FRAXE intellectual disability

Summary

FRAXE intellectual disability (MONDO:0010659) is a disease caused by AFF2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: AFF2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 64
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000713	Agitation	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0009904	Prominent ear helix	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0100023	Recurrent hand flapping	Frequent (30-79%)
HP:0100710	Impulsivity	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0012172	Stereotypical body rocking	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	FRAXE intellectual disability
Mondo ID	MONDO:0010659
OMIM	309548
Orphanet	100973
DOID	DOID:0080984
SNOMED CT	716709002
UMLS	C0751157
MedGen	155512
GARD	0002378
Is cancer (heuristic)	no

Also known as: fragile site, folic acid type · fragile XE syndrome · FRAXE intellectual disability · FRAXE mental retardation syndrome · FRAXE syndrome · intellectual developmental disorder, X-linked 109, X-linked recessive · intellectual disability associated with fragile site FRAXE · mental retardation, X-linked, associated with fragile site FRAXE · X-linked intellectual disability associated with fragile site FRAXE · X-linked mental retardation associated with fragile site FRAXE

Data availability: 64 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › non-syndromic X-linked intellectual disability › FRAXE intellectual disability

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked 63, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 99, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 102, intellectual disability, X-linked 61, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

64 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 7 pathogenic, 5 benign, 5 likely pathogenic, 3 benign/likely benign, 3 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
10526	NM_001169122.2(AFF2):c.-460GCC[6_25]	AFF2	Pathogenic	no assertion criteria provided
1703601	GRCh37/hg19 Xq28(chrX:147458752-147628024)	AFF2	Pathogenic	no assertion criteria provided
29983	NG_016313.2:g.(5527_156380)_(156514_166289)del	AFF2	Pathogenic	no assertion criteria provided
4082297	NM_002025.4(AFF2):c.3476+1G>A	AFF2	Pathogenic	criteria provided, single submitter
4279015	NM_002025.4:c.1350_1397+1491del	AFF2	Pathogenic	criteria provided, single submitter
625801	GRCh37/hg19 Xq28(chrX:147642893-147870805)	AFF2	Pathogenic	criteria provided, single submitter
975105	NM_002025.4(AFF2):c.3448G>T (p.Asp1150Tyr)	AFF2	Pathogenic	no assertion criteria provided
1327917	NM_002025.4(AFF2):c.3481C>T (p.Arg1161Ter)	AFF2	Likely pathogenic	no assertion criteria provided
1332788	NM_002025.4(AFF2):c.2885G>A (p.Cys962Tyr)	AFF2	Likely pathogenic	criteria provided, single submitter
3573463	NM_002025.4(AFF2):c.1699G>T (p.Glu567Ter)	AFF2	Likely pathogenic	criteria provided, single submitter
3598108	NM_002025.4(AFF2):c.232_233delinsG (p.Tyr78fs)	AFF2	Likely pathogenic	criteria provided, single submitter
4077095	NM_002025.4(AFF2):c.3489_3490dup (p.Ser1164fs)	AFF2	Likely pathogenic	criteria provided, single submitter
3572853	NM_002025.4(AFF2):c.901A>G (p.Ile301Val)	AFF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431909	NM_002025.4(AFF2):c.3267+5G>A	AFF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
94027	NM_002025.4(AFF2):c.3088A>C (p.Ile1030Leu)	AFF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17967	NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)	SERPINA1	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
1029402	NM_002025.4(AFF2):c.1467A>T (p.Glu489Asp)	AFF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029403	NM_002025.4(AFF2):c.3010A>T (p.Thr1004Ser)	AFF2	Uncertain significance	criteria provided, single submitter
128283	NM_002025.4(AFF2):c.1830G>C (p.Leu610Phe)	AFF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1305777	NM_002025.4(AFF2):c.2614G>C (p.Glu872Gln)	AFF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679659	NM_002025.4(AFF2):c.48-60738G>C	AFF2	Uncertain significance	criteria provided, single submitter
1699495	NM_002025.4(AFF2):c.3164G>A (p.Ser1055Asn)	AFF2	Uncertain significance	criteria provided, single submitter
1708052	NM_002025.4(AFF2):c.3163A>G (p.Ser1055Gly)	AFF2	Uncertain significance	criteria provided, single submitter
219173	NM_002025.4(AFF2):c.*4554C>G	AFF2	Uncertain significance	criteria provided, single submitter
2335186	NM_002025.4(AFF2):c.3712C>T (p.Arg1238Cys)	AFF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431756	NM_002025.4(AFF2):c.1012C>A (p.Pro338Thr)	AFF2	Uncertain significance	criteria provided, single submitter
2438902	NM_002025.4(AFF2):c.2637G>T (p.Leu879Phe)	AFF2	Uncertain significance	criteria provided, single submitter
2438903	NM_002025.4(AFF2):c.2820C>A (p.Asp940Glu)	AFF2	Uncertain significance	criteria provided, single submitter
2438904	NM_002025.4(AFF2):c.511G>T (p.Ala171Ser)	AFF2	Uncertain significance	criteria provided, single submitter
2438905	NM_002025.4(AFF2):c.3017T>C (p.Val1006Ala)	AFF2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
AFF2	Definitive	X-linked	FRAXE intellectual disability	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AFF2	Orphanet:100973	FRAXE intellectual disability
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin deficiency

