Ritscher-Schinzel syndrome 1

Summary

Ritscher-Schinzel syndrome 1 (MONDO:0009073) is a disease caused by WASHC5 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: WASHC5 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Ritscher-Schinzel syndrome 1
Mondo ID	MONDO:0009073
OMIM	220210
DOID	DOID:0060571
UMLS	C4551776
MedGen	1634646
GARD	0015160
Is cancer (heuristic)	no

Also known as: Ritscher-Schinzel syndrome · Ritscher-Schinzel syndrome 1 · Ritscher-Schinzel syndrome caused by mutation in WASHC5 · Ritscher-Schinzel syndrome type 1 · RTSC · RTSC1 · WASHC5 Ritscher-Schinzel syndrome

Data availability: 37 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Ritscher-Schinzel syndrome › Ritscher-Schinzel syndrome 1

Related subtypes (3): 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

37 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 8 likely pathogenic, 6 conflicting classifications of pathogenicity, 5 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
218105	NM_014008.5(CCDC22):c.49A>G (p.Thr17Ala)	CCDC22	Pathogenic	no assertion criteria provided
218106	NM_014008.5(CCDC22):c.1670A>G (p.Tyr557Cys)	CCDC22	Pathogenic	no assertion criteria provided
3233573	NM_014846.4(WASHC5):c.210del (p.Lys70fs)	WASHC5	Pathogenic	criteria provided, single submitter
463137	NM_014846.4(WASHC5):c.1771T>C (p.Ser591Pro)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4847578	NM_014846.4(WASHC5):c.2812C>T (p.Gln938Ter)	WASHC5	Pathogenic	criteria provided, single submitter
986025	NM_014846.4(WASHC5):c.232C>T (p.Gln78Ter)	WASHC5	Pathogenic	criteria provided, single submitter
2431692	NM_014846.4(WASHC5):c.3209del (p.Pro1070fs)	LOC126860498	Likely pathogenic	criteria provided, single submitter
3256600	NM_014846.4(WASHC5):c.3182-2A>G	LOC126860498	Likely pathogenic	criteria provided, single submitter
92129	NM_014846.4(WASHC5):c.3335+2T>A	LOC126860498	Likely pathogenic	criteria provided, single submitter
2576957	NM_014846.4(WASHC5):c.2954+3_2954+4delinsGC	WASHC5	Likely pathogenic	no assertion criteria provided
3256753	NM_014846.4(WASHC5):c.1859T>C (p.Val620Ala)	WASHC5	Likely pathogenic	no assertion criteria provided
4343215	NM_014846.4(WASHC5):c.2955-1G>A	WASHC5	Likely pathogenic	criteria provided, single submitter
4687443	NM_014846.4(WASHC5):c.2016+1G>A	WASHC5	Likely pathogenic	criteria provided, single submitter
570582	NM_014846.4(WASHC5):c.1151-2A>G	WASHC5	Likely pathogenic	criteria provided, single submitter
1063307	NM_014846.4(WASHC5):c.2008C>T (p.Arg670Ter)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2230355	NM_014846.4(WASHC5):c.2836G>A (p.Glu946Lys)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
583269	NM_014846.4(WASHC5):c.682C>T (p.Arg228Ter)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802440	NM_014846.4(WASHC5):c.420T>A (p.Cys140Ter)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
935991	NM_014846.4(WASHC5):c.735G>C (p.Glu245Asp)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
986026	NM_014846.4(WASHC5):c.2489G>A (p.Arg830Gln)	WASHC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632587	NM_020134.4(DPYSL5):c.139G>A (p.Gly47Arg)	DPYSL5	Uncertain significance	criteria provided, single submitter
4293931	NM_014846.4(WASHC5):c.3268C>T (p.Arg1090Trp)	LOC126860498	Uncertain significance	criteria provided, single submitter
1030373	NM_014846.4(WASHC5):c.2257C>T (p.Arg753Cys)	WASHC5	Uncertain significance	criteria provided, single submitter
1030375	NM_014846.4(WASHC5):c.2849A>G (p.Lys950Arg)	WASHC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299699	NM_014846.4(WASHC5):c.2429A>T (p.Lys810Met)	WASHC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801336	NM_014846.4(WASHC5):c.2954+3_2954+4delinsCG	WASHC5	Uncertain significance	criteria provided, single submitter
2431685	NM_014846.4(WASHC5):c.1136A>G (p.His379Arg)	WASHC5	Uncertain significance	criteria provided, single submitter
3255170	NM_014846.4(WASHC5):c.1102_1103del (p.Asp368fs)	WASHC5	Uncertain significance	criteria provided, single submitter
374553	NM_014846.4(WASHC5):c.2422A>G (p.Ile808Val)	WASHC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892877	NM_014846.4(WASHC5):c.1796G>A (p.Arg599His)	WASHC5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
WASHC5	Strong	Autosomal recessive	Ritscher-Schinzel syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WASHC5	Orphanet:100989	Autosomal dominant spastic paraplegia type 8
WASHC5	Orphanet:7	3C syndrome
DPYSL5	Orphanet:528084	Non-specific syndromic intellectual disability
DPYSL5	Orphanet:7	3C syndrome
CCDC22	Orphanet:7	3C syndrome

