertebral anomalies syndrome, intellectual disability-cardiac anomalies-short stature-joint laxity syndrome, intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome, frontonasal dysplasia-bifid nose-upper limb anomalies syndrome, microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome, diaphragmatic hernia-short bowel-asplenia syndrome, warts-immunodeficiency-lymphedema-anogenital dysplasia syndrome, Cramp-fasciculation syndrome, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, blepharophimosis-intellectual disability syndrome/genitopatellar overlap syndrome, CCNK-related neurodevelopmental disorder-severe intellectual disability-facial dysmorphism syndrome, cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome, KLHL7-related Bohring-Opitz-like syndrome, KLHL7-related cold-induced sweating-like syndrome, KAT6B-related multiple congenital anomalies syndrome, oculogastrointestinal-neurodevelopmental syndrome, spastic paraparesis-cataracts-speech delay syndrome, Ruzicka-Goerz-Anton syndrome, Sammartino-Decreccio syndrome, Samson-Gardner syndrome, Samson-Viljoen syndrome, Sanderson-Fraser syndrome, Sandhaus-Ben-Ami syndrome, prostatic malacoplakia associated with prostatic abscess, Saul-Wilkes-Stevenson syndrome, macrogyria, pseudobulbar palsy and intellectual disability, Schwartz-Cohen-addad-Lambert syndrome, Schlegelberger-Grote syndrome, Schrander-stumpel-Theunissen-Hulsmans syndrome, Saal-Bulas syndrome, Sackey-Sakati-Aur syndrome, Slti-Salem syndrome, Zerres Rietschel Majewski syndrome, Zazam Sheriff Phillips syndrome, Zadik-Barak-Levin syndrome, weinstein kliman scully syndrome, thickened earlobes with conductive deafness from incus-stapes abnormalities, ichthyosis linearis circumflexa, infantile striato thalamic degeneration, Landy-Donnai syndrome, merlob grunebaum reisner syndrome, Pavone Fiumara Rizzo syndrome, pfeiffer rockelein syndrome, Pfeiffer Tietze Welte syndrome, phosphoribosylpyrophosphate synthetase deficiency, piepkorn karp hickok syndrome, podder-tolmie syndrome, pointer syndrome, richieri-costa guion-almeida cohen syndrome, Rubinstein Taybi like syndrome, ruvalcaba churesigaew myhre syndrome, short limb dwarf lethal colavita kozlowski type, Mallory-Weiss syndrome, superior vena cava syndrome, piriformis syndrome, engraftment syndrome, Adams-Stokes syndrome, Leriche syndrome, multiple organ dysfunction syndrome, posterior leukoencephalopathy syndrome, cardio-renal syndrome, Rahman syndrome, X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, Lopes-Maciel-Rodan syndrome, Stankiewicz-Isidor syndrome, Skraban-Deardorff syndrome, joint laxity, short stature, and myopia, Sweeney-Cox syndrome, Alkuraya-Kucinskas syndrome, Jaberi-Elahi syndrome, neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, hearing impairment and infertile male syndrome, cardiocutaneous syndrome, neonatal diabetes, congenital sensorineural hearing loss and congenital cataracts, cardioectodermal syndrome, cannabinoid hyperemesis syndrome, retrograde cricopharyngeus dysfunction, Zinner syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, IFAP syndrome, DICER1-related tumor predisposition, Roberts-SC phocomelia syndrome, carcinoid syndrome, Bonnevie-Ullrich syndrome, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, RNU4ATAC spectrum disorder, syndromic congenital heart disease, hand-foot syndrome, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, gastrointestinal defects and immunodeficiency syndrome 1, achalasia-alacrima syndrome, black locks with albinism and deafness