Cowden disease

Summary

Cowden disease (MONDO:0016063) is a disease (an umbrella term covering 8 Mondo subtypes) with 11 cohort genes and 13 clinical trials. The dominant Reactome pathway is Maturation of TCA enzymes and regulation of TCA cycle (3 cohort genes). Top therapeutic interventions include everolimus, fludeoxyglucose f 18, and dactolisib.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 675
• Phenotypes (HPO): 57
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.45	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000853	Goiter	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0003002	Breast carcinoma	Very frequent (80-99%)
HP:0005595	Generalized hyperkeratosis	Very frequent (80-99%)
HP:0008069	Neoplasm of the skin	Very frequent (80-99%)
HP:0012733	Macule	Very frequent (80-99%)
HP:0012740	Papilloma	Very frequent (80-99%)
HP:0100780	Conjunctival hamartoma	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0200063	Colorectal polyposis	Very frequent (80-99%)
HP:0000036	Abnormality of the penis	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000221	Furrowed tongue	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000820	Abnormality of the thyroid gland	Frequent (30-79%)
HP:0000995	Melanocytic nevus	Frequent (30-79%)
HP:0001048	Cavernous hemangioma	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001482	Subcutaneous nodule	Frequent (30-79%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0002858	Meningioma	Frequent (30-79%)
HP:0004390	Hamartomatous polyposis	Frequent (30-79%)
HP:0009720	Adenoma sebaceum	Frequent (30-79%)
HP:0010614	Fibroma	Frequent (30-79%)
HP:0012032	Lipoma	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0100579	Mucosal telangiectasiae	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000130	Abnormality of the uterus	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000771	Gynecomastia	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005374	Cellular immunodeficiency	Occasional (5-29%)
HP:0005584	Renal cell carcinoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cowden disease
Mondo ID	MONDO:0016063
MeSH	D006223
OMIM	158350
Orphanet	201
DOID	DOID:6457
NCIT	C3076
SNOMED CT	58037000
UMLS	C0018553
MedGen	5420
GARD	0006202
MedDRA	10051906
Is cancer (heuristic)	no

Also known as: CD · Cowden disease · Cowden syndrome · Cowden’s disease · MHAM · multiple hamartoma syndrome

Data availability: 675 ClinVar variants · 9 GenCC gene-disease records · 5 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Cowden disease

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (8): Cowden syndrome 1, Cowden syndrome 2, Cowden syndrome 3, Cowden syndrome 4, Cowden syndrome 5, Cowden syndrome 6, Cowden syndrome 7, sacral hemangiomas multiple congenital abnormalities

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:

