Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

Summary

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (MONDO:0060502) is a disease caused by PLAA (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLAA (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 30
• Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000319	Smooth philtrum	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0000954	Single transverse palmar crease	Frequent (30-79%)
HP:0001007	Hirsutism	Frequent (30-79%)
HP:0001162	Postaxial hand polydactyly	Frequent (30-79%)
HP:0001187	Hyperextensibility of the finger joints	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001283	Bulbar palsy	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001830	Postaxial foot polydactyly	Frequent (30-79%)
HP:0001838	Rocker bottom foot	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002104	Apnea	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0002352	Leukoencephalopathy	Frequent (30-79%)
HP:0002478	Progressive spastic quadriplegia	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0002536	Abnormal cortical gyration	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0005781	Contractures of the large joints	Frequent (30-79%)
HP:0007514	Edema of the dorsum of hands	Frequent (30-79%)
HP:0008278	Cerebellar cortical atrophy	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012098	Edema of the dorsum of feet	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0012762	Cerebral white matter atrophy	Frequent (30-79%)
HP:0031162	Impaired oropharyngeal swallow response	Frequent (30-79%)
HP:0100807	Long fingers	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000975	Hyperhidrosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies
Mondo ID	MONDO:0060502
OMIM	617527
Orphanet	521426
UMLS	C4479631
MedGen	1380260
GARD	0017960
Is cancer (heuristic)	no

Also known as: NDMSBA · neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

Data availability: 30 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

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, 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, 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

30 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 8 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
242318	NM_001348768.2(HECW2):c.3988C>T (p.Arg1330Trp)	HECW2	Pathogenic	criteria provided, multiple submitters, no conflicts
427940	NM_001031689.3(PLAA):c.2254C>T (p.Leu752Phe)	PLAA	Pathogenic	no assertion criteria provided
427941	NM_001031689.3(PLAA):c.68G>T (p.Gly23Val)	PLAA	Pathogenic	no assertion criteria provided
427942	NM_001031689.3(PLAA):c.68dup (p.Leu24fs)	PLAA	Pathogenic	no assertion criteria provided
807466	NM_001031689.3(PLAA):c.240_241insTAG (p.Pro81Ter)	PLAA	Pathogenic	criteria provided, single submitter
828067	NM_001031689.3(PLAA):c.120C>G (p.Asp40Glu)	PLAA	Pathogenic	criteria provided, single submitter
975038	NM_001031689.3(PLAA):c.1049A>T (p.Glu350Val)	PLAA	Pathogenic	no assertion criteria provided
975039	NM_001031689.3(PLAA):c.829T>C (p.Cys277Arg)	PLAA	Pathogenic	no assertion criteria provided
812649	NM_016146.6(TRAPPC4):c.454+3A>G	TRAPPC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333605	NM_001031689.3(PLAA):c.850_860del (p.Asp284fs)	PLAA	Likely pathogenic	criteria provided, single submitter
1806265	NM_001031689.3(PLAA):c.1570C>T (p.Arg524Ter)	PLAA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2497674	NM_001031689.3(PLAA):c.1800G>A (p.Trp600Ter)	PLAA	Likely pathogenic	criteria provided, single submitter
694395	NM_001031689.3(PLAA):c.2350del (p.Lys783_Val784insTer)	PLAA	Likely pathogenic	criteria provided, single submitter
1030979	NM_001031689.3(PLAA):c.2323T>C (p.Tyr775His)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033217	NM_001031689.3(PLAA):c.1370G>C (p.Gly457Ala)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033218	NM_001031689.3(PLAA):c.-16C>T	PLAA	Uncertain significance	criteria provided, single submitter
1033219	NM_001031689.3(PLAA):c.911C>G (p.Thr304Arg)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333483	NM_001031689.3(PLAA):c.340A>G (p.Thr114Ala)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1439737	NM_001031689.3(PLAA):c.790G>A (p.Ala264Thr)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1440518	NM_001031689.3(PLAA):c.1068C>G (p.Ile356Met)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1701741	NM_001031689.3(PLAA):c.481C>T (p.Pro161Ser)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2013465	NM_001031689.3(PLAA):c.1957_1958delinsAT (p.Pro653Ile)	PLAA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2430379	NM_001031689.3(PLAA):c.215G>A (p.Cys72Tyr)	PLAA	Uncertain significance	criteria provided, single submitter
2434916	NM_001031689.3(PLAA):c.1036C>A (p.Pro346Thr)	PLAA	Uncertain significance	criteria provided, single submitter
3065124	NM_001031689.3(PLAA):c.1496G>A (p.Arg499His)	PLAA	Uncertain significance	criteria provided, single submitter
3780439	NM_001031689.3(PLAA):c.1039+2dup	PLAA	Uncertain significance	criteria provided, single submitter
4278149	NM_001031689.3(PLAA):c.2126A>G (p.Tyr709Cys)	PLAA	Uncertain significance	criteria provided, single submitter
1659125	NM_001031689.3(PLAA):c.1486+6A>T	PLAA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
780798	NM_001031689.3(PLAA):c.957C>T (p.His319=)	PLAA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
973095	NM_001031689.3(PLAA):c.2264A>G (p.Asp755Gly)	PLAA	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
PLAA	Strong	Autosomal recessive	neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLAA	Orphanet:521426	PLAA-associated neurodevelopmental disorder
TRAPPC4	Orphanet:528084	Non-specific 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
PLAA	HGNC:9043	ENSG00000137055	Q9Y263	Phospholipase A-2-activating protein	gencc,clinvar
TRAPPC4	HGNC:19943	ENSG00000196655	Q9Y296	Trafficking protein particle complex subunit 4	clinvar
HECW2	HGNC:29853	ENSG00000138411	Q9P2P5	E3 ubiquitin-protein ligase HECW2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLAA	Phospholipase A-2-activating protein	Plays a role in protein ubiquitination, sorting and degradation through its association with VCP.
TRAPPC4	Trafficking protein particle complex subunit 4	Core component of the TRAPP complexes which has a function of guanine nucleotide exchange factor activity for Rab1 GTPase.
HECW2	E3 ubiquitin-protein ligase HECW2	E3 ubiquitin-protein ligase that mediates ubiquitination of TP73.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	2	11.5×	0.019
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLAA	Scaffold/PPI	no		WD40_rpt, ARM-like, PUL_dom
TRAPPC4	Other/Unknown	no		TRAPPC, Longin-like_dom_sf
HECW2	Scaffold/PPI	no		C2_dom, HECT_dom, WW_dom