syndrome, Birt-Hogg-Dube syndrome, trigeminal trophic syndrome, developmental and/or epileptic encephalopathy with spike-wave activation in sleep, syndromic microspherophakia, painful legs and moving toes syndrome, congenital aphakia-iris hypoplasia-microphthalmia-microcornea syndrome, hereditary persistence of fetal hemoglobin-intellectual disability syndrome, developmental delay-immunodeficiency-leukoencephalopathy-hypohomocysteinemia syndrome, primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome, post-cardiac arrest syndrome, early-onset obesity-hyperphagia-severe developmental delay syndrome, hereditary alpha tryptasemia syndrome, KINSSHIP syndrome, developmental delay, hypotrophy, and dysmorphic features without moebius syndrome, breast implant illness, cataracts, hearing impairment, nephrotic syndrome, and enterocolitis, craniosynostosis-facial dysmorphism-chiari-1 malformation-developmental and language delay syndrome, MYT1L-related developmental delay-intellectual disability-obesity syndrome, Houge-Janssens syndrome, xerosis and growth failure with immune and pulmonary dysfunction syndrome, Fliedner-Zweier syndrome, Lui-Jee-Baron syndrome, Long-Olsen-Distelmaier syndrome, Tan-Almurshedi syndrome, diabetes, deafness, developmental delay, and short stature syndrome, Alfadhel syndrome, Hoxha-Aliu syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, congenital insensitivity to pain syndrome, Marsili type, Yuksel-Vogel-Bauer syndrome, polydactyly-macrocephaly syndrome, pyoderma gangrenosum-acne-hidradenitis suppurativa-ankylosing spondylitis syndrome, psoriatic arthritis-pyoderma gangrenosum-acne-hidradenitis suppurativa syndrome, megalencephaly-polydactyly syndrome, Leigh syndrome, mitochondrial, auroneurodental syndrome, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, Grisel syndrome, arterial tortuosity-bone fragility syndrome, dialysis disequilibrium syndrome, brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome due to MEF2C mutation, Kariminejad neurodevelopmental syndrome, myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, brain malformation renal syndrome, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, Karayol-Borroto-Haghshenas neurodevelopmental syndrome, neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, Morimoto-Ryu-Malicdan neuromuscular syndrome, neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, neurodevelopmental disorder with variable familial hypercholanemia, Pan-Chung-Bellen syndrome, telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature, Muggenthaler-Chowdhury-Chioza syndrome, Tayoun-Maawali syndrome, ragopathy, cardiovascular-kidney-metabolic syndrome, craniofaciocardiohepatic syndrome, FICUS syndrome, Li-Takada-Miyake syndrome, Guillouet-Gordon syndrome, ICHAD syndrome, cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, oculovertebral syndrome, Alsahan-Harris syndrome, Ververi-Brady syndrome, Dursun-Ozgul neurodevelopmental syndrome, immune dysregulation, neurodevelopmental defects, and colitis, Harel-Tora neurodevelopmental syndrome, Valence-Farazi cerebellar ataxia syndrome, dyschromatosis, ichthyosis, deafness, and atopic disease, Ramond-Elliott neurodevelopmental syndrome, STAD syndrome, craniosynostosis-scoliosis syndrome, loin pain hematuria syndrome, IRF6-related condition, linkeropathy, NDUFB11-related disorders, CRYAB-related myofibrillar myopathy-cataract-cardiomyopathy spectrum disorder, TSEN2-related neurodevelopmental disorder with or without thrombotic microangiopathy, antiphospholipid syndrome