270 likely benign, 226 uncertain significance, 32 pathogenic, 31 conflicting classifications of pathogenicity, 18 benign/likely benign, 12 pathogenic/likely pathogenic, 6 benign, 3 likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1057635	NM_006218.4(PIK3CA):c.2908G>A (p.Glu970Lys)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156446	NM_006218.4(PIK3CA):c.353G>A (p.Gly118Asp)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
1691391	NM_006218.4(PIK3CA):c.3061T>C (p.Tyr1021His)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179173	NM_006218.4(PIK3CA):c.3129G>A (p.Met1043Ile)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217291	NM_006218.4(PIK3CA):c.311C>T (p.Pro104Leu)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217292	NM_006218.4(PIK3CA):c.3129G>T (p.Met1043Ile)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
217293	NM_006218.4(PIK3CA):c.1635G>T (p.Glu545Asp)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
280875	NM_006218.4(PIK3CA):c.323G>A (p.Arg108His)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31944	NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)	PIK3CA	Pathogenic	reviewed by expert panel
31945	NM_006218.4(PIK3CA):c.1258T>C (p.Cys420Arg)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376049	NM_006218.4(PIK3CA):c.263G>A (p.Arg88Gln)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376246	NM_006218.4(PIK3CA):c.3062A>G (p.Tyr1021Cys)	PIK3CA	Pathogenic	criteria provided, single submitter
376470	NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376476	NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys)	PIK3CA	Pathogenic	reviewed by expert panel
376478	NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376498	NM_006218.4(PIK3CA):c.1030G>A (p.Val344Met)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
39703	NM_006218.4(PIK3CA):c.2740G>A (p.Gly914Arg)	PIK3CA	Pathogenic	reviewed by expert panel
39704	NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
39705	NM_006218.4(PIK3CA):c.3139C>T (p.His1047Tyr)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
39706	NM_006218.4(PIK3CA):c.1356AGA[1] (p.Glu453del)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
419222	NM_006218.4(PIK3CA):c.1093G>A (p.Glu365Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
419390	NM_006218.4(PIK3CA):c.3131A>G (p.Asn1044Ser)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
1212448	NM_000314.8(PTEN):c.492+1G>A	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458563	NM_000314.8(PTEN):c.511dup (p.Gln171fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1458931	NM_000314.8(PTEN):c.1007dup (p.Tyr336Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
183726	NM_000314.8(PTEN):c.406T>C (p.Cys136Arg)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
184277	NM_000314.8(PTEN):c.830C>T (p.Thr277Ile)	PTEN	Pathogenic	reviewed by expert panel
186094	NM_000314.8(PTEN):c.475A>G (p.Arg159Gly)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189509	NM_000314.8(PTEN):c.802-2A>G	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
224543	NM_000314.8(PTEN):c.408T>G (p.Cys136Trp)	PTEN	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 89 · Orphanet: 55 · 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
PTEN	Definitive	Autosomal dominant	Cowden syndrome 1	17
AKT1	Supportive	Autosomal dominant	Cowden disease	7
KLLN	Supportive	Autosomal dominant	Cowden disease	2
PIK3CA	Supportive	Autosomal dominant	Cowden disease	9
SDHB	Supportive	Autosomal dominant	Cowden disease	16
SDHC	Supportive	Autosomal dominant	Cowden disease	11
SDHD	Supportive	Autosomal dominant	Cowden disease	16
SEC23B	Supportive	Autosomal dominant	Cowden disease	9
USF3	Supportive	Autosomal dominant	Cowden disease	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHB	Orphanet:139411	Carney triad
SDHB	Orphanet:201	Cowden syndrome
SDHB	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHB	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHB	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:44890	Gastrointestinal stromal tumor
SDHB	Orphanet:97286	Carney-Stratakis syndrome
SDHC	Orphanet:139411	Carney triad
SDHC	Orphanet:201	Cowden syndrome
SDHC	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHC	Orphanet:44890	Gastrointestinal stromal tumor
SDHC	Orphanet:97286	Carney-Stratakis syndrome
SDHD	Orphanet:100093	Carcinoid syndrome
SDHD	Orphanet:201	Cowden syndrome
SDHD	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHD	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHD	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHD	Orphanet:97286	Carney-Stratakis syndrome
USF3	Orphanet:201	Cowden syndrome
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	gencc,clinvar
SDHC	HGNC:10682	ENSG00000143252	Q99643	Succinate dehydrogenase cytochrome b560 subunit, mitochondrial	gencc,clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	gencc,clinvar
USF3	HGNC:30494	ENSG00000176542	Q68DE3	Basic helix-loop-helix domain-containing protein USF3	gencc,clinvar
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	gencc,clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	gencc,clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	gencc,clinvar
SEC23B	HGNC:10702	ENSG00000101310	Q15437	Protein transport protein Sec23B	gencc
AKT1	HGNC:391	ENSG00000142208	P31749	RAC-alpha serine/threonine-protein kinase	gencc
ZNF639	HGNC:30950	ENSG00000121864	Q9UID6	Zinc finger protein 639	clinvar
MLDHR	HGNC:55481	ENSG00000289051	C0HLV8	PTEN upstream open reading frame MP31	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHB	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHC	Succinate dehydrogenase cytochrome b560 subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHD	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
USF3	Basic helix-loop-helix domain-containing protein USF3	Involved in the negative regulation of epithelial-mesenchymal transition, the process by which epithelial cells lose their polarity and adhesion properties to become mesenchymal cells with enhanced migration and invasive properties.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
SEC23B	Protein transport protein Sec23B	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
AKT1	RAC-alpha serine/threonine-protein kinase	AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
ZNF639	Zinc finger protein 639	Binds DNA and may function as a transcriptional repressor.
MLDHR	PTEN upstream open reading frame MP31	Inhibits lactate dehydrogenase (LDH)-mediated conversion of lactate to pyruvate in mitochondria by competing with mitochondrial LDH for binding to NAD(+).