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
gastrocnemius	1
muscle of leg	1
secondary oocyte	1
adenohypophysis	1
cortical plate	1
islet of Langerhans	1
Brodmann (1909) area 23	1
left ventricle myocardium	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLAA	273	ubiquitous	marker	gastrocnemius, secondary oocyte, muscle of leg
TRAPPC4	134	ubiquitous	marker	cortical plate, islet of Langerhans, adenohypophysis
HECW2	227	ubiquitous	marker	left ventricle myocardium, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLAA	2,176
HECW2	2,127
TRAPPC4	1,173

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLAA	Q9Y263	5
TRAPPC4	Q9Y296	3
HECW2	Q9P2P5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Syndecan interactions	1	211.5×	0.019	TRAPPC4
COPII-mediated vesicle transport	1	81.6×	0.021	TRAPPC4
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.021	TRAPPC4
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.053	HECW2

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
positive regulation of synaptic vesicle recycling	1	5617.3×	0.004	PLAA
negative regulation of protein K63-linked ubiquitination	1	1404.3×	0.007	PLAA
ubiquitin recycling	1	1123.5×	0.007	PLAA
positive regulation of prostaglandin biosynthetic process	1	624.1×	0.009	PLAA
vesicle coat assembly	1	510.7×	0.009	TRAPPC4
obsolete vesicle tethering	1	330.4×	0.010	TRAPPC4
positive regulation of neuron migration	1	330.4×	0.010	PLAA
regulation of dendrite morphogenesis	1	244.2×	0.010	HECW2
positive regulation of dendrite extension	1	244.2×	0.010	PLAA
COPII vesicle coat assembly	1	234.1×	0.010	TRAPPC4
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	181.2×	0.012	PLAA
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.012	HECW2
dendrite development	1	130.6×	0.014	TRAPPC4
phospholipid metabolic process	1	114.6×	0.015	PLAA
macroautophagy	1	80.2×	0.020	PLAA
endoplasmic reticulum to Golgi vesicle-mediated transport	1	45.3×	0.033	TRAPPC4
autophagy	1	36.7×	0.038	TRAPPC4
cellular response to lipopolysaccharide	1	32.7×	0.040	PLAA
ubiquitin-dependent protein catabolic process	1	24.8×	0.050	HECW2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	17.4×	0.068	PLAA
nervous system development	1	15.3×	0.073	PLAA
protein ubiquitination	1	13.8×	0.077	HECW2
inflammatory response	1	12.6×	0.081	PLAA
signal transduction	1	5.3×	0.176	PLAA

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
PLAA	0	0
TRAPPC4	0	0
HECW2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLAA	4	Binding:4

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PLAA, TRAPPC4, HECW2

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)
PLAA	4	—
TRAPPC4	0	—
HECW2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.