Subtypes (10): MELAS syndrome caused by mutation in MTTL1, MELAS syndrome caused by mutation in MTTQ, MELAS syndrome caused by mutation in MTTH, MELAS syndrome caused by mutation in MTTK, MELAS syndrome caused by mutation in MTTC, MELAS syndrome caused by mutation in MTTS1, MELAS syndrome caused by mutation in MTND1, MELAS syndrome caused by mutation in MTND5, MELAS syndrome caused by mutation in MTND6, MELAS syndrome caused by mutation in MTTS2

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:

225 benign, 209 uncertain significance, 91 likely benign, 37 likely pathogenic, 15 benign/likely benign, 10 pathogenic, 8 conflicting classifications of pathogenicity, 4 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9563	NC_012920.1(MT-TS1):m.7445A>G	MT-CO1	Pathogenic	reviewed by expert panel
4293139	NC_012920.1(MT-RNR1):m.758T>C	MT-ND5	Pathogenic	criteria provided, single submitter
693516	NC_012920.1(MT-ND5):m.13094T>C	MT-ND5	Pathogenic	reviewed by expert panel
9689	NC_012920.1(MT-ND6):m.14459G>A	MT-ND5	Pathogenic	reviewed by expert panel
9702	NC_012920.1(MT-ND5):m.13513G>A	MT-ND5	Pathogenic	reviewed by expert panel
9694	NC_012920.1(MT-ND6):m.14487T>C	MT-ND6	Pathogenic	reviewed by expert panel
9579	NC_012920.1(MT-TK):m.8344A>G	MT-TK	Pathogenic	reviewed by expert panel
9589	NC_012920.1(MT-TL1):m.3243A>G	MT-TL1	Pathogenic	reviewed by expert panel
9590	NC_012920.1(MT-TL1):m.3271T>C	MT-TL1	Pathogenic	reviewed by expert panel
42226	NC_012920.1(MT-TS1):m.7471dup	MT-TS1	Pathogenic	reviewed by expert panel
431952	NM_002693.3(POLG):c.2584G>A (p.Ala862Thr)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191364	NC_012920.1(MT-ATP6):m.8969G>A	MT-ATP6	Likely pathogenic	reviewed by expert panel
2687510	NC_012920.1(MT-CYB):m.15215G>A	MT-CYB	Likely pathogenic	criteria provided, single submitter
223247	NC_012920.1(MT-TL1):m.3291T>C	MT-ND1	Likely pathogenic	reviewed by expert panel
155889	NC_012920.1(MT-ND5):m.13514A>G	MT-ND5	Likely pathogenic	reviewed by expert panel
2443068	NC_012920.1(MT-ND5):m.12923G>A	MT-ND5	Likely pathogenic	criteria provided, single submitter
693440	NC_012920.1(MT-ND5):m.12425del	MT-ND5	Likely pathogenic	reviewed by expert panel
693512	NC_012920.1(MT-ND5):m.13046T>C	MT-ND5	Likely pathogenic	reviewed by expert panel
9703	NC_012920.1(MT-ND5):m.13042G>A	MT-ND5	Likely pathogenic	reviewed by expert panel
693726	NC_012920.1(MT-ND6):m.14465G>A	MT-ND6	Likely pathogenic	reviewed by expert panel
9692	NC_012920.1(MT-ND6):m.14453G>A	MT-ND6	Likely pathogenic	reviewed by expert panel
9617	NC_012920.1(MT-TE):m.14709T>C	MT-TE	Likely pathogenic	reviewed by expert panel
9618	NC_012920.1(MT-TE):m.14674T>C	MT-TE	Likely pathogenic	reviewed by expert panel
9576	NC_012920.1(MT-TF):m.616T>C	MT-TF	Likely pathogenic	reviewed by expert panel
30004	NC_012920.1(MT-TH):m.12201T>C	MT-TH	Likely pathogenic	reviewed by expert panel
9610	NC_012920.1(MT-TH):m.12147G>A	MT-TH	Likely pathogenic	reviewed by expert panel
9580	NC_012920.1(MT-TK):m.8356T>C	MT-TK	Likely pathogenic	reviewed by expert panel
9581	NC_012920.1(MT-TK):m.8363G>A	MT-TK	Likely pathogenic	reviewed by expert panel
689856	NC_012920.1(MT-TL1):m.3243A>T	MT-TL1	Likely pathogenic	reviewed by expert panel
689861	NC_012920.1(MT-TL1):m.3255G>A	MT-TL1	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 86 · 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
MT-CO1	Supportive	Mitochondrial	MELAS syndrome	4
MT-CO2	Supportive	Mitochondrial	MELAS syndrome	2
MT-ND1	Supportive	Mitochondrial	MELAS syndrome	5
MT-ND4	Supportive	Mitochondrial	MELAS syndrome	5
MT-ND5	Supportive	Mitochondrial	MELAS syndrome	5
MT-ND6	Supportive	Mitochondrial	MELAS syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-CO1	Orphanet:104	Leber hereditary optic neuropathy
MT-CO1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO1	Orphanet:550	MELAS
MT-CO1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:99845	Genetic recurrent myoglobinuria
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-ND4	Orphanet:104	Leber hereditary optic neuropathy
MT-ND4	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND4	Orphanet:550	MELAS
MT-ND4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-ND4	Orphanet:99718	Leber plus disease
MT-ND5	Orphanet:104	Leber hereditary optic neuropathy
MT-ND5	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND5	Orphanet:550	MELAS
MT-ND5	Orphanet:551	MERRF
MT-ND6	Orphanet:104	Leber hereditary optic neuropathy
MT-ND6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND6	Orphanet:550	MELAS
MT-ND6	Orphanet:99718	Leber plus disease
MT-CO2	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO2	Orphanet:550	MELAS
MT-ATP6	Orphanet:104	Leber hereditary optic neuropathy
MT-ATP6	Orphanet:225154	Familial infantile bilateral striatal necrosis
MT-ATP6	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ATP6	Orphanet:320360	MT-ATP6-related mitochondrial spastic paraplegia
MT-ATP6	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP6	Orphanet:644	NARP syndrome
MT-CO3	Orphanet:104	Leber hereditary optic neuropathy
MT-CO3	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO3	Orphanet:550	MELAS
MT-CO3	Orphanet:99845	Genetic recurrent myoglobinuria
MT-CYB	Orphanet:104	Leber hereditary optic neuropathy
MT-CYB	Orphanet:137675	Histiocytoid cardiomyopathy
MT-CYB	Orphanet:1460	Isolated complex III deficiency
MT-ND3	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND3	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:99718	Leber plus disease
MT-TE	Orphanet:254864	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
MT-TE	Orphanet:2596	Myopathy and diabetes mellitus
MT-TF	Orphanet:550	MELAS
MT-TF	Orphanet:551	MERRF
MT-TF	Orphanet:620371	Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation
MT-TH	Orphanet:550	MELAS
MT-TH	Orphanet:551	MERRF
MT-TH	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-TI	Orphanet:620371	Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation

