Macrocephaly-autism syndrome

Summary

Macrocephaly-autism syndrome (MONDO:0011537) is a disease caused by PTEN (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PTEN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 158
• Phenotypes (HPO): 24
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000729	Autistic behavior	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0000957	Cafe-au-lait spot	Occasional (5-29%)
HP:0001012	Multiple lipomas	Occasional (5-29%)
HP:0001054	Numerous nevi	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0031447	Penile freckling	Occasional (5-29%)
HP:0200008	Intestinal polyposis	Occasional (5-29%)
HP:0000316	Hypertelorism	Very rare (<1-4%)
HP:0001177	Preaxial hand polydactyly	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001397	Hepatic steatosis	Very rare (<1-4%)
HP:0001829	Foot polydactyly	Very rare (<1-4%)
HP:0002007	Frontal bossing	Very rare (<1-4%)
HP:0002890	Thyroid carcinoma	Very rare (<1-4%)
HP:0003196	Short nose	Very rare (<1-4%)
HP:0006781	Hurthle cell thyroid adenoma	Very rare (<1-4%)
HP:0007018	Attention deficit hyperactivity disorder	Very rare (<1-4%)
HP:0011800	Midface retrusion	Very rare (<1-4%)
HP:0032203	Lymphoid nodular hyperplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	macrocephaly-autism syndrome
Mondo ID	MONDO:0011537
MeSH	C565342
OMIM	605309
Orphanet	210548
DOID	DOID:0060867
UMLS	C1854416
MedGen	381416
GARD	0017112
Is cancer (heuristic)	no

Also known as: macrocephaly-intellectual disability-autism syndrome

Data availability: 158 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › macrocephaly-autism syndrome

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, 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, Cowden disease, 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

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

158 retrieved; paginated sample, class counts are floors:

47 pathogenic, 43 uncertain significance, 19 likely pathogenic, 16 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 7 likely benign, 7 benign/likely benign, 3 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1320095	NM_000314.8(PTEN):c.784_785del (p.Asn262fs)	PTEN	Pathogenic	criteria provided, single submitter
1333638	NM_000314.8(PTEN):c.493-1G>T	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341516	NM_000314.8(PTEN):c.494G>T (p.Gly165Val)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142027	NM_000314.8(PTEN):c.48T>A (p.Tyr16Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
142259	NM_000314.8(PTEN):c.741dup (p.Pro248fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
142269	NM_000314.8(PTEN):c.737C>T (p.Pro246Leu)	PTEN	Pathogenic	reviewed by expert panel
1458931	NM_000314.8(PTEN):c.1007dup (p.Tyr336Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1802604	NM_000314.8(PTEN):c.243T>G (p.Phe81Leu)	PTEN	Pathogenic	criteria provided, single submitter
1805089	NM_000314.8(PTEN):c.867del (p.Lys289_Val290insTer)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
184277	NM_000314.8(PTEN):c.830C>T (p.Thr277Ile)	PTEN	Pathogenic	reviewed by expert panel
186396	NM_000314.8(PTEN):c.733C>T (p.Gln245Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
189474	NM_000314.8(PTEN):c.202T>C (p.Tyr68His)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189475	NM_000314.8(PTEN):c.253+1G>T	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
189483	NM_000314.8(PTEN):c.289C>T (p.Gln97Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
189500	NM_000314.8(PTEN):c.517C>T (p.Arg173Cys)	PTEN	Pathogenic	reviewed by expert panel
209187	NM_000314.8(PTEN):c.1048dup (p.Thr350fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
211972	NM_000314.8(PTEN):c.900del (p.Ile300fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
216987	NM_000314.8(PTEN):c.860C>G (p.Ser287Ter)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
232932	NM_000314.8(PTEN):c.253+1dup	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235334	NM_000314.8(PTEN):c.531T>G (p.Tyr177Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
2442249	NM_000314.8(PTEN):c.436_437insG (p.Leu146fs)	PTEN	Pathogenic	criteria provided, single submitter
2443989	NM_000314.8(PTEN):c.188dup (p.Asn63fs)	PTEN	Pathogenic	criteria provided, single submitter
2502345	NM_000314.8(PTEN):c.827A>G (p.Asn276Ser)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
2674416	NM_000314.8(PTEN):c.731del (p.Pro244fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
280031	NM_000314.8(PTEN):c.634+5G>A	PTEN	Pathogenic	reviewed by expert panel
3250363	NM_000314.8(PTEN):c.226dup (p.Tyr76fs)	PTEN	Pathogenic	criteria provided, single submitter
3600494	NM_000314.8(PTEN):c.764del (p.Val255fs)	PTEN	Pathogenic	criteria provided, single submitter
372481	NM_000314.8(PTEN):c.320A>T (p.Asp107Val)	PTEN	Pathogenic	reviewed by expert panel
3777037	NM_000314.8(PTEN):c.790del (p.Met264fs)	PTEN	Pathogenic	criteria provided, single submitter
3892210	NM_000314.8(PTEN):c.225_238del (p.His75fs)	PTEN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 18 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PTEN	Strong	Autosomal dominant	macrocephaly-autism syndrome	17
HEPACAM	Supportive	Autosomal dominant	macrocephaly-autism syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
HEPACAM	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
HEPACAM	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	gencc,clinvar
HEPACAM	HGNC:26361	ENSG00000165478	Q14CZ8	Hepatic and glial cell adhesion molecule	gencc
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
HEPACAM	Hepatic and glial cell adhesion molecule	Involved in regulating cell motility and cell-matrix interactions.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	28.0×	0.106
Antibody/Immunoglobulin	1	9.7×	0.149
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
HEPACAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
KLLN	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
endothelial cell	1
sperm	1
lateral globus pallidus	1
medial globus pallidus	1
substantia nigra pars reticulata	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
HEPACAM	167	broad	marker	lateral globus pallidus, substantia nigra pars reticulata, medial globus pallidus
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
HEPACAM	661
KLLN	234

