syndromic X-linked intellectual disability Hedera type

Summary

syndromic X-linked intellectual disability Hedera type (MONDO:0010319) is a disease caused by ATP6AP2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6AP2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 190
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002069	Bilateral tonic-clonic seizure	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002600	Hyporeflexia of lower limbs	Frequent (30-79%)
HP:0007076	Extrapyramidal muscular rigidity	Frequent (30-79%)
HP:0010819	Atonic seizure	Frequent (30-79%)
HP:0012391	Hyporeflexia of upper limbs	Frequent (30-79%)
HP:0000338	Hypomimic face	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0001621	Weak voice	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001848	Calcaneovalgus deformity	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002345	Action tremor	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0010527	Astereognosia	Occasional (5-29%)
HP:0010529	Echolalia	Occasional (5-29%)
HP:0011812	Agraphesthesia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Hedera type
Mondo ID	MONDO:0010319
MeSH	C564516
OMIM	300423
Orphanet	93952
DOID	DOID:0060806
UMLS	C1845543
MedGen	337257
GARD	0016834
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, syndromic, Hedera type, X-linked recessive · intellectual disability, X-linked, syndromic, Hedera type · mental retardation, X-linked, syndromic, Hedera type · mental retardation, X-linked, with epilepsy · MRXE · MRXSH · X-linked intellectual disability with epilepsy

Data availability: 190 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › X-linked intellectual disability-epilepsy syndrome › syndromic X-linked intellectual disability Hedera type

Related subtypes (3): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, X-linked dominant intellectual disability-epilepsy syndrome

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

190 retrieved; paginated sample, class counts are floors:

87 uncertain significance, 76 likely benign, 12 conflicting classifications of pathogenicity, 6 benign, 5 benign/likely benign, 3 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10801	NM_005765.3(ATP6AP2):c.321C>T (p.Asp107=)	ATP6AP2	Pathogenic	criteria provided, multiple submitters, no conflicts
3336071	NM_005765.3(ATP6AP2):c.284C>A (p.Ser95Ter)	ATP6AP2	Pathogenic	criteria provided, single submitter
869368	NM_005765.3(ATP6AP2):c.301-11_301-10del	ATP6AP2	Pathogenic	no assertion criteria provided
1698925	NM_005765.3(ATP6AP2):c.628G>T (p.Asp210Tyr)	ATP6AP2	Likely pathogenic	criteria provided, single submitter
1040448	NM_005765.3(ATP6AP2):c.455G>A (p.Arg152His)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346475	NM_005765.3(ATP6AP2):c.539A>G (p.Asp180Gly)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
199114	NM_005765.3(ATP6AP2):c.980A>G (p.Asn327Ser)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204912	NM_005765.3(ATP6AP2):c.490G>A (p.Val164Ile)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204914	NM_005765.3(ATP6AP2):c.19C>T (p.Leu7Phe)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204915	NM_005765.3(ATP6AP2):c.217C>T (p.Arg73Trp)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2075421	NM_005765.3(ATP6AP2):c.225C>T (p.Thr75=)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2844074	NM_005765.3(ATP6AP2):c.365C>T (p.Pro122Leu)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286695	NM_005765.3(ATP6AP2):c.534+7G>A	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
380358	NM_005765.3(ATP6AP2):c.922A>C (p.Asn308His)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
429667	NM_005765.3(ATP6AP2):c.190G>A (p.Ala64Thr)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533691	NM_005765.3(ATP6AP2):c.858G>A (p.Ala286=)	ATP6AP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016932	NM_005765.3(ATP6AP2):c.530A>G (p.Asn177Ser)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1023367	NM_005765.3(ATP6AP2):c.289C>T (p.Pro97Ser)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1056573	NM_005765.3(ATP6AP2):c.496A>T (p.Ser166Cys)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1059262	NM_005765.3(ATP6AP2):c.209A>T (p.His70Leu)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1206077	NM_005765.3(ATP6AP2):c.595C>T (p.Arg199Cys)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1359640	NM_005765.3(ATP6AP2):c.536T>C (p.Val179Ala)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1381753	NM_005765.3(ATP6AP2):c.673C>T (p.Arg225Cys)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1401326	NM_005765.3(ATP6AP2):c.226G>A (p.Val76Ile)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1416589	NM_005765.3(ATP6AP2):c.724G>A (p.Asp242Asn)	ATP6AP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1422943	NM_005765.3(ATP6AP2):c.692A>T (p.Glu231Val)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1424480	NM_005765.3(ATP6AP2):c.589-3A>G	ATP6AP2	Uncertain significance	criteria provided, single submitter
1435119	NM_005765.3(ATP6AP2):c.259G>C (p.Ala87Pro)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1461326	NM_005765.3(ATP6AP2):c.942G>A (p.Met314Ile)	ATP6AP2	Uncertain significance	criteria provided, single submitter
1462415	NM_005765.3(ATP6AP2):c.106C>T (p.Pro36Ser)	ATP6AP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
ATP6AP2	Strong	X-linked	syndromic X-linked intellectual disability Hedera type	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6AP2	Orphanet:363654	X-linked parkinsonism-spasticity syndrome
ATP6AP2	Orphanet:93952	X-linked intellectual disability, Hedera type