Cohort genes → proteins

34 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	34

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	gencc,clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	gencc,clinvar
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	gencc,clinvar
MT-ND5	HGNC:7461	ENSG00000198786	P03915	NADH-ubiquinone oxidoreductase chain 5	gencc,clinvar
MT-ND6	HGNC:7462	ENSG00000198695	P03923	NADH-ubiquinone oxidoreductase chain 6	gencc,clinvar
MT-CO2	HGNC:7421	ENSG00000198712	P00403	Cytochrome c oxidase subunit 2	gencc
MT-ATP6	HGNC:7414	ENSG00000198899	P00846	ATP synthase F(0) complex subunit a	clinvar
MT-CO3	HGNC:7422	ENSG00000198938	P00414	Cytochrome c oxidase subunit 3	clinvar
MT-CYB	HGNC:7427	ENSG00000198727	P00156	Cytochrome b	clinvar
MT-ND3	HGNC:7458	ENSG00000198840	P03897	NADH-ubiquinone oxidoreductase chain 3	clinvar
MT-TA	HGNC:7475	ENSG00000210127		mitochondrially encoded tRNA-Ala (GCN)	clinvar
MT-TC	HGNC:7477	ENSG00000210140		mitochondrially encoded tRNA-Cys (UGU/C)	clinvar
MT-TD	HGNC:7478	ENSG00000210154		mitochondrially encoded tRNA-Asp (GAU/C)	clinvar
MT-TE	HGNC:7479	ENSG00000210194		mitochondrially encoded tRNA-Glu (GAA/G)	clinvar
MT-TF	HGNC:7481	ENSG00000210049		mitochondrially encoded tRNA-Phe (UUU/C)	clinvar
MT-TG	HGNC:7486	ENSG00000210164		mitochondrially encoded tRNA-Gly (GGN)	clinvar
MT-TH	HGNC:7487	ENSG00000210176		mitochondrially encoded tRNA-His (CAU/C)	clinvar
MT-TI	HGNC:7488	ENSG00000210100		mitochondrially encoded tRNA-Ile (AUU/C)	clinvar
MT-TK	HGNC:7489	ENSG00000210156		mitochondrially encoded tRNA-Lys (AAA/G)	clinvar
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	clinvar
MT-TL2	HGNC:7491	ENSG00000210191		mitochondrially encoded tRNA-Leu (CUN) 2	clinvar
MT-TM	HGNC:7492	ENSG00000210112		mitochondrially encoded tRNA-Met (AUA/G)	clinvar
MT-TN	HGNC:7493	ENSG00000210135		mitochondrially encoded tRNA-Asn (AAU/C)	clinvar
MT-TP	HGNC:7494	ENSG00000210196		mitochondrially encoded tRNA-Pro (CCN)	clinvar
MT-TQ	HGNC:7495	ENSG00000210107		mitochondrially encoded tRNA-Gln (CAA/G)	clinvar
MT-TR	HGNC:7496	ENSG00000210174		mitochondrially encoded tRNA-Arg (CGN)	clinvar
MT-TS1	HGNC:7497	ENSG00000210151		mitochondrially encoded tRNA-Ser (UCN) 1	clinvar
MT-TS2	HGNC:7498	ENSG00000210184		mitochondrially encoded tRNA-Ser (AGU/C) 2	clinvar
MT-TT	HGNC:7499	ENSG00000210195		mitochondrially encoded tRNA-Thr (ACN)	clinvar
MT-TV	HGNC:7500	ENSG00000210077		mitochondrially encoded tRNA-Val (GUN)	clinvar
MT-TW	HGNC:7501	ENSG00000210117		mitochondrially encoded tRNA-Trp (UGA/G)	clinvar
MT-TY	HGNC:7502	ENSG00000210144		mitochondrially encoded tRNA-Tyr (UAU/C)	clinvar
NDUFS1	HGNC:7707	ENSG00000023228	P28331	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-CO1	Cytochrome c oxidase subunit 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.
MT-ND5	NADH-ubiquinone oxidoreductase chain 5	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND6	NADH-ubiquinone oxidoreductase chain 6	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-CO2	Cytochrome c oxidase subunit 2	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-ATP6	ATP synthase F(0) complex subunit a	Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
MT-CO3	Cytochrome c oxidase subunit 3	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CYB	Cytochrome b	Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain.
MT-ND3	NADH-ubiquinone oxidoreductase chain 3	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
NDUFS1	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 33 · Druggable fraction: 0.03

