Ritscher-Schinzel syndrome

Summary

Ritscher-Schinzel syndrome (MONDO:0019078) is a disease with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 408
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000235	Abnormality of the fontanelles or cranial sutures	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001305	Dandy-Walker malformation	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000269	Prominent occiput	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001633	Abnormal mitral valve morphology	Frequent (30-79%)
HP:0001636	Tetralogy of Fallot	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0001650	Aortic valve stenosis	Frequent (30-79%)
HP:0001702	Abnormal tricuspid valve morphology	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004383	Hypoplastic left heart	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006695	Atrioventricular canal defect	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000329	Facial hemangioma	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000384	Preauricular skin tag	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000567	Chorioretinal coloboma	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000835	Adrenal hypoplasia	Occasional (5-29%)
HP:0000921	Missing ribs	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001161	Hand polydactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ritscher-Schinzel syndrome
Mondo ID	MONDO:0019078
MeSH	C535313
OMIM	220210
Orphanet	7
DOID	DOID:0060565
SNOMED CT	718556007
UMLS	C0796137
MedGen	163220
GARD	0005666
Is cancer (heuristic)	no

Also known as: 3C syndrome · CCC dysplasia · cranio-cerebello-cardiac dysplasia · Craniocerebellocardiac dysplasia · craniocerebellocardiac dysplasia · Dandy-Walker like malformation with atrioventricular septal defect · Dandy-Walker-like malformation with ASD · Dandy-Walker-like malformation with atrioventricular septal defect · Ritscher Schinzel syndrome · Ritscher-Schinzel cranio-cerebello-cardiac syndrome · Ritscher-Schinzel syndrome

Data availability: 408 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Ritscher-Schinzel 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, 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, 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

Subtypes (4): Ritscher-Schinzel syndrome 1, Ritscher-Schinzel syndrome 2, Ritscher-Schinzel syndrome 4, Ritscher-Schinzel syndrome 3

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

408 retrieved; paginated sample, class counts are floors:

