syndromic X-linked intellectual disability 14

Summary

syndromic X-linked intellectual disability 14 (MONDO:0010398) is a disease caused by UPF3B (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: UPF3B (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 243

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability 14
Mondo ID	MONDO:0010398
MeSH	C567063
OMIM	300676
DOID	DOID:0060821
UMLS	C1970822
MedGen	372646
GARD	0024723
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked syndromic 14, X-linked recessive · intellectual disability, X-linked, syndromic 14 · intellectual disability, X-linked, syndromic type 14 · mental retardation, X-linked, syndromic 14 · mental retardation, X-linked, syndromic type 14 · MRXS14 · syndromic X-linked intellectual disability 14 · syndromic X-linked intellectual disability type 14 · UPF3B X-linked syndromic intellectual disability · X-linked syndromic intellectual disability caused by mutation in UPF3B

Data availability: 243 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 › syndromic intellectual disability › X-linked syndromic intellectual disability › syndromic X-linked intellectual disability 14

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, 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, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

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

243 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 83 likely benign, 26 benign, 16 conflicting classifications of pathogenicity, 14 pathogenic, 12 benign/likely benign, 9 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424705	NC_000023.10:g.(?117629935)(119761021_?)del	RHOXF2	Pathogenic	criteria provided, single submitter
11399	NM_080632.3(UPF3B):c.867_868del (p.Gly290fs)	UPF3B	Pathogenic	no assertion criteria provided
11400	NM_080632.3(UPF3B):c.1288C>T (p.Arg430Ter)	UPF3B	Pathogenic	criteria provided, single submitter
11401	NM_080632.3(UPF3B):c.478T>G (p.Tyr160Asp)	UPF3B	Pathogenic	no assertion criteria provided
1275792	NM_080632.3(UPF3B):c.684_685del (p.Glu230fs)	UPF3B	Pathogenic	criteria provided, multiple submitters, no conflicts
1323743	NM_080632.3(UPF3B):c.670G>T (p.Glu224Ter)	UPF3B	Pathogenic	criteria provided, single submitter
1699417	NM_080632.3(UPF3B):c.1166_1167del (p.Lys389fs)	UPF3B	Pathogenic	criteria provided, single submitter
198608	NM_080632.3(UPF3B):c.674_677del (p.Arg225fs)	UPF3B	Pathogenic	criteria provided, multiple submitters, no conflicts
2092837	NM_080632.3(UPF3B):c.160delinsAC (p.Val54fs)	UPF3B	Pathogenic	criteria provided, single submitter
3255086	NM_080632.3(UPF3B):c.442_443del (p.Asp148fs)	UPF3B	Pathogenic	criteria provided, single submitter
420043	NM_080632.3(UPF3B):c.697_698del (p.Arg233fs)	UPF3B	Pathogenic	criteria provided, multiple submitters, no conflicts
4685508	NM_080632.3(UPF3B):c.280_283del (p.Tyr94fs)	UPF3B	Pathogenic	criteria provided, single submitter
488634	NM_080632.3(UPF3B):c.1351del (p.Arg451fs)	UPF3B	Pathogenic	criteria provided, single submitter
807522	NM_080632.3(UPF3B):c.575_578del (p.Glu191_Leu192insTer)	UPF3B	Pathogenic	criteria provided, single submitter
1325336	NM_080632.3(UPF3B):c.982G>T (p.Glu328Ter)	UPF3B	Likely pathogenic	criteria provided, single submitter
1712323	NM_080632.3(UPF3B):c.270T>G (p.Tyr90Ter)	UPF3B	Likely pathogenic	criteria provided, single submitter
1804141	NM_080632.3(UPF3B):c.1147G>T (p.Glu383Ter)	UPF3B	Likely pathogenic	criteria provided, single submitter
3027439	NM_080632.3(UPF3B):c.240del (p.Phe80fs)	UPF3B	Likely pathogenic	criteria provided, single submitter
4072032	NM_080632.3(UPF3B):c.263+2_263+3insTAAAAAAAA	UPF3B	Likely pathogenic	criteria provided, single submitter
4291127	NM_080632.3(UPF3B):c.1265_1266del (p.Lys422fs)	UPF3B	Likely pathogenic	criteria provided, single submitter
4795117	NM_080632.3(UPF3B):c.624+2T>G	UPF3B	Likely pathogenic	criteria provided, single submitter
981402	NM_080632.3(UPF3B):c.1060C>T (p.Arg354Ter)	UPF3B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
988748	NM_080632.3(UPF3B):c.646_647del (p.Glu216fs)	UPF3B	Likely pathogenic	no assertion criteria provided
1012886	NM_080632.3(UPF3B):c.277A>G (p.Met93Val)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1190148	NM_080632.3(UPF3B):c.1235C>T (p.Ser412Leu)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342827	NM_080632.3(UPF3B):c.1087A>G (p.Arg363Gly)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1597732	NM_080632.3(UPF3B):c.1136G>A (p.Arg379His)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1769242	NM_080632.3(UPF3B):c.1001C>T (p.Pro334Leu)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2039555	NM_080632.3(UPF3B):c.263+14_263+18dup	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212546	NM_080632.3(UPF3B):c.1121G>A (p.Arg374His)	UPF3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
UPF3B	Definitive	X-linked	syndromic X-linked intellectual disability 14	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UPF3B	Orphanet:776	Lujan-Fryns syndrome
UPF3B	Orphanet:777	X-linked non-syndromic intellectual disability