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
Other/Unknown	33	1.7×	1e-07
Enzyme (other)	1	0.3×	0.948

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase
MT-ND5	Other/Unknown	no		Proton_antipo_N, ND/Mrp_TM, NU5C-like
MT-ND6	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6
MT-CO2	Other/Unknown	no		Copper_CuA, CcO_II-like_C, Cupredoxin
MT-ATP6	Other/Unknown	no		ATP_synth_F0_asu, ATP_synth_F0_asu_AS, F0_ATP_A_sf
MT-CO3	Other/Unknown	no		Cyt_c_oxidase-like_su3, Cyt_c_oxidase_su3_a-hlx, Cyt_c/ubiquinol_Oxase_su3
MT-CYB	Other/Unknown	no		Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM
MT-ND3	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf
MT-TA	Other/Unknown	no
MT-TC	Other/Unknown	no
MT-TD	Other/Unknown	no
MT-TE	Other/Unknown	no
MT-TF	Other/Unknown	no
MT-TG	Other/Unknown	no
MT-TH	Other/Unknown	no
MT-TI	Other/Unknown	no
MT-TK	Other/Unknown	no
MT-TL1	Other/Unknown	no
MT-TL2	Other/Unknown	no
MT-TM	Other/Unknown	no
MT-TN	Other/Unknown	no
MT-TP	Other/Unknown	no
MT-TQ	Other/Unknown	no
MT-TR	Other/Unknown	no
MT-TS1	Other/Unknown	no
MT-TS2	Other/Unknown	no
MT-TT	Other/Unknown	no
MT-TV	Other/Unknown	no
MT-TW	Other/Unknown	no
MT-TY	Other/Unknown	no
NDUFS1	Other/Unknown	no		NADH_UbQ_OxRdtase_75kDa_su_CS, 2Fe-2S_ferredoxin-type, Mopterin_OxRdtase
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

