syndromic X-linked intellectual disability Nascimento type

Summary

syndromic X-linked intellectual disability Nascimento type (MONDO:0010461) is a disease caused by UBE2A (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UBE2A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 26
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

64 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0002194	Delayed gross motor development	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0009765	Low hanging columella	Very frequent (80-99%)
HP:0000054	Micropenis	Frequent (30-79%)
HP:0000076	Vesicoureteral reflux	Frequent (30-79%)
HP:0000233	Thin vermilion border	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000475	Broad neck	Frequent (30-79%)
HP:0000582	Upslanted palpebral fissure	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)
HP:0002230	Generalized hirsutism	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0003265	Neonatal hyperbilirubinemia	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006610	Wide intermamillary distance	Frequent (30-79%)
HP:0007103	Hypointensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0010529	Echolalia	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000430	Underdeveloped nasal alae	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0001718	Mitral stenosis	Occasional (5-29%)
HP:0001719	Double outlet right ventricle	Occasional (5-29%)
HP:0001776	Bilateral talipes equinovarus	Occasional (5-29%)
HP:0001845	Overlapping toe	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0002002	Deep philtrum	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Nascimento type
Mondo ID	MONDO:0010461
OMIM	300860
Orphanet	163956
DOID	DOID:0060820
UMLS	C3275464
MedGen	477095
GARD	0017005
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked syndromic, Nascimento type, X-linked recessive · intellectual disability, X-linked syndromic, Nascimento-type · intellectual disability, X-linked, syndromic, Nascimento type · mental retardation, X-linked, syndromic 30 · mental retardation, X-linked, syndromic, Nascimento type · MRXSN · syndromic X-linked intellectual disability Nascimento type · X-linked intellectual disability-nail dystrophy-seizures syndrome

Data availability: 26 ClinVar variants · 5 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 Nascimento type

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 14, 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 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

26 retrieved; paginated sample, class counts are floors:

10 likely pathogenic, 9 uncertain significance, 7 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3370380	GRCh38/hg38 Xq24(chrX:119539765-119707314)x0	LOC130068596	Pathogenic	no assertion criteria provided
2579183	GRCh38/hg38 Xq24(chrX:119582581-119589158)x0	NKRF	Pathogenic	criteria provided, single submitter
29993	NM_003336.4(UBE2A):c.32G>A (p.Arg11Gln)	UBE2A	Pathogenic	no assertion criteria provided
3254933	NM_003336.4(UBE2A):c.126-2A>G	UBE2A	Pathogenic	criteria provided, single submitter
437188	NM_003336.4(UBE2A):c.67G>A (p.Gly23Arg)	UBE2A	Pathogenic	criteria provided, single submitter
625798	GRCh37/hg19 Xq24(chrX:118714474-118718137)	UBE2A	Pathogenic	criteria provided, single submitter
9922	NM_003336.4(UBE2A):c.382C>T (p.Gln128Ter)	UBE2A	Pathogenic	no assertion criteria provided
1333497	NM_003336.4(UBE2A):c.421_422del (p.Val141fs)	UBE2A	Likely pathogenic	criteria provided, single submitter
2572051	NM_003336.4(UBE2A):c.439C>T (p.Gln147Ter)	UBE2A	Likely pathogenic	criteria provided, single submitter
3061895	NM_003336.4(UBE2A):c.330+1del	UBE2A	Likely pathogenic	criteria provided, single submitter
3775532	NM_003336.4(UBE2A):c.330+1G>C	UBE2A	Likely pathogenic	criteria provided, single submitter
4849266	NM_003336.4(UBE2A):c.260dup (p.Cys88fs)	UBE2A	Likely pathogenic	no assertion criteria provided
559652	NM_003336.4(UBE2A):c.373del (p.Gln125fs)	UBE2A	Likely pathogenic	no assertion criteria provided
804078	NM_003336.4(UBE2A):c.31_42del (p.Asp12_Arg15del)	UBE2A	Likely pathogenic	criteria provided, single submitter
915473	NM_003336.4(UBE2A):c.299ATG[1] (p.Asp101del)	UBE2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
915474	NM_003336.4(UBE2A):c.242-3_244del	UBE2A	Likely pathogenic	criteria provided, single submitter
976781	NM_003336.4(UBE2A):c.330+1G>A	UBE2A	Likely pathogenic	no assertion criteria provided
1805779	NM_003336.4(UBE2A):c.39C>A (p.Phe13Leu)	UBE2A	Uncertain significance	criteria provided, single submitter
2498374	NM_003336.4(UBE2A):c.352C>A (p.Pro118Thr)	UBE2A	Uncertain significance	no assertion criteria provided
3376419	NM_003336.4(UBE2A):c.394_396del (p.Glu132del)	UBE2A	Uncertain significance	criteria provided, single submitter
3777742	NM_003336.4(UBE2A):c.320C>T (p.Thr107Ile)	UBE2A	Uncertain significance	criteria provided, single submitter
4082023	NM_003336.4(UBE2A):c.126-2dup	UBE2A	Uncertain significance	no assertion criteria provided
589444	NM_003336.4(UBE2A):c.403C>T (p.Arg135Trp)	UBE2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
915472	NM_003336.4(UBE2A):c.295A>G (p.Thr99Ala)	UBE2A	Uncertain significance	criteria provided, single submitter
915475	NM_003336.4(UBE2A):c.184G>A (p.Glu62Lys)	UBE2A	Uncertain significance	criteria provided, single submitter
915476	NM_003336.4(UBE2A):c.283C>T (p.Arg95Cys)	UBE2A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
UBE2A	Definitive	X-linked	syndromic X-linked intellectual disability Nascimento type	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBE2A	Orphanet:163956	X-linked intellectual disability, Nascimento type

