X-linked intellectual disability with marfanoid habitus

Summary

X-linked intellectual disability with marfanoid habitus (MONDO:0010655) is a disease caused by MED12 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: MED12 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 63
• Phenotypes (HPO): 34

Clinical features

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001519	Disproportionate tall stature	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Very frequent (80-99%)
HP:0001611	Hypernasal speech	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0000053	Macroorchidism	Frequent (30-79%)
HP:0000275	Narrow face	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000678	Dental crowding	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability with marfanoid habitus
Mondo ID	MONDO:0010655
MeSH	C537724
OMIM	309520
Orphanet	776
DOID	DOID:0080985
SNOMED CT	422437002
UMLS	C0796022
MedGen	167096
GARD	0003307
Is cancer (heuristic)	no

Also known as: Lujan syndrome · Lujan-Fryns syndrome · Lujan-Fryns syndrome, X-linked recessive · Marfanoid habitus, mild general hypotonia, hypernasal voice, normal testicular size and distinct craniofacial anomalies · mental retardation, X-linked, with Marfanoid habitus

Data availability: 63 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › X-linked intellectual disability with marfanoid habitus

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

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

63 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 10 conflicting classifications of pathogenicity, 9 benign/likely benign, 5 benign, 4 pathogenic/likely pathogenic, 2 likely benign, 1 likely pathogenic, 1 not provided, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028860	NM_005120.3(MED12):c.6408+1G>A	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11520	NM_005120.3(MED12):c.2881C>T (p.Arg961Trp)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11521	NM_005120.3(MED12):c.3020A>G (p.Asn1007Ser)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213640	NM_005120.3(MED12):c.3883C>T (p.Arg1295Cys)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382729	NM_005120.3(MED12):c.3129del (p.Ser1044fs)	MED12	Pathogenic	criteria provided, single submitter
1804009	NM_005120.3(MED12):c.2546C>T (p.Ser849Phe)	MED12	Likely pathogenic	criteria provided, single submitter
1319901	NM_005120.3(MED12):c.439G>A (p.Ala147Thr)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1696529	NM_005120.3(MED12):c.4413G>A (p.Lys1471=)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805137	NM_005120.3(MED12):c.949T>C (p.Ser317Pro)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213627	NM_005120.3(MED12):c.6097A>G (p.Met2033Val)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213631	NM_005120.3(MED12):c.1039A>G (p.Ser347Gly)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213632	NM_005120.3(MED12):c.1264C>T (p.Arg422Trp)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213633	NM_005120.3(MED12):c.1849A>G (p.Thr617Ala)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2903386	NM_005120.3(MED12):c.6128G>A (p.Arg2043His)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931587	NM_005120.3(MED12):c.1996A>G (p.Met666Val)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95246	NM_005120.3(MED12):c.2849+14C>T	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857059	NM_005120.3(MED12):c.1376C>T (p.Thr459Ile)	LOC126863275	Uncertain significance	criteria provided, single submitter
983040	NM_005120.3(MED12):c.1439T>C (p.Leu480Pro)	LOC126863275	Uncertain significance	criteria provided, single submitter
1019021	NM_005120.3(MED12):c.617G>A (p.Arg206Gln)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028858	NM_005120.3(MED12):c.3613C>T (p.Arg1205Cys)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028859	NM_005120.3(MED12):c.3692-7A>G	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1200703	NM_005120.3(MED12):c.3760G>A (p.Gly1254Arg)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1305779	NM_005120.3(MED12):c.5005G>A (p.Asp1669Asn)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333933	NM_005120.3(MED12):c.5834C>G (p.Thr1945Ser)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1360673	NM_005120.3(MED12):c.6076A>G (p.Met2026Val)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1526230	NM_005120.3(MED12):c.1746G>A (p.Thr582=)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1904410	NM_005120.3(MED12):c.6371C>T (p.Ala2124Val)	MED12	Uncertain significance	criteria provided, single submitter
1979426	NM_005120.3(MED12):c.6397_6408delTCCCAGCCCCAG (p.Ser2133_Gln2136del)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
213641	NM_005120.3(MED12):c.4021C>T (p.Arg1341Trp)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2144781	NM_005120.3(MED12):c.616C>T (p.Arg206Trp)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 8 · 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
MED12	Definitive	X-linked	X-linked intellectual disability with marfanoid habitus	21
UPF3B	Definitive	X-linked	syndromic X-linked intellectual disability 14	6
ZDHHC9	Definitive	X-linked	syndromic X-linked intellectual disability Raymond type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
ZDHHC9	Orphanet:776	Lujan-Fryns syndrome
UPF3B	Orphanet:776	Lujan-Fryns syndrome
UPF3B	Orphanet:777	X-linked non-syndromic intellectual disability