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.45

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
Phosphatase	1	7.6×	0.232
Kinase	2	5.0×	0.232
Transcription factor	3	2.2×	0.232
Enzyme (other)	2	2.2×	0.290
Other/Unknown	3	0.5×	0.987

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
SDHC	Enzyme (other)	yes	1.3.5.1	SuccDH_FuR_B_TM-su, Succ_DH_cytb556, Succ_DH_cyt_bsu_CS
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
USF3	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, USF3_bHLH
KLLN	Other/Unknown	no
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
SEC23B	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
AKT1	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
ZNF639	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
MLDHR	Other/Unknown	no		MP31

Expression context

Cohort genes with no expression data: 1.

9 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)	10
unknown	1

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
islet of Langerhans	2
tibialis anterior	2
endothelial cell	2
ganglionic eminence	2
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
right adrenal gland	1
right adrenal gland cortex	1
jejunal mucosa	1
jejunum	1
rectum	1
deltoid	1
kidney epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
adrenal tissue	1
tendon	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
SDHC	134	ubiquitous	marker	islet of Langerhans, right adrenal gland cortex, right adrenal gland
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
USF3	254	ubiquitous	yes	kidney epithelium, deltoid, tibialis anterior
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
SEC23B	289	ubiquitous	marker	endothelial cell, islet of Langerhans, parotid gland
AKT1	273	ubiquitous	marker	stromal cell of endometrium, ganglionic eminence, endometrium epithelium
ZNF639	264	ubiquitous	marker	cortical plate, calcaneal tendon, ganglionic eminence
MLDHR

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKT1	16,601
PTEN	11,626
SDHB	5,471
SDHC	5,278
PIK3CA	5,157
SEC23B	2,460
SDHD	2,229
USF3	1,167
ZNF639	890
KLLN	234

