Cardiac anomalies - developmental delay - facial dysmorphism syndrome

Summary

Cardiac anomalies - developmental delay - facial dysmorphism syndrome (MONDO:0014773) is a disease caused by MED13L (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MED13L (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 297
• Phenotypes (HPO): 66

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000194	Open mouth	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000414	Bulbous nose	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000582	Upslanted palpebral fissure	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000294	Low anterior hairline	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000311	Round face	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000384	Preauricular skin tag	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000687	Widely spaced teeth	Occasional (5-29%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001155	Abnormality of the hand	Occasional (5-29%)
HP:0001159	Syndactyly	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0002236	Frontal upsweep of hair	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac anomalies - developmental delay - facial dysmorphism syndrome
Mondo ID	MONDO:0014773
OMIM	616789
Orphanet	369891
UMLS	C5192431
MedGen	1675852
GARD	0017588
Is cancer (heuristic)	no

Also known as: Asadollahi-Rauch syndrome · ASRAS · cardiac anomalies - developmental delay - facial dysmorphism syndrome · developmental delay-facial dysmorphism syndrome due to MED13L deficiency · impaired intellectual development and distinctive facial features with or without cardiac defects · intellectual disability and distinctive facial features with or without cardiac defects · MED13L haploinsufficiency syndrome · MED13L syndrome · MED13L-related intellectual disability · MED13L-related syndrome · mental retardation and distinctive FACIAL features with or without CARDIAC defects · mental retardation and distinctive Facial features with or without Cardiac defects · MRFACD · MRFACD syndrome

Data availability: 297 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 › cardiac anomalies - developmental delay - facial dysmorphism syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, 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, 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

297 retrieved; paginated sample, class counts are floors:

107 uncertain significance, 92 pathogenic, 52 likely pathogenic, 22 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 9 benign/likely benign, 5 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
221559	NC_000012.11:g.(116484299_116497981)_(116681549_116695774)dup	LOC128706664	Pathogenic	no assertion criteria provided
1033770	NM_015335.5(MED13L):c.4271_4276delinsTTCCC (p.Cys1424fs)	MED13L	Pathogenic	criteria provided, single submitter
1033771	NM_015335.5(MED13L):c.4975_4976insC (p.Ile1659fs)	MED13L	Pathogenic	criteria provided, single submitter
1164009	NM_015335.5(MED13L):c.541_556delinsA (p.Val181_His186delinsAsn)	MED13L	Pathogenic	no assertion criteria provided
1164010	NM_015335.5(MED13L):c.2320del (p.Ile774fs)	MED13L	Pathogenic	no assertion criteria provided
1172667	NM_015335.5(MED13L):c.3154C>T (p.Arg1052Ter)	MED13L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319952	NM_015335.5(MED13L):c.6195dup (p.Gly2066fs)	MED13L	Pathogenic	no assertion criteria provided
1320085	NM_015335.5(MED13L):c.5244_5248dup (p.Met1750fs)	MED13L	Pathogenic	criteria provided, single submitter
1330286	NM_015335.5(MED13L):c.4213G>T (p.Glu1405Ter)	MED13L	Pathogenic	criteria provided, single submitter
1679237	NM_015335.5(MED13L):c.3309del (p.Glu1105fs)	MED13L	Pathogenic	criteria provided, single submitter
1685943	NM_015335.5(MED13L):c.4041G>A (p.Trp1347Ter)	MED13L	Pathogenic	criteria provided, single submitter
1699209	NM_015335.5(MED13L):c.5364+1dup	MED13L	Pathogenic	criteria provided, single submitter
1699335	NM_015335.5(MED13L):c.3205C>T (p.Gln1069Ter)	MED13L	Pathogenic	criteria provided, single submitter
1700209	NM_015335.5(MED13L):c.5941C>T (p.Gln1981Ter)	MED13L	Pathogenic	criteria provided, single submitter
1700210	NM_015335.5(MED13L):c.329G>A (p.Trp110Ter)	MED13L	Pathogenic	criteria provided, single submitter
1701743	NM_015335.5(MED13L):c.319dup (p.Glu107fs)	MED13L	Pathogenic	criteria provided, single submitter
1722316	NM_015335.5(MED13L):c.4011_4024del (p.Ile1338fs)	MED13L	Pathogenic	criteria provided, single submitter
1805294	NM_015335.5(MED13L):c.6017_6035del (p.Gln2006fs)	MED13L	Pathogenic	criteria provided, single submitter
1805304	NM_015335.5(MED13L):c.4539_4542del (p.Pro1512_Tyr1513insTer)	MED13L	Pathogenic	criteria provided, single submitter
1805335	NM_015335.5(MED13L):c.278del (p.Asn93fs)	MED13L	Pathogenic	criteria provided, single submitter
1805347	NM_015335.5(MED13L):c.4087del (p.His1363fs)	MED13L	Pathogenic	criteria provided, multiple submitters, no conflicts
1805357	NM_015335.5(MED13L):c.3383_3384del (p.Asn1127_Phe1128insTer)	MED13L	Pathogenic	criteria provided, single submitter
1805842	NM_015335.5(MED13L):c.6039del (p.Asn2014fs)	MED13L	Pathogenic	criteria provided, single submitter
221555	NM_015335.5(MED13L):c.1708_1709del (p.Ser570fs)	MED13L	Pathogenic	criteria provided, multiple submitters, no conflicts
221556	NM_015335.5(MED13L):c.6118_6125del (p.Gly2040fs)	MED13L	Pathogenic	criteria provided, single submitter
221557	NM_015335.5(MED13L):c.480-1G>T	MED13L	Pathogenic	no assertion criteria provided
221561	NM_015335.5(MED13L):c.3765del (p.Cys1256fs)	MED13L	Pathogenic	criteria provided, single submitter
224115	NM_015335.5(MED13L):c.124dup (p.Asp42fs)	MED13L	Pathogenic	criteria provided, single submitter
224153	NM_015335.5(MED13L):c.6485C>T (p.Thr2162Met)	MED13L	Pathogenic	criteria provided, multiple submitters, no conflicts
2497747	NM_015335.5(MED13L):c.4132G>T (p.Glu1378Ter)	MED13L	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
MED13L	Definitive	Autosomal dominant	cardiac anomalies - developmental delay - facial dysmorphism syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED13L	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries
MED13L	Orphanet:369891	Developmental delay-facial dysmorphism syndrome due to MED13L deficiency
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
NPR2	Orphanet:329191	Tall stature-long halluces-multiple extra-epiphyses syndrome
NPR2	Orphanet:40	Acromesomelic dysplasia, Maroteaux type