181 uncertain significance, 138 likely benign, 33 conflicting classifications of pathogenicity, 22 benign, 14 benign/likely benign, 11 pathogenic, 5 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1014986	NM_014846.4(WASHC5):c.1424G>A (p.Trp475Ter)	WASHC5	Pathogenic	criteria provided, single submitter
1161	NM_014846.4(WASHC5):c.1876G>T (p.Val626Phe)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162	NM_014846.4(WASHC5):c.1857G>C (p.Leu619Phe)	WASHC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1510703	NM_014846.4(WASHC5):c.913G>T (p.Glu305Ter)	WASHC5	Pathogenic	criteria provided, single submitter
2926285	NM_014846.4(WASHC5):c.633T>G (p.Tyr211Ter)	WASHC5	Pathogenic	criteria provided, single submitter
2938986	NM_014846.4(WASHC5):c.1368del (p.Ser458fs)	WASHC5	Pathogenic	criteria provided, single submitter
2940559	NM_014846.4(WASHC5):c.2438_2439del (p.Pro813fs)	WASHC5	Pathogenic	criteria provided, single submitter
3763973	NM_014846.4(WASHC5):c.3163C>T (p.Gln1055Ter)	WASHC5	Pathogenic	criteria provided, single submitter
410079	NM_014846.4(WASHC5):c.2086G>A (p.Gly696Ser)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
463137	NM_014846.4(WASHC5):c.1771T>C (p.Ser591Pro)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4791041	NM_014846.4(WASHC5):c.1443_1447del (p.Lys481fs)	WASHC5	Pathogenic	criteria provided, single submitter
495056	NM_014846.4(WASHC5):c.1772C>T (p.Ser591Phe)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
573798	NM_014846.4(WASHC5):c.3024_3025del (p.Leu1009fs)	WASHC5	Pathogenic	criteria provided, single submitter
576266	NM_014846.4(WASHC5):c.511C>T (p.Arg171Ter)	WASHC5	Pathogenic	criteria provided, single submitter
578334	NM_014846.4(WASHC5):c.2087G>A (p.Gly696Asp)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2023842	NM_014846.4(WASHC5):c.2595_2599del (p.Gln865fs)	WASHC5-AS1	Pathogenic	criteria provided, single submitter
1067377	NC_000008.10:g.(?126079753)(126096155_?)del	WASHC5	Likely pathogenic	criteria provided, single submitter
1430473	NM_014846.4(WASHC5):c.2505-1G>C	WASHC5	Likely pathogenic	criteria provided, single submitter
1985363	NM_014846.4(WASHC5):c.186+1G>C	WASHC5	Likely pathogenic	criteria provided, single submitter
4790773	NM_014846.4(WASHC5):c.2771-2A>G	WASHC5	Likely pathogenic	criteria provided, single submitter
1344370	NM_014846.4(WASHC5):c.3276C>T (p.Thr1092=)	LOC126860498	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2931251	NM_014846.4(WASHC5):c.3182-16A>G	LOC126860498	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463140	NM_014846.4(WASHC5):c.3210G>A (p.Pro1070=)	LOC126860498	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911127	NM_014846.4(WASHC5):c.3282G>A (p.Gln1094=)	LOC126860498	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063307	NM_014846.4(WASHC5):c.2008C>T (p.Arg670Ter)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1175788	NM_014846.4(WASHC5):c.2380-6T>C	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1285109	NM_014846.4(WASHC5):c.1217A>G (p.Asn406Ser)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307647	NM_014846.4(WASHC5):c.1945A>G (p.Ile649Val)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2057136	NM_014846.4(WASHC5):c.740G>A (p.Arg247His)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218709	NM_014846.4(WASHC5):c.1007G>C (p.Arg336Thr)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
CCDC22	Strong	X-linked	Ritscher-Schinzel syndrome 2	6
WASHC5	Strong	Autosomal recessive	Ritscher-Schinzel syndrome 1	7
VPS35L	Limited	Autosomal recessive	Ritscher-Schinzel syndrome 3	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS35L	Orphanet:7	3C syndrome
WASHC5	Orphanet:100989	Autosomal dominant spastic paraplegia type 8
WASHC5	Orphanet:7	3C syndrome
CCDC22	Orphanet:7	3C syndrome
NSMCE2	Orphanet:436182	Microcephalic primordial dwarfism-insulin resistance syndrome
NSMCE2	Orphanet:808	Seckel syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS35L	HGNC:24641	ENSG00000103544	Q7Z3J2	VPS35 endosomal protein-sorting factor-like	gencc,clinvar
WASHC5	HGNC:28984	ENSG00000164961	Q12768	WASH complex subunit 5	gencc,clinvar
CCDC22	HGNC:28909	ENSG00000101997	O60826	Coiled-coil domain-containing protein 22	gencc
NSMCE2	HGNC:26513	ENSG00000156831	Q96MF7	E3 SUMO-protein ligase NSE2	clinvar
WASHC5-AS1	HGNC:43440	ENSG00000253167		WASHC5 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS35L	VPS35 endosomal protein-sorting factor-like	Acts as a component of the retriever complex.
WASHC5	WASH complex subunit 5	Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fi…
CCDC22	Coiled-coil domain-containing protein 22	Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex.
NSMCE2	E3 SUMO-protein ligase NSE2	E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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
Transcription factor	1	1.6×	0.476
Other/Unknown	4	1.4×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS35L	Other/Unknown	no		VPS35L
WASHC5	Other/Unknown	no		WASH_strumpellin
CCDC22	Other/Unknown	no		CCDC22, CCDC22_CC, CCDC22_N
NSMCE2	Transcription factor	no		Znf_MIZ, Znf_RING/FYVE/PHD, Nse2(Mms21)
WASHC5-AS1	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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	2
stromal cell of endometrium	2
corpus callosum	2
buccal mucosa cell	1
calcaneal tendon	1
granulocyte	1
leukocyte	1
monocyte	1
bone marrow cell	1
tibialis anterior	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS35L	282	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, colonic epithelium
WASHC5	283	ubiquitous	marker	corpus callosum, calcaneal tendon, stromal cell of endometrium
CCDC22	258	ubiquitous	yes	granulocyte, monocyte, leukocyte
NSMCE2	259	ubiquitous	marker	colonic epithelium, bone marrow cell, tibialis anterior
WASHC5-AS1	127		yes	male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCDC22	1,910
NSMCE2	1,550
WASHC5	1,115
VPS35L	685
WASHC5-AS1	0