Intra-cohort edges

A	B	Sources
AKT1	PIK3CA	biogrid_interaction, string_interaction
AKT1	PTEN	string_interaction
AKT1	SDHC	intact
AKT1	SDHD	intact
KLLN	PIK3CA	string_interaction
KLLN	PTEN	string_interaction
KLLN	SDHB	string_interaction
KLLN	SDHD	string_interaction
KLLN	SEC23B	string_interaction
KLLN	USF3	string_interaction
PIK3CA	PTEN	string_interaction
PTEN	SDHD	intact
SDHB	SDHC	string_interaction
SDHB	SDHD	biogrid_interaction, string_interaction
SDHC	SDHD	biogrid_interaction, intact, string_interaction
SEC23B	USF3	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
AKT1	P31749	43
PTEN	P60484	12
SDHB	P21912	6
SDHC	Q99643	2
SDHD	O14521	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEC23B	Q15437	92.41
MLDHR	C0HLV8	83.86
ZNF639	Q9UID6	53.24
KLLN	B2CW77	51.20
USF3	Q68DE3	36.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 178. Enrichment computed across 11 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of TCA enzymes and regulation of TCA cycle	3	285.5×	2e-05	SDHB, SDHC, SDHD
Citric acid cycle (TCA cycle)	3	211.5×	2e-05	SDHB, SDHC, SDHD
Respiratory electron transport	3	47.6×	0.001	SDHB, SDHC, SDHD
CD28 dependent PI3K/Akt signaling	2	131.3×	0.004	PIK3CA, AKT1
FLT3 Signaling	2	115.3×	0.004	PIK3CA, AKT1
Negative regulation of the PI3K/AKT network	2	92.8×	0.006	PTEN, AKT1
Synthesis of PIPs at the plasma membrane	2	70.5×	0.008	PIK3CA, PTEN
Regulation of PTEN stability and activity	2	61.4×	0.010	PTEN, AKT1
Extra-nuclear estrogen signaling	2	56.8×	0.010	PIK3CA, AKT1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	53.6×	0.010	PIK3CA, AKT1
VEGFA-VEGFR2 Pathway	2	46.4×	0.012	PIK3CA, AKT1
TP53 Regulates Metabolic Genes	2	43.3×	0.012	PTEN, AKT1
Downstream TCR signaling	2	42.8×	0.012	PIK3CA, PTEN
PTEN Loss of Function in Cancer	1	951.7×	0.013	PTEN
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	32.3×	0.018	PIK3CA, AKT1
Aerobic respiration and respiratory electron transport	2	29.5×	0.021	SDHB, SDHC
AKT-mediated inactivation of FOXO1A	1	475.8×	0.022	AKT1
Inhibition of TSC complex formation by AKT (PKB)	1	380.7×	0.024	AKT1
Metabolism of nitric oxide: NOS3 activation and regulation	1	380.7×	0.024	AKT1
G-protein beta:gamma signalling	1	317.2×	0.024	AKT1
MET activates PI3K/AKT signaling	1	317.2×	0.024	PIK3CA
Metabolism of cofactors	1	317.2×	0.024	AKT1
Activated NTRK3 signals through PI3K	1	317.2×	0.024	PIK3CA
PIP3 activates AKT signaling	2	22.3×	0.024	PIK3CA, AKT1
Activated NTRK2 signals through PI3K	1	271.9×	0.025	PIK3CA
Signaling by LTK in cancer	1	271.9×	0.025	PIK3CA
RUNX2 regulates genes involved in cell migration	1	237.9×	0.027	AKT1
PI3K/AKT activation	1	211.5×	0.027	PIK3CA
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1	1	211.5×	0.027	AKT1
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	190.3×	0.027	AKT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, succinate to ubiquinone	3	919.2×	5e-07	SDHB, SDHC, SDHD
tricarboxylic acid cycle	3	139.3×	1e-04	SDHB, SDHC, SDHD
proton motive force-driven mitochondrial ATP synthesis	3	71.8×	7e-04	SDHB, SDHC, SDHD
phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	57.5×	1e-03	PIK3CA, PTEN, AKT1
anoikis	2	235.7×	0.001	PIK3CA, AKT1
negative regulation of macroautophagy	2	204.3×	0.002	PIK3CA, AKT1
insulin-like growth factor receptor signaling pathway	2	90.1×	0.007	PIK3CA, AKT1
regulation of neuron projection development	2	78.6×	0.008	PTEN, AKT1
negative regulation of epithelial to mesenchymal transition	2	74.7×	0.008	USF3, PTEN
response to muscle inactivity	1	1532.0×	0.009	PIK3CA
mammalian oogenesis stage	1	1532.0×	0.009	AKT1
positive regulation of endodeoxyribonuclease activity	1	1532.0×	0.009	AKT1
regulation of catecholamine secretion	1	1532.0×	0.009	SDHD
regulation of tRNA methylation	1	1532.0×	0.009	AKT1
negative regulation of protein maturation	1	1532.0×	0.009	AKT1
response to butyrate	1	1532.0×	0.009	PIK3CA
positive regulation of smooth muscle cell proliferation	2	60.1×	0.009	PIK3CA, AKT1
glucose metabolic process	2	46.4×	0.010	PIK3CA, AKT1
epidermal growth factor receptor signaling pathway	2	45.1×	0.010	PIK3CA, AKT1
aerobic respiration	2	45.1×	0.010	SDHB, SDHC
insulin receptor signaling pathway	2	40.3×	0.012	PIK3CA, AKT1
negative regulation of protein localization to lysosome	1	766.0×	0.014	AKT1
negative regulation of synaptic vesicle clustering	1	766.0×	0.014	PTEN
response to L-leucine	1	510.7×	0.015	PIK3CA
negative regulation of keratinocyte migration	1	510.7×	0.015	PTEN
cellular response to hydrostatic pressure	1	510.7×	0.015	PIK3CA
cellular response to rapamycin	1	510.7×	0.015	AKT1
negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway	1	510.7×	0.015	AKT1
positive regulation of protein localization to endoplasmic reticulum	1	510.7×	0.015	AKT1
positive regulation of cell growth	2	33.3×	0.015	ZNF639, AKT1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 9