21 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)	34
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skeletal muscle tissue	14
apex of heart	13
sural nerve	12
duodenum	5
granulocyte	4
rectum	4
prefrontal cortex	4
caudate nucleus	4
zone of skin	3
mucosa of stomach	3
adrenal tissue	3
putamen	3
adipose tissue	2
frontal cortex	2
right uterine tube	2
left uterine tube	2
amygdala	2
vermiform appendix	2
stromal cell of endometrium	1
gastrocnemius	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-ND4	134	ubiquitous	marker	right uterine tube, apex of heart, zone of skin
MT-ND5	247	ubiquitous	marker	heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus
MT-ND6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, right uterine tube
MT-CO2	134	ubiquitous	marker	granulocyte, rectum, transverse colon
MT-ATP6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, descending thoracic aorta
MT-CO3	134	ubiquitous	marker	zone of skin, endocervix, rectum
MT-CYB	134	ubiquitous	marker	apex of heart, pituitary gland, zone of skin
MT-ND3	134	ubiquitous	marker	granulocyte, adipose tissue, left lobe of thyroid gland
MT-TA	118		yes	skeletal muscle tissue, duodenum, apex of heart
MT-TC	118		marker	skeletal muscle tissue, duodenum, adrenal tissue
MT-TD	116	broad	yes	apex of heart, sural nerve, skeletal muscle tissue
MT-TE	118	broad	marker	skeletal muscle tissue, sural nerve, apex of heart
MT-TF	118	ubiquitous	marker	prefrontal cortex, amygdala, skeletal muscle tissue
MT-TG	117	tissue_specific	yes	apex of heart, sural nerve, skeletal muscle tissue
MT-TH	118	broad	yes	sural nerve, apex of heart, putamen
MT-TI	117	broad	yes	skeletal muscle tissue, sural nerve, putamen
MT-TK	118		yes	sural nerve, skeletal muscle tissue, caudate nucleus
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
MT-TL2	118	broad	yes	apex of heart, putamen, caudate nucleus
MT-TM	118		marker	prefrontal cortex, apex of heart, caudate nucleus
MT-TN	118	tissue_specific	yes	duodenum, skeletal muscle tissue, vermiform appendix
MT-TP	118	broad	marker	rectum, smooth muscle tissue, mucosa of stomach
MT-TQ	118	tissue_specific	yes	skeletal muscle tissue, sural nerve, apex of heart
MT-TR	116	tissue_specific	yes	sural nerve, skeletal muscle tissue, apex of heart
MT-TS1	118	tissue_specific	yes	duodenum, apex of heart, vermiform appendix
MT-TS2	116	ubiquitous	marker	sural nerve, apex of heart, prefrontal cortex
MT-TT	118	broad	yes	skeletal muscle tissue, sural nerve, substantia nigra
MT-TV	118	ubiquitous	marker	sural nerve, prefrontal cortex, amygdala

Protein interactions among cohort

Intra-cohort edges: 37.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS1	3,899
MT-CO1	3,547
MT-ND1	3,537
POLG	3,400
MT-CYB	3,317
MT-CO2	3,057
MT-ND3	2,923
MT-ATP6	2,869
MT-ND5	2,825
MT-CO3	1,791

Intra-cohort edges

A	B	Sources
MT-ATP6	MT-CO1	string_interaction
MT-ATP6	MT-CO2	string_interaction
MT-ATP6	MT-CO3	string_interaction
MT-ATP6	MT-CYB	string_interaction
MT-ATP6	MT-ND1	string_interaction
MT-ATP6	MT-ND3	string_interaction
MT-ATP6	MT-ND5	string_interaction
MT-ATP6	MT-ND6	string_interaction
MT-CO1	MT-CO2	string_interaction
MT-CO1	MT-CO3	string_interaction
MT-CO1	MT-CYB	string_interaction
MT-CO1	MT-ND1	string_interaction
MT-CO1	MT-ND3	string_interaction
MT-CO1	MT-ND5	string_interaction
MT-CO1	MT-ND6	string_interaction
MT-CO2	MT-CO3	intact, string_interaction
MT-CO2	MT-CYB	string_interaction
MT-CO2	MT-ND3	string_interaction
MT-CO2	MT-ND5	string_interaction
MT-CO2	MT-ND6	string_interaction
MT-CO2	POLG	string_interaction
MT-CO3	MT-CYB	string_interaction
MT-CO3	MT-ND1	string_interaction
MT-CO3	MT-ND3	string_interaction
MT-CO3	MT-ND5	string_interaction
MT-CO3	MT-ND6	string_interaction
MT-CYB	MT-ND1	string_interaction
MT-CYB	MT-ND3	string_interaction
MT-CYB	MT-ND5	string_interaction
MT-CYB	MT-ND6	string_interaction
MT-ND1	MT-ND3	string_interaction
MT-ND1	MT-ND5	string_interaction
MT-ND1	MT-ND6	string_interaction
MT-ND3	MT-ND5	string_interaction
MT-ND3	MT-ND6	string_interaction
MT-ND5	MT-ND6	string_interaction
MT-ND6	NDUFS1	biogrid_interaction

