FG syndrome 4

Summary

FG syndrome 4 (MONDO:0010318) is a disease caused by CASK (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CASK (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	FG syndrome 4
Mondo ID	MONDO:0010318
OMIM	300422
UMLS	C1845546
MedGen	336965
Is cancer (heuristic)	no

Also known as: CASK FG syndrome · cask FG syndrome · CASK-related FG syndrome · FG syndrome 4 · FG syndrome caused by mutation in cask · FG syndrome type 4 · FGS4 · mental retardation, X-linked, with or without Nystagmus

Data availability: 49 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › FG syndrome › FG syndrome 4

Related subtypes (5): FG syndrome 2, FG syndrome 3, FG syndrome 5, Aarskog-Scott syndrome, X-linked, FG syndrome 1

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

49 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 8 pathogenic, 8 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic/likely pathogenic, 1 likely benign, 1 benign, 1 vus-high

ClinVar	Variant (HGVS)	Gene	Classification	Review
11532	NM_001367721.1(CASK):c.83G>T (p.Arg28Leu)	CASK	Pathogenic	no assertion criteria provided
11535	NM_001367721.1(CASK):c.2755T>C (p.Trp919Arg)	CASK	Pathogenic	no assertion criteria provided
1343138	NM_001367721.1(CASK):c.2317+5G>A	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158086	NM_001367721.1(CASK):c.82C>T (p.Arg28Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
1707714	NC_000023.10:g.(?41387096)(41396627_?)del	CASK	Pathogenic	criteria provided, single submitter
265316	NM_001367721.1(CASK):c.2521-2A>G	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075664	NM_001367721.1(CASK):c.1843-1G>A	CASK	Pathogenic	criteria provided, single submitter
418109	NM_001367721.1(CASK):c.1837C>T (p.Arg613Ter)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423284	NM_001367721.1(CASK):c.59+2T>C	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434588	NM_001367721.1(CASK):c.846C>G (p.Tyr282Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
575647	NM_001367721.1(CASK):c.305A>G (p.Glu102Gly)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689749	NM_001367721.1(CASK):c.913_914dup (p.Gly306fs)	CASK	Pathogenic	criteria provided, single submitter
810578	NM_001367721.1(CASK):c.1466G>A (p.Arg489Gln)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930346	NM_001367721.1(CASK):c.916-1G>A	CASK	Pathogenic	criteria provided, single submitter
11534	NM_001367721.1(CASK):c.2129A>G (p.Asp710Gly)	CASK	Likely pathogenic	criteria provided, single submitter
1319147	NM_001367721.1(CASK):c.1424G>T (p.Ser475Ile)	CASK	Likely pathogenic	criteria provided, single submitter
29937	NM_001367721.1(CASK):c.2183A>G (p.Tyr728Cys)	CASK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254723	NM_001367721.1(CASK):c.464C>T (p.Ser155Leu)	CASK	Likely pathogenic	criteria provided, single submitter
4291118	NM_001367721.1:c.1156-4408_1503+2676dup	CASK	Likely pathogenic	criteria provided, single submitter
619127	NM_001367721.1(CASK):c.2561T>C (p.Val854Ala)	CASK	Likely pathogenic	criteria provided, single submitter
11533	NM_001367721.1(CASK):c.802T>C (p.Tyr268His)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11536	NM_001367721.1(CASK):c.1186C>T (p.Pro396Ser)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158084	NM_001367721.1(CASK):c.764G>A (p.Arg255His)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676836	NM_001367721.1(CASK):c.1082C>T (p.Thr361Ile)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587634	NM_001367721.1(CASK):c.761G>A (p.Arg254His)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803985	NM_001367721.1(CASK):c.787G>A (p.Glu263Lys)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
948190	NM_001367721.1(CASK):c.1714C>T (p.Arg572Cys)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
976147	NM_001367721.1(CASK):c.616G>A (p.Gly206Ser)	CASK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1311876	NM_001367721.1(CASK):c.1504G>A (p.Gly502Arg)	CASK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330235	NM_001367721.1(CASK):c.2434G>C (p.Glu812Gln)	CASK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
CASK	Definitive	X-linked	FG syndrome 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cortical plate	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASK	4,223

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASK	O14936	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Dopamine Neurotransmitter Release Cycle	1	496.5×	0.006	CASK
Nephrin family interactions	1	475.8×	0.006	CASK
Syndecan interactions	1	423.0×	0.006	CASK
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.006	CASK
Sensory processing of sound by outer hair cells of the cochlea	1	203.9×	0.006	CASK
Neurexins and neuroligins	1	196.9×	0.006	CASK
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.006	CASK

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cellular response to growth factor stimulus	1	8426.0×	0.001	CASK
negative regulation of wound healing	1	1296.3×	0.002	CASK
positive regulation of calcium ion import	1	936.2×	0.002	CASK
negative regulation of cell-matrix adhesion	1	887.0×	0.002	CASK
calcium ion import	1	802.5×	0.002	CASK
regulation of neurotransmitter secretion	1	766.0×	0.002	CASK
negative regulation of keratinocyte proliferation	1	702.2×	0.002	CASK
regulation of synaptic vesicle exocytosis	1	455.5×	0.003	CASK
establishment of localization in cell	1	160.5×	0.008	CASK
intracellular protein localization	1	104.7×	0.011	CASK
cell adhesion	1	37.5×	0.029	CASK
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	CASK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CASK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASK	9	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CASK	92	Binding:92

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CASK
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.