Intra-cohort edges

A	B	Sources
KLLN	PTEN	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTEN	P60484	12
HEPACAM	Q14CZ8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTEN Loss of Function in Cancer	1	5710.0×	0.002	PTEN
Regulation of PTEN mRNA translation	1	1142.0×	0.004	PTEN
Regulation of PTEN localization	1	1038.2×	0.004	PTEN
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.007	PTEN
Transcriptional Regulation by MECP2	1	317.2×	0.007	PTEN
Negative regulation of the PI3K/AKT network	1	278.5×	0.007	PTEN
Ovarian tumor domain proteases	1	278.5×	0.007	PTEN
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PTEN
Regulation of PTEN stability and activity	1	184.2×	0.007	PTEN
Regulation of PTEN gene transcription	1	178.4×	0.007	PTEN
TP53 Regulates Metabolic Genes	1	129.8×	0.008	PTEN
Downstream TCR signaling	1	128.3×	0.008	PTEN
Ub-specific processing proteases	1	53.1×	0.019	PTEN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of synaptic vesicle clustering	1	2808.7×	0.007	PTEN
negative regulation of keratinocyte migration	1	1872.4×	0.007	PTEN
rhythmic synaptic transmission	1	1404.3×	0.007	PTEN
central nervous system myelin maintenance	1	936.2×	0.007	PTEN
negative regulation of cell cycle G1/S phase transition	1	802.5×	0.007	PTEN
negative regulation of wound healing, spreading of epidermal cells	1	802.5×	0.007	PTEN
spindle assembly involved in female meiosis	1	624.1×	0.007	PTEN
central nervous system neuron axonogenesis	1	624.1×	0.007	PTEN
postsynaptic density assembly	1	624.1×	0.007	PTEN
protein localization to cell-cell junction	1	624.1×	0.007	HEPACAM
neuron-neuron synaptic transmission	1	561.7×	0.007	PTEN
negative regulation of peptidyl-serine phosphorylation	1	561.7×	0.007	PTEN
negative regulation of cell size	1	561.7×	0.007	PTEN
presynaptic membrane assembly	1	561.7×	0.007	PTEN
negative regulation of organ growth	1	468.1×	0.007	PTEN
forebrain morphogenesis	1	468.1×	0.007	PTEN
multicellular organismal response to stress	1	432.1×	0.007	PTEN
negative regulation of axonogenesis	1	432.1×	0.007	PTEN
cellular response to electrical stimulus	1	432.1×	0.007	PTEN
negative regulation of excitatory postsynaptic potential	1	432.1×	0.007	PTEN
maternal behavior	1	374.5×	0.008	PTEN
prepulse inhibition	1	374.5×	0.008	PTEN
locomotor rhythm	1	351.1×	0.008	PTEN
synapse maturation	1	312.1×	0.008	PTEN
dendritic spine morphogenesis	1	295.6×	0.008	PTEN
apoptotic process	2	19.1×	0.008	PTEN, KLLN
negative regulation of focal adhesion assembly	1	255.3×	0.009	PTEN
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	234.1×	0.009	PTEN
negative regulation of vascular associated smooth muscle cell proliferation	1	224.7×	0.009	PTEN
phosphatidylinositol dephosphorylation	1	216.1×	0.009	PTEN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTEN	0	0
HEPACAM	0	0
KLLN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTEN	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PTEN, HEPACAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KLLN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTEN	8	—
HEPACAM	0	—
KLLN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06462430	Not specified	RECRUITING	PTEN Hamartoma Tumor Syndrome Pediatric Patient Registry