Druggability breadth: 5 of 11 evidence-associated genes (45%) 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
PIK3CA	IDELALISIB
AKT1	CAPIVASERTIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
AKT1	30	4
SDHB	0	0
SDHC	0	0
SDHD	0	0
USF3	0	0
KLLN	0	0
PTEN	0	0
SEC23B	0	0
ZNF639	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	AKT1, PIK3CA
CAPIVASERTIB	4	AKT1
MILTEFOSINE	4	AKT1
NICLOSAMIDE	4	AKT1
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	AKT1, PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	AKT1, PIK3CA
AFURESERTIB	3	AKT1
LINIFANIB	3	AKT1
PERIFOSINE	3	AKT1
FASUDIL	3	AKT1
QUERCETIN	3	AKT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
AKT1	1,942	Binding:1900, Functional:34, ADMET:7, Toxicity:1
PTEN	8	Binding:8
SDHB	4	Binding:4
SEC23B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
SDHC	1.3.5.1	succinate dehydrogenase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
AKT1	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PIK3CA	2,034
AKT1	1,942

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	AKT1, PIK3CA
CAPIVASERTIB	4	AKT1
MILTEFOSINE	4	AKT1
NICLOSAMIDE	4	AKT1
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	AKT1, PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	AKT1, PIK3CA
AFURESERTIB	3	AKT1
LINIFANIB	3	AKT1
PERIFOSINE	3	AKT1
FASUDIL	3	AKT1
QUERCETIN	3	AKT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	PIK3CA, AKT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	SDHB, SDHC, PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	SDHD, USF3, KLLN, SEC23B, ZNF639, MLDHR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTEN	8	AKT1
SDHB	4	—
SDHC	0	—
SDHD	0	—
USF3	0	—
KLLN	0	—
SEC23B	1	—
ZNF639	0	—
MLDHR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	2
PHASE1	2
PHASE4	1
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03306446	PHASE4	UNKNOWN	Changing the coUrse of cRohn’s Disease With an Early Use of Adalimumab
NCT07218575	PHASE2/PHASE3	NOT_YET_RECRUITING	Double-Blind Trial of Everolimus for Improving Social Abilities in PTEN Germline Mutations
NCT00600275	PHASE1/PHASE2	COMPLETED	A Phase I/II Study of BGT226 in Adult Patients With Advanced Solid Malignancies Including Patients With Advanced Breast Cancer
NCT00971789	PHASE2	COMPLETED	Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes
NCT04094675	PHASE2	COMPLETED	Sirolimus for Cowden Syndrome With Colon Polyposis
NCT00620594	PHASE1	COMPLETED	A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
NCT01757964	PHASE1	COMPLETED	Bacteriotherapy in Pediatric Inflammatory Bowel Disease
NCT03702309	Not specified	RECRUITING	Liquid Biopsy Evaluation and Repository Development at Princess Margaret
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT02856763	Not specified	COMPLETED	Predictive Factors of ANTI-TNF Response in Luminal Crohn’s Disease Complicated by Abscess
NCT03487900	Not specified	UNKNOWN	Is the Endoscopic Remission Evaluation, Using the CREDO 1 Index / Score in CD Patients in Clinical Remission at Baseline, Predictive of Sustained Clinical Remission Using a 2-year Follow up
NCT03498625	Not specified	COMPLETED	Crohn’s Disease Endoscopic REmission Definition in an Objective Way
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EVEROLIMUS	4	1
FLUDEOXYGLUCOSE F 18	4	1
DACTOLISIB	3	1
BGT-226 FREE BASE	2	2