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
WASHC5	HGNC:28984	ENSG00000164961	Q12768	WASH complex subunit 5	gencc,clinvar
DPYSL5	HGNC:20637	ENSG00000157851	Q9BPU6	Dihydropyrimidinase-related protein 5	clinvar
CCDC22	HGNC:28909	ENSG00000101997	O60826	Coiled-coil domain-containing protein 22	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
DPYSL5	Dihydropyrimidinase-related protein 5	Involved in the negative regulation of dendrite outgrowth.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WASHC5	Other/Unknown	no		WASH_strumpellin
DPYSL5	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
CCDC22	Other/Unknown	no		CCDC22, CCDC22_CC, CCDC22_N

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
corpus callosum	1
stromal cell of endometrium	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WASHC5	283	ubiquitous	marker	corpus callosum, calcaneal tendon, stromal cell of endometrium
DPYSL5	133	broad	marker	cortical plate, ganglionic eminence, ventricular zone
CCDC22	258	ubiquitous	yes	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCDC22	1,910
DPYSL5	1,690
WASHC5	1,115

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCDC22	O60826	4
DPYSL5	Q9BPU6	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: 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
CRMPs in Sema3A signaling	1	317.2×	0.013	DPYSL5
Neddylation	1	23.7×	0.084	CCDC22
Post-translational protein modification	1	9.6×	0.135	CCDC22
Metabolism of proteins	1	6.2×	0.155	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of actin nucleation	1	2808.7×	0.004	WASHC5
meiotic spindle assembly	1	1872.4×	0.004	WASHC5
endosome fission	1	1872.4×	0.004	WASHC5
polar body extrusion after meiotic divisions	1	1123.5×	0.005	WASHC5
regulation of vesicle size	1	802.5×	0.005	WASHC5
negative regulation of dendrite morphogenesis	1	624.1×	0.005	DPYSL5
protein transport	2	29.3×	0.005	WASHC5, CCDC22
regulation of Arp2/3 complex-mediated actin nucleation	1	351.1×	0.008	WASHC5
protein-containing complex localization	1	330.4×	0.008	WASHC5
intracellular copper ion homeostasis	1	312.1×	0.008	CCDC22
oocyte maturation	1	200.6×	0.010	WASHC5
Golgi to plasma membrane transport	1	187.2×	0.010	CCDC22
positive regulation of ubiquitin-dependent protein catabolic process	1	187.2×	0.010	CCDC22
actin filament polymerization	1	160.5×	0.011	WASHC5
endosome organization	1	124.8×	0.013	WASHC5
lysosome organization	1	102.1×	0.015	WASHC5
endocytic recycling	1	89.2×	0.016	CCDC22
endosomal transport	1	81.4×	0.016	WASHC5
negative regulation of canonical NF-kappaB signal transduction	1	57.3×	0.022	CCDC22
positive regulation of neuron projection development	1	45.7×	0.026	WASHC5
axon guidance	1	30.2×	0.037	DPYSL5
positive regulation of canonical NF-kappaB signal transduction	1	24.2×	0.044	CCDC22
nervous system development	1	15.3×	0.067	DPYSL5
signal transduction	1	5.3×	0.176	DPYSL5

Therapeutics

Drug target analysis

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

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
WASHC5	0	0
DPYSL5	0	0
CCDC22	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

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	WASHC5, DPYSL5, CCDC22

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)
WASHC5	1	—
DPYSL5	0	—
CCDC22	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.