Structural data

PDB: 12 · AlphaFold-only: 0 · No structure: 22

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
MT-ATP6	P00846	10
MT-ND4	C0HME5	7
MT-ND5	P03915	7
NDUFS1	P28331	7
MT-ND1	P03886	5
MT-ND6	P03923	5
MT-CYB	P00156	5
MT-ND3	P03897	5
MT-CO2	P00403	4
MT-CO1	P00395	3
MT-CO3	P00414	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 34 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation termination	10	91.5×	3e-18	MT-CO1, MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ATP6, MT-CO2, MT-CO3 (+2 more)
Respiratory electron transport	10	79.3×	6e-18	MT-CO1, MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-CO2, MT-CO3, MT-CYB (+2 more)
Mitochondrial protein degradation	7	66.6×	1e-11	MT-CO1, MT-ND1, MT-ND5, MT-ND6, MT-ATP6, MT-CO2, NDUFS1
Complex I biogenesis	6	82.8×	1e-10	MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ND3, NDUFS1
Complex IV assembly	3	57.1×	5e-05	MT-CO1, MT-CO2, MT-CO3
Cytoprotection by HMOX1	3	46.0×	9e-05	MT-CO1, MT-CO2, MT-CO3
TP53 Regulates Metabolic Genes	3	32.4×	2e-04	MT-CO1, MT-CO2, MT-CO3
Aerobic respiration and respiratory electron transport	2	14.8×	0.016	MT-ATP6, NDUFS1
Strand-asynchronous mitochondrial DNA replication	1	95.2×	0.019	POLG
Formation of ATP by chemiosmotic coupling	1	47.6×	0.033	MT-ATP6
Complex III assembly	1	36.6×	0.039	MT-CYB
Cristae formation	1	28.8×	0.046	MT-ATP6
Mitochondrial biogenesis	1	14.0×	0.085	MT-ATP6
Organelle biogenesis and maintenance	1	5.5×	0.191	MT-ATP6
Metabolism of proteins	2	2.1×	0.269	MT-ATP6, NDUFS1
Metabolism	2	1.9×	0.277	MT-ATP6, NDUFS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proton motive force-driven mitochondrial ATP synthesis	7	153.6×	2e-13	MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ATP6, MT-ND3, NDUFS1
aerobic respiration	7	144.6×	2e-13	MT-CO1, MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ND3, NDUFS1
mitochondrial electron transport, NADH to ubiquinone	6	179.3×	4e-12	MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ND3, NDUFS1
cellular respiration	5	180.0×	4e-10	MT-CO1, MT-CO2, MT-CO3, MT-CYB, NDUFS1
mitochondrial respiratory chain complex I assembly	5	171.3×	4e-10	MT-ND1, MT-ND4, MT-ND5, MT-ND6, NDUFS1
electron transport coupled proton transport	3	1053.2×	7e-09	MT-ND4, MT-ND5, MT-CYB
response to hypoxia	6	47.9×	7e-09	MT-CO1, MT-ND1, MT-ND4, MT-ND5, MT-CO2, MT-CYB
mitochondrial electron transport, cytochrome c to oxygen	3	191.5×	2e-06	MT-CO1, MT-CO2, MT-CO3
response to copper ion	2	255.3×	1e-04	MT-CO1, MT-CYB
response to hyperoxia	2	187.2×	2e-04	MT-ATP6, MT-CYB
response to ethanol	3	36.6×	2e-04	MT-ND4, MT-CO2, MT-CYB
cerebellum development	2	59.8×	0.002	MT-CO1, MT-ND4
ATP synthesis coupled electron transport	1	1404.3×	0.002	MT-CO2
response to D-galactosamine	1	1404.3×	0.002	MT-CYB
response to cobalamin	1	702.2×	0.004	MT-CYB
DNA replication proofreading	1	468.1×	0.006	POLG
response to oxidative stress	2	21.8×	0.009	MT-CO1, MT-ND3
respiratory chain complex IV assembly	1	200.6×	0.011	MT-CO3
response to mercury ion	1	200.6×	0.011	MT-CYB
response to light intensity	1	175.5×	0.012	MT-ND3
response to hydroperoxide	1	140.4×	0.014	MT-ND1
response to glucagon	1	140.4×	0.014	MT-CYB
mitochondrial DNA replication	1	127.7×	0.014	POLG
mitochondrial electron transport, ubiquinol to cytochrome c	1	108.0×	0.016	MT-CYB
base-excision repair, gap-filling	1	93.6×	0.018	POLG
DNA metabolic process	1	87.8×	0.018	POLG
response to xenobiotic stimulus	2	11.5×	0.019	MT-ND1, MT-CYB
respiratory electron transport chain	1	70.2×	0.021	MT-CO1
proton motive force-driven ATP synthesis	1	66.9×	0.022	MT-ATP6
response to cadmium ion	1	61.1×	0.023	MT-CYB

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Arginine, Dichloroacetic Acid, Idebenone.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 32