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
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gencc,clinvar
ZDHHC9	HGNC:18475	ENSG00000188706	Q9Y397	Palmitoyltransferase ZDHHC9	gencc
UPF3B	HGNC:20439	ENSG00000125351	Q9BZI7	Regulator of nonsense transcripts 3B	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
ZDHHC9	Palmitoyltransferase ZDHHC9	Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, GSDMD, HRAS, NRAS and CGAS.
UPF3B	Regulator of nonsense transcripts 3B	Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
ZDHHC9	Enzyme (other)	yes	2.3.1.225	Palmitoyltrfase_DHHC, PFA4/ZDH16/20/ERF2-like
UPF3B	Other/Unknown	no		UPF3_dom, Nucleotide-bd_a/b_plait_sf, UPF3B_RRM-like

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
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
corpus callosum	1
inferior vagus X ganglion	1
kidney epithelium	1
embryo	1
esophagus squamous epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
ZDHHC9	238	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, kidney epithelium
UPF3B	277	ubiquitous	marker	sural nerve, esophagus squamous epithelium, embryo

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED12	3,322
UPF3B	1,677
ZDHHC9	1,045

Intra-cohort edges

A	B	Sources
UPF3B	ZDHHC9	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MED12	Q93074	3
UPF3B	Q9BZI7	3
ZDHHC9	Q9Y397	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAS processing	1	158.6×	0.052	ZDHHC9
Maturation of spike protein	1	88.5×	0.052	ZDHHC9
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.052	MED12
mRNA 3’-end processing	1	65.6×	0.052	UPF3B
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.052	MED12
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.052	MED12
RSV-host interactions	1	52.1×	0.052	MED12
Adipogenesis	1	52.1×	0.052	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.052	MED12
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	50.8×	0.052	UPF3B
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.052	MED12
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.052	MED12
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	32.5×	0.061	UPF3B
PPARA activates gene expression	1	31.5×	0.061	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.064	MED12
Epigenetic regulation of gene expression	1	23.8×	0.068	MED12
Regulation of expression of SLITs and ROBOs	1	23.1×	0.068	UPF3B
mRNA Splicing - Major Pathway	1	18.2×	0.081	UPF3B
Metabolism of lipids	1	10.5×	0.127	MED12
Viral Infection Pathways	1	10.3×	0.127	MED12
Infectious disease	1	8.3×	0.149	MED12
RNA Polymerase II Transcription	1	7.5×	0.156	MED12
Gene expression (Transcription)	1	6.0×	0.187	MED12
Generic Transcription Pathway	1	5.0×	0.209	MED12
Developmental Biology	1	4.8×	0.209	MED12
Disease	1	4.4×	0.220	MED12
Metabolism	1	3.9×	0.237	MED12

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
axis elongation involved in somitogenesis	1	1872.4×	0.009	MED12
positive regulation of mRNA cis splicing, via spliceosome	1	1404.3×	0.009	UPF3B
non-canonical inflammasome complex assembly	1	936.2×	0.009	ZDHHC9
positive regulation of pyroptotic inflammatory response	1	802.5×	0.009	ZDHHC9
positive regulation of cGAS/STING signaling pathway	1	702.2×	0.009	ZDHHC9
embryonic neurocranium morphogenesis	1	624.1×	0.009	MED12
host-mediated activation of viral process	1	468.1×	0.010	ZDHHC9
peptidyl-L-cysteine S-palmitoylation	1	401.2×	0.010	ZDHHC9
Schwann cell development	1	351.1×	0.010	MED12
random inactivation of X chromosome	1	312.1×	0.011	UPF3B
embryonic brain development	1	267.5×	0.011	MED12
post-anal tail morphogenesis	1	244.2×	0.011	MED12
endoderm development	1	208.1×	0.012	MED12
oligodendrocyte development	1	200.6×	0.012	MED12
spinal cord development	1	170.2×	0.013	MED12
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	156.0×	0.013	UPF3B
Wnt signaling pathway, planar cell polarity pathway	1	151.8×	0.013	MED12
post-translational protein modification	1	140.4×	0.013	ZDHHC9
protein targeting to membrane	1	98.5×	0.018	ZDHHC9
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.018	MED12
mRNA transport	1	87.8×	0.018	UPF3B
somatic stem cell population maintenance	1	82.6×	0.018	MED12
positive regulation of translation	1	75.9×	0.019	UPF3B
positive regulation of neuron differentiation	1	66.1×	0.021	UPF3B
neural tube closure	1	62.4×	0.021	MED12
protein maturation	1	54.5×	0.023	ZDHHC9
MAPK cascade	1	51.1×	0.024	ZDHHC9
neuron projection development	1	40.7×	0.029	UPF3B
brain development	1	26.5×	0.041	UPF3B
heart development	1	26.2×	0.041	MED12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MED12	1	2
ZDHHC9	0	0
UPF3B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6
ZDHHC9	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ZDHHC9	2.3.1.225	protein S-acyltransferase

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

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	MED12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	1	ZDHHC9
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	UPF3B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZDHHC9	1	—
UPF3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.