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
AFF2	HGNC:3776	ENSG00000155966	P51816	AF4/FMR2 family member 2	gencc,clinvar
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AFF2	AF4/FMR2 family member 2	RNA-binding protein.
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AFF2	Other/Unknown	no		AF4/FMR2, AF4_int, AF4/FMR2_CHD
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cortical plate	1
ganglionic eminence	1
blood	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AFF2	174	broad	marker	cortical plate, ganglionic eminence, calcaneal tendon
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SERPINA1	3,617
AFF2	1,625

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINA1	P01009	46

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AFF2	P51816	49.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Cargo concentration in the ER	1	335.9×	0.023	SERPINA1
COPII-mediated vesicle transport	1	163.1×	0.023	SERPINA1
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.023	SERPINA1
ER to Golgi Anterograde Transport	1	132.8×	0.023	SERPINA1
Platelet activation, signaling and aggregation	1	105.7×	0.023	SERPINA1
Transport to the Golgi and subsequent modification	1	102.9×	0.023	SERPINA1
Post-translational protein phosphorylation	1	100.2×	0.023	SERPINA1
Platelet degranulation	1	87.8×	0.023	SERPINA1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.023	SERPINA1
Asparagine N-linked glycosylation	1	60.1×	0.030	SERPINA1
Membrane Trafficking	1	37.1×	0.040	SERPINA1
Hemostasis	1	36.0×	0.040	SERPINA1
Vesicle-mediated transport	1	34.8×	0.040	SERPINA1
Innate Immune System	1	25.5×	0.050	SERPINA1
Neutrophil degranulation	1	23.1×	0.052	SERPINA1
Post-translational protein modification	1	19.2×	0.059	SERPINA1
Immune System	1	13.0×	0.081	SERPINA1
Metabolism of proteins	1	12.4×	0.081	SERPINA1

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
nuclear speck organization	1	2106.5×	0.005	AFF2
acute-phase response	1	210.7×	0.023	SERPINA1
learning or memory	1	120.4×	0.023	AFF2
regulation of RNA splicing	1	109.4×	0.023	AFF2
blood coagulation	1	86.9×	0.023	SERPINA1
RNA splicing	1	44.1×	0.028	AFF2
regulation of gene expression	1	41.7×	0.028	AFF2
brain development	1	39.8×	0.028	AFF2
mRNA processing	1	39.4×	0.028	AFF2
negative regulation of gene expression	1	34.5×	0.029	AFF2

Therapeutics

Drug target analysis

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

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
AFF2	1	2
SERPINA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	AFF2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AFF2	8	Binding:8

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

1 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)
MOLIBRESIB	2	AFF2

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	1	AFF2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SERPINA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SERPINA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.