Druggability breadth: 11 of 34 evidence-associated genes (32%) 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
MT-CO2	CELECOXIB
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO2	6	4
POLG	1	4
MT-CO1	0	0
MT-ND1	0	0
MT-ND4	0	0
MT-ND5	0	0
MT-ND6	0	0
MT-ATP6	0	0
MT-CO3	0	0
MT-CYB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
ADEFOVIR DIPIVOXIL	4	POLG
TOLFENAMIC ACID	2	MT-CO2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MT-CO2	47	Binding:41, ADMET:5, Toxicity:1
POLG	33	Binding:30, ADMET:2, Functional:1
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1
MT-ND1	5	Binding:5
NDUFS1	5	Binding:5
MT-ND5	4	Binding:4
MT-ND6	4	Binding:4
MT-ND3	4	Binding:4
MT-ATP6	1	Binding:1
MT-CO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MT-CO1	7.1.1.9	cytochrome-c oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 34; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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)
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
ADEFOVIR DIPIVOXIL	4	POLG
TOLFENAMIC ACID	2	MT-CO2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MT-CO2, POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MT-CO1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	31	MT-ND1, MT-ND4, MT-ND5, MT-ND6, MT-ATP6, MT-CO3, MT-CYB, MT-ND3, MT-TA, MT-TC (+21 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MT-CO1	19	MT-CO2
MT-CO3	1	MT-CO2
MT-ND1	5	—
MT-ND4	0	—
MT-ND5	4	—
MT-ND6	4	—
MT-ATP6	1	—
MT-CYB	0	—
MT-ND3	4	—
MT-TA	0	—
MT-TC	0	—
MT-TD	0	—
MT-TE	0	—
MT-TF	0	—
MT-TG	0	—
MT-TH	0	—
MT-TI	0	—
MT-TK	0	—
MT-TL1	0	—
MT-TL2	0	—
MT-TM	0	—
MT-TN	0	—
MT-TP	0	—
MT-TQ	0	—
MT-TR	0	—
MT-TS1	0	—
MT-TS2	0	—
MT-TT	0	—
MT-TV	0	—
MT-TW	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	9
Not specified	9
PHASE1	4
PHASE1/PHASE2	2
EARLY_PHASE1	2
PHASE4	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01831934	PHASE4	COMPLETED	Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT06644534	PHASE2	RECRUITING	A Study to Assess TTI-0102 vs Placebo in MELAS Patients
NCT06792500	PHASE1/PHASE2	RECRUITING	A Basket Clinical Study to Assess Glycerol Tributyrate in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like Episodes (MELAS) or Leber’s Hereditary Optic Neuropathy-Plus (LHON-Plus)
NCT00068913	PHASE2	UNKNOWN	Evaluating the Effectiveness of a Dichloroacetate in MELAS Syndrome
NCT00887562	PHASE2	COMPLETED	Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes
NCT01603446	PHASE2	COMPLETED	L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04475549	PHASE2	TERMINATED	Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03056209	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetic Study of KL1333 in Healthy Male Volunteers
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT03952234	PHASE1	COMPLETED	L-Citrulline Dose Finding Safety Study in MELAS
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT01339494	EARLY_PHASE1	COMPLETED	Nitric Oxide Production in MELAS Syndrome
NCT01532791	Not specified	RECRUITING	Natural History Study - Mitochondrial Disease
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06013397	Not specified	NOT_YET_RECRUITING	Effectiveness of Ketogenic Diet in MELAS Syndrome
NCT00004353	Not specified	COMPLETED	Study of the Metabolism of Pyruvate and Related Problems in Patients With Lactic Acidemia
NCT02114554	Not specified	UNKNOWN	Mitochondrial nt3243 A>G Mutation in Taiwan
NCT03432871	Not specified	COMPLETED	Nicotinamide Riboside and Mitochondrial Biogenesis
NCT04948138	Not specified	COMPLETED	Glutamine Supplement in MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes) Syndrome
NCT05255328	Not specified	UNKNOWN	Clinical Long Term Evaluation of Glutamine Supplement in MELAS Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GLYCERIN	4	1
IDEBENONE	4	1
TRIGLYCERIDES, MEDIUM-CHAIN	4	1
SONLICROMANOL	3	5
ARGININE	3	2
DICHLOROACETIC ACID	3	1
L-CITRULLINE	3	1
MEDIUM-CHAIN TRIGLYCERIDES	3	1
NICOTINAMIDE RIBOSIDE	3	1
NAPAZIMONE	2	2
ZAGOCIGUAT	2	1