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
UBE2A	HGNC:12472	ENSG00000077721	P49459	Ubiquitin-conjugating enzyme E2 A	gencc,clinvar
NKRF	HGNC:19374	ENSG00000186416	O15226	NF-kappa-B-repressing factor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBE2A	Ubiquitin-conjugating enzyme E2 A	E2 ubiquitin-conjugating enzyme that accepts ubiquitin from the ubiquitin-activating enzyme E1 and transfers it to a E3 ubiquitin-protein ligase.
NKRF	NF-kappa-B-repressing factor	Enhances the ATPase activity of DHX15 by acting like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity of DHX15.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UBE2A	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
NKRF	Other/Unknown	no		G_patch_dom, R3H_dom, dsRBD_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
mucosa of transverse colon	1
placenta	1
Brodmann (1909) area 23	1
parietal lobe	1
postcentral gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBE2A	295	ubiquitous	marker	endothelial cell, mucosa of transverse colon, placenta
NKRF	251	ubiquitous	yes	postcentral gyrus, Brodmann (1909) area 23, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBE2A	4,659
NKRF	2,466

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBE2A	P49459	5
NKRF	O15226	2

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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.008	UBE2A
E3 ubiquitin ligases ubiquitinate target proteins	1	193.6×	0.008	UBE2A
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	UBE2A

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
DNA damage tolerance	1	842.6×	0.012	UBE2A
positive regulation of mitophagy	1	561.7×	0.012	UBE2A
protein K11-linked ubiquitination	1	195.9×	0.017	UBE2A
response to UV	1	183.2×	0.017	UBE2A
G2/M transition of mitotic cell cycle	1	156.0×	0.017	UBE2A
protein K48-linked ubiquitination	1	84.3×	0.026	UBE2A
protein polyubiquitination	1	57.7×	0.032	UBE2A
ubiquitin-dependent protein catabolic process	1	37.1×	0.039	UBE2A
chromatin remodeling	1	36.5×	0.039	UBE2A
DNA repair	1	31.9×	0.040	UBE2A
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.045	UBE2A
negative regulation of DNA-templated transcription	1	15.8×	0.068	NKRF
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	NKRF

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
UBE2A	0	0
NKRF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NKRF	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBE2A	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme

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	1	UBE2A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NKRF

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)
UBE2A	0	—
NKRF	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.