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED13L	HGNC:22962	ENSG00000123066	Q71F56	Mediator of RNA polymerase II transcription subunit 13-like	gencc,clinvar
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	clinvar
NPR2	HGNC:7944	ENSG00000159899	P20594	Atrial natriuretic peptide receptor 2	clinvar
ACACA	HGNC:84	ENSG00000278540	Q13085	Acetyl-CoA carboxylase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED13L	Mediator of RNA polymerase II transcription subunit 13-like	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
NPR2	Atrial natriuretic peptide receptor 2	Receptor for the C-type natriuretic peptide NPPC/CNP hormone.
ACACA	Acetyl-CoA carboxylase 1	Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Kinase	1	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED13L	Other/Unknown	no		Med13_C, Mediator_Med13_N, MID_MedPIWI
NPRL2	Other/Unknown	no		NPR2-like
NPR2	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, ANPR/GUC
ACACA	Enzyme (other)	yes	6.4.1.2	Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
calcaneal tendon	1
colonic epithelium	1
tendon	1
granulocyte	1
right uterine tube	1
adrenal tissue	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED13L	297	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon
NPRL2	285	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
NPR2	267	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
ACACA	134	ubiquitous	marker	cortical plate, adrenal tissue, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACACA	4,113
MED13L	1,606
NPRL2	1,222
NPR2	885