Intra-cohort edges

A	B	Sources
CCDC22	VPS35L	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS35L	Q7Z3J2	7
CCDC22	O60826	4
NSMCE2	Q96MF7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WASHC5	Q12768	90.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 5 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
SUMOylation of DNA damage response and repair proteins	1	48.8×	0.102	NSMCE2
Neddylation	1	15.8×	0.155	CCDC22
Neutrophil degranulation	1	7.7×	0.185	VPS35L
Post-translational protein modification	1	6.4×	0.185	CCDC22
Metabolism of proteins	1	4.1×	0.223	CCDC22

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
Golgi to plasma membrane transport	2	280.9×	5e-04	VPS35L, CCDC22
protein transport	3	32.9×	7e-04	VPS35L, WASHC5, CCDC22
endocytic recycling	2	133.8×	8e-04	VPS35L, CCDC22
regulation of actin nucleation	1	2106.5×	0.003	WASHC5
meiotic spindle assembly	1	1404.3×	0.003	WASHC5
endosome fission	1	1404.3×	0.003	WASHC5
positive regulation of maintenance of mitotic sister chromatid cohesion	1	842.6×	0.004	NSMCE2
polar body extrusion after meiotic divisions	1	842.6×	0.004	WASHC5
regulation of vesicle size	1	601.9×	0.005	WASHC5
telomere maintenance via recombination	1	383.0×	0.008	NSMCE2
positive regulation of mitotic metaphase/anaphase transition	1	300.9×	0.008	NSMCE2
chromatin looping	1	300.9×	0.008	NSMCE2
regulation of Arp2/3 complex-mediated actin nucleation	1	263.3×	0.008	WASHC5
protein-containing complex localization	1	247.8×	0.008	WASHC5
intracellular copper ion homeostasis	1	234.1×	0.008	CCDC22
regulation of telomere maintenance	1	210.7×	0.009	NSMCE2
oocyte maturation	1	150.5×	0.011	WASHC5
positive regulation of ubiquitin-dependent protein catabolic process	1	140.4×	0.011	CCDC22
actin filament polymerization	1	120.4×	0.013	WASHC5
endosome organization	1	93.6×	0.015	WASHC5
protein sumoylation	1	81.0×	0.017	NSMCE2
lysosome organization	1	76.6×	0.017	WASHC5
cellular senescence	1	73.9×	0.017	NSMCE2
endosomal transport	1	61.1×	0.020	WASHC5
negative regulation of canonical NF-kappaB signal transduction	1	43.0×	0.027	CCDC22
double-strand break repair via homologous recombination	1	39.0×	0.028	NSMCE2
positive regulation of neuron projection development	1	34.2×	0.031	WASHC5
positive regulation of canonical NF-kappaB signal transduction	1	18.2×	0.056	CCDC22
cell division	1	11.5×	0.084	NSMCE2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS35L	0	0
WASHC5	0	0
CCDC22	0	0
NSMCE2	0	0
WASHC5-AS1	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
WASHC5	1	Binding:1
CCDC22	1	Binding:1
NSMCE2	1	Binding:1

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

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	5	VPS35L, WASHC5, CCDC22, NSMCE2, WASHC5-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS35L	0	—
WASHC5	1	—
CCDC22	1	—
NSMCE2	1	—
WASHC5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.