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
UPF3B	HGNC:20439	ENSG00000125351	Q9BZI7	Regulator of nonsense transcripts 3B	gencc,clinvar
C1GALT1C1	HGNC:24338	ENSG00000171155	Q96EU7	C1GALT1-specific chaperone 1	clinvar
RHOXF2	HGNC:30011	ENSG00000131721	Q9BQY4	Rhox homeobox family member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UPF3B	Regulator of nonsense transcripts 3B	Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery.
C1GALT1C1	C1GALT1-specific chaperone 1	Probable chaperone required for the generation of 1 O-glycan Gal-beta1-3GalNAc-alpha1-Ser/Thr (T antigen), which is a precursor for many extended O-glycans in glycoproteins.
RHOXF2	Rhox homeobox family member 2	Transcription factor maybe involved in reproductive processes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UPF3B	Other/Unknown	no		UPF3_dom, Nucleotide-bd_a/b_plait_sf, UPF3B_RRM-like
C1GALT1C1	Enzyme (other)	yes	2.4.1.122	C1GALT1/C1GALT1_chp1
RHOXF2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
esophagus squamous epithelium	1
sural nerve	1
calcaneal tendon	1
islet of Langerhans	1
rectum	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UPF3B	277	ubiquitous	marker	sural nerve, esophagus squamous epithelium, embryo
C1GALT1C1	134	ubiquitous	marker	islet of Langerhans, calcaneal tendon, rectum
RHOXF2	22	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UPF3B	1,677
RHOXF2	948
C1GALT1C1	806

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UPF3B	Q9BZI7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C1GALT1C1	Q96EU7	87.21
RHOXF2	Q9BQY4	64.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Defective C1GALT1C1 causes TNPS	1	335.9×	0.030	C1GALT1C1
Diseases associated with O-glycosylation of proteins	1	107.7×	0.030	C1GALT1C1
mRNA 3’-end processing	1	98.5×	0.030	UPF3B
O-linked glycosylation of mucins	1	92.1×	0.030	C1GALT1C1
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	76.1×	0.030	UPF3B
O-linked glycosylation	1	72.3×	0.030	C1GALT1C1
Diseases of glycosylation	1	65.6×	0.030	C1GALT1C1
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	48.8×	0.036	UPF3B
Diseases of metabolism	1	40.2×	0.038	C1GALT1C1
Regulation of expression of SLITs and ROBOs	1	34.6×	0.040	UPF3B
mRNA Splicing - Major Pathway	1	27.3×	0.046	UPF3B
Post-translational protein modification	1	9.6×	0.118	C1GALT1C1
Disease	1	6.5×	0.155	C1GALT1C1
Metabolism of proteins	1	6.2×	0.155	C1GALT1C1

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
platelet morphogenesis	1	1872.4×	0.005	C1GALT1C1
positive regulation of mRNA cis splicing, via spliceosome	1	1404.3×	0.005	UPF3B
random inactivation of X chromosome	1	312.1×	0.015	UPF3B
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	156.0×	0.021	UPF3B
platelet activation	1	89.2×	0.021	C1GALT1C1
mRNA transport	1	87.8×	0.021	UPF3B
neuron development	1	85.1×	0.021	RHOXF2
positive regulation of translation	1	75.9×	0.021	UPF3B
protein O-linked glycosylation	1	74.9×	0.021	C1GALT1C1
positive regulation of neuron differentiation	1	66.1×	0.021	UPF3B
neuron projection development	1	40.7×	0.031	UPF3B
brain development	1	26.5×	0.043	UPF3B
positive regulation of gene expression	1	12.9×	0.081	RHOXF2
regulation of transcription by RNA polymerase II	1	3.9×	0.236	RHOXF2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RHOXF2	1	2
UPF3B	0	0
C1GALT1C1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RHOXF2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RHOXF2	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C1GALT1C1	2.4.1.122	N-acetylgalactosaminide beta-1,3-galactosyltransferase

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

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	RHOXF2

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	RHOXF2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	C1GALT1C1
E	Difficult family or no structure, no drug	1	UPF3B

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)
UPF3B	0	—
C1GALT1C1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.