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPRL2	Q8WTW4	10
ACACA	Q13085	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPR2	P20594	84.00
MED13L	Q71F56	56.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defects in biotin (Btn) metabolism	1	571.0×	0.026	ACACA
Defective HLCS causes multiple carboxylase deficiency	1	407.9×	0.026	ACACA
ChREBP activates metabolic gene expression	1	317.2×	0.026	ACACA
Biotin transport and metabolism	1	259.6×	0.026	ACACA
Carnitine shuttle	1	190.3×	0.026	ACACA
Physiological factors	1	167.9×	0.026	NPR2
Defects in vitamin and cofactor metabolism	1	150.3×	0.026	ACACA
Metabolism of lipids	2	15.8×	0.026	MED13L, ACACA
Fatty acyl-CoA biosynthesis	1	109.8×	0.031	ACACA
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	79.3×	0.039	ACACA
Activation of gene expression by SREBF (SREBP)	1	64.9×	0.043	ACACA
Amino acids regulate mTORC1	1	50.1×	0.044	NPRL2
Respiratory Syncytial Virus Infection Pathway	1	49.2×	0.044	MED13L
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.044	ACACA
Integration of energy metabolism	1	43.9×	0.044	ACACA
RSV-host interactions	1	39.1×	0.044	MED13L
Adipogenesis	1	39.1×	0.044	MED13L
Regulation of lipid metabolism by PPARalpha	1	35.2×	0.044	MED13L
Metabolism of steroids	1	34.4×	0.044	ACACA
Fatty acid metabolism	1	32.8×	0.044	ACACA
Transcriptional regulation of white adipocyte differentiation	1	32.4×	0.044	MED13L
Disease	2	6.5×	0.044	MED13L, ACACA
Metabolism of vitamins and cofactors	1	29.1×	0.046	ACACA
Cardiac conduction	1	27.2×	0.047	NPR2
Metabolism	2	5.8×	0.049	MED13L, ACACA
PPARA activates gene expression	1	23.6×	0.050	MED13L
Diseases of metabolism	1	20.1×	0.056	ACACA
Muscle contraction	1	19.3×	0.056	NPR2
Viral Infection Pathways	1	7.7×	0.132	MED13L
Infectious disease	1	6.2×	0.157	MED13L

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vestibulocochlear nerve maturation	1	4213.0×	0.006	NPR2
response to luteinizing hormone	1	2106.5×	0.006	NPR2
activation of meiosis involved in egg activation	1	2106.5×	0.006	NPR2
malonyl-CoA biosynthetic process	1	2106.5×	0.006	ACACA
cumulus cell differentiation	1	1404.3×	0.006	NPR2
gastric emptying	1	1404.3×	0.006	NPR2
c-di-GMP signaling	1	1404.3×	0.006	NPR2
negative regulation of kinase activity	1	1053.2×	0.006	NPRL2
negative regulation of meiotic cell cycle	1	1053.2×	0.006	NPR2
genitalia morphogenesis	1	842.6×	0.006	NPR2
negative regulation of oocyte maturation	1	842.6×	0.006	NPR2
meiotic cell cycle process involved in oocyte maturation	1	702.2×	0.006	NPR2
acetyl-CoA metabolic process	1	601.9×	0.006	ACACA
female genitalia development	1	601.9×	0.006	NPR2
bone growth	1	601.9×	0.006	NPR2
growth plate cartilage development	1	526.6×	0.006	NPR2
cellular response to cGMP	1	526.6×	0.006	NPR2
response to fibroblast growth factor	1	526.6×	0.006	NPR2
response to salt	1	526.6×	0.006	NPR2
lymph vessel development	1	468.1×	0.006	NPR2
fatty-acyl-CoA biosynthetic process	1	468.1×	0.006	ACACA
vascular wound healing	1	468.1×	0.006	NPR2
axonogenesis involved in innervation	1	421.3×	0.006	NPR2
cellular response to peptide	1	421.3×	0.006	NPR2
vacuole organization	1	383.0×	0.006	NPR2
cGMP biosynthetic process	1	351.1×	0.007	NPR2
receptor guanylyl cyclase signaling pathway	1	324.1×	0.007	NPR2
cellular response to granulocyte macrophage colony-stimulating factor stimulus	1	324.1×	0.007	NPR2
collateral sprouting	1	300.9×	0.007	NPR2
startle response	1	280.9×	0.007	NPR2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
ACACA	BEMPEDOIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACACA	4	4
MED13L	0	0
NPRL2	0	0
NPR2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEMPEDOIC ACID	4	ACACA
PF-05175157	2	ACACA
FIRSOCOSTAT	2	ACACA
CLESACOSTAT	2	ACACA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ACACA	71	Binding:71
NPR2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NPR2	4.6.1.2	guanylate cyclase
ACACA	6.4.1.2	acetyl-CoA carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
BEMPEDOIC ACID	4	ACACA
PF-05175157	2	ACACA
FIRSOCOSTAT	2	ACACA
CLESACOSTAT	2	ACACA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACACA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	NPR2
E	Difficult family or no structure, no drug	2	MED13L, NPRL2

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)
MED13L	0	—
NPRL2	0	—
NPR2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.