Ritscher-Schinzel syndrome 2

Summary

Ritscher-Schinzel syndrome 2 (MONDO:0010499) is a disease caused by CCDC22 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CCDC22 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Ritscher-Schinzel syndrome 2
Mondo ID	MONDO:0010499
OMIM	300963
DOID	DOID:0060572
UMLS	C4225419
MedGen	897005
GARD	0015278
Is cancer (heuristic)	no

Also known as: CCDC22 Ritscher-Schinzel syndrome · Ritscher-Schinzel syndrome 2 · Ritscher-Schinzel syndrome 2, X-linked recessive · Ritscher-Schinzel syndrome caused by mutation in CCDC22 · Ritscher-Schinzel syndrome type 2 · RTSC2

Data availability: 45 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 2

Related subtypes (3): Ritscher-Schinzel syndrome 1, 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

45 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 4 pathogenic, 3 benign, 2 conflicting classifications of pathogenicity, 1 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
1273	NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
802049	NM_173660.5(DOK7):c.1143del (p.Glu382fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
835508	NM_173660.5(DOK7):c.54+25_55-38del	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699426	NM_014008.5(CCDC22):c.622G>A (p.Glu208Lys)	CCDC22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805884	NM_014008.5(CCDC22):c.142G>A (p.Ala48Thr)	CCDC22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031225	NM_014008.5(CCDC22):c.110C>T (p.Ala37Val)	CCDC22	Uncertain significance	criteria provided, single submitter
1031226	NM_014008.5(CCDC22):c.1610C>T (p.Ala537Val)	CCDC22	Uncertain significance	criteria provided, single submitter
1032585	NM_014008.5(CCDC22):c.1343G>T (p.Arg448Leu)	CCDC22	Uncertain significance	criteria provided, single submitter
1032586	NM_014008.5(CCDC22):c.383G>A (p.Arg128Gln)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1193798	NM_014008.5(CCDC22):c.1730C>T (p.Thr577Ile)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1306352	NM_014008.5(CCDC22):c.1873C>T (p.Arg625Trp)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1334483	NM_014008.5(CCDC22):c.1212+4G>T	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1527951	NM_014008.5(CCDC22):c.2T>C (p.Met1Thr)	CCDC22	Uncertain significance	criteria provided, single submitter
1679235	NM_014008.5(CCDC22):c.1882T>C (p.Ter628Arg)	CCDC22	Uncertain significance	criteria provided, single submitter
1805180	NM_014008.5(CCDC22):c.319C>T (p.Arg107Cys)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2207497	NM_014008.5(CCDC22):c.973G>T (p.Val325Phe)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431198	NM_014008.5(CCDC22):c.49A>C (p.Thr17Pro)	CCDC22	Uncertain significance	criteria provided, single submitter
2431770	NM_014008.5(CCDC22):c.1852G>C (p.Ala618Pro)	CCDC22	Uncertain significance	criteria provided, single submitter
2439787	NM_014008.5(CCDC22):c.1222G>A (p.Glu408Lys)	CCDC22	Uncertain significance	criteria provided, single submitter
2439788	NM_014008.5(CCDC22):c.552G>C (p.Gln184His)	CCDC22	Uncertain significance	criteria provided, single submitter
2439789	NM_014008.5(CCDC22):c.382C>T (p.Arg128Trp)	CCDC22	Uncertain significance	criteria provided, single submitter
2439790	NM_014008.5(CCDC22):c.559C>T (p.Pro187Ser)	CCDC22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439791	NM_014008.5(CCDC22):c.1610C>G (p.Ala537Gly)	CCDC22	Uncertain significance	criteria provided, single submitter
2439792	NM_014008.5(CCDC22):c.1501G>A (p.Val501Met)	CCDC22	Uncertain significance	criteria provided, single submitter
2439793	NM_014008.5(CCDC22):c.1000C>G (p.Leu334Val)	CCDC22	Uncertain significance	criteria provided, single submitter
2439794	NM_014008.5(CCDC22):c.1862T>G (p.Leu621Arg)	CCDC22	Uncertain significance	criteria provided, single submitter
2439795	NM_014008.5(CCDC22):c.542G>A (p.Arg181Gln)	CCDC22	Uncertain significance	criteria provided, single submitter
2441877	NM_014008.5(CCDC22):c.190C>G (p.Arg64Gly)	CCDC22	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCDC22	Orphanet:7	3C syndrome
DOK7	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
DOK7	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CCDC22	HGNC:28909	ENSG00000101997	O60826	Coiled-coil domain-containing protein 22	gencc,clinvar
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
DOK7	Protein Dok-7	Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCDC22	Other/Unknown	no		CCDC22, CCDC22_CC, CCDC22_N
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1
apex of heart	1
right atrium auricular region	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCDC22	258	ubiquitous	yes	granulocyte, monocyte, leukocyte
DOK7	180	broad	yes	apex of heart, tibialis anterior, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCDC22	1,910
DOK7	704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCDC22	O60826	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DOK7	Q18PE1	65.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neddylation	1	47.4×	0.063	CCDC22
Post-translational protein modification	1	19.2×	0.078	CCDC22
Metabolism of proteins	1	12.4×	0.081	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 2 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 protein tyrosine kinase activity	1	1053.2×	0.005	DOK7
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.005	DOK7
enzyme-linked receptor protein signaling pathway	1	648.1×	0.005	DOK7
intracellular copper ion homeostasis	1	468.1×	0.005	CCDC22
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.005	DOK7
positive regulation of Rac protein signal transduction	1	324.1×	0.005	DOK7
receptor clustering	1	312.1×	0.005	DOK7
Golgi to plasma membrane transport	1	280.9×	0.005	CCDC22
Rac protein signal transduction	1	280.9×	0.005	DOK7
positive regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.005	CCDC22
neuromuscular junction development	1	263.3×	0.005	DOK7
endocytic recycling	1	133.8×	0.009	CCDC22
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.013	CCDC22
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.029	CCDC22
protein transport	1	21.9×	0.045	CCDC22

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCDC22	0	0
DOK7	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
CCDC22	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CCDC22, DOK7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CCDC22	1	—
DOK7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.