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
ATP6AP2	HGNC:18305	ENSG00000182220	O75787	Renin receptor	gencc,clinvar
MED14	HGNC:2370	ENSG00000180182	O60244	Mediator of RNA polymerase II transcription subunit 14	clinvar
NYX	HGNC:8082	ENSG00000188937	Q9GZU5	Nyctalopin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6AP2	Renin receptor	Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system.
MED14	Mediator of RNA polymerase II transcription subunit 14	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
NYX	Nyctalopin	Required for normal vision.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6AP2	Other/Unknown	no		Renin_rcpt, Renin_r_C, RENR_N
MED14	Other/Unknown	no		Mediator_Med14, Med14_RM8, Med14_RM2
NYX	Other/Unknown	no		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp

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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
tibia	1
visceral pleura	1
cartilage tissue	1
jejunal mucosa	1
secondary oocyte	1
pancreatic ductal cell	1
primordial germ cell in gonad	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6AP2	295	ubiquitous	marker	visceral pleura, tibia, germinal epithelium of ovary
MED14	285	ubiquitous	marker	secondary oocyte, jejunal mucosa, cartilage tissue
NYX	20	tissue_specific	yes	tendon of biceps brachii, primordial germ cell in gonad, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED14	5,271
ATP6AP2	2,236
NYX	1,227

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MED14	O60244	11
ATP6AP2	O75787	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NYX	Q9GZU5	82.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	335.9×	0.035	ATP6AP2
Metabolism of Angiotensinogen to Angiotensins	1	317.2×	0.035	ATP6AP2
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.035	MED14
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.035	MED14
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.035	MED14
RSV-host interactions	1	78.2×	0.035	MED14
Adipogenesis	1	78.2×	0.035	MED14
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.035	MED14
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.035	MED14
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.035	MED14
PPARA activates gene expression	1	47.2×	0.044	MED14
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.046	MED14
Epigenetic regulation of gene expression	1	35.7×	0.049	MED14
Metabolism of lipids	1	15.8×	0.098	MED14
Viral Infection Pathways	1	15.4×	0.098	MED14
Infectious disease	1	12.4×	0.111	MED14
Neutrophil degranulation	1	11.5×	0.111	ATP6AP2
RNA Polymerase II Transcription	1	11.3×	0.111	MED14
Gene expression (Transcription)	1	8.9×	0.132	MED14
Generic Transcription Pathway	1	7.5×	0.146	MED14
Developmental Biology	1	7.2×	0.146	MED14
Disease	1	6.5×	0.154	MED14
Metabolism	1	5.8×	0.165	MED14

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
eye pigmentation	1	5617.3×	0.004	ATP6AP2
central nervous system maturation	1	2808.7×	0.004	ATP6AP2
rostrocaudal neural tube patterning	1	1872.4×	0.004	ATP6AP2
positive regulation of transforming growth factor beta1 production	1	936.2×	0.006	ATP6AP2
head morphogenesis	1	702.2×	0.007	ATP6AP2
Golgi lumen acidification	1	561.7×	0.007	ATP6AP2
angiotensin maturation	1	432.1×	0.007	ATP6AP2
endosomal lumen acidification	1	401.2×	0.007	ATP6AP2
intracellular pH reduction	1	401.2×	0.007	ATP6AP2
synaptic vesicle lumen acidification	1	312.1×	0.008	ATP6AP2
vacuolar acidification	1	244.2×	0.009	ATP6AP2
lysosomal lumen acidification	1	224.7×	0.009	ATP6AP2
regulation of MAPK cascade	1	151.8×	0.012	ATP6AP2
positive regulation of Wnt signaling pathway	1	127.7×	0.013	ATP6AP2
proton transmembrane transport	1	104.0×	0.015	ATP6AP2
positive regulation of transcription elongation by RNA polymerase II	1	100.3×	0.015	MED14
RNA polymerase II preinitiation complex assembly	1	90.6×	0.015	MED14
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.015	MED14
somatic stem cell population maintenance	1	82.6×	0.015	MED14
positive regulation of canonical Wnt signaling pathway	1	51.5×	0.023	ATP6AP2
visual perception	1	26.5×	0.043	NYX
positive regulation of DNA-templated transcription	1	9.3×	0.113	MED14
positive regulation of transcription by RNA polymerase II	1	5.0×	0.197	MED14
regulation of transcription by RNA polymerase II	1	3.9×	0.236	MED14

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6AP2	0	0
MED14	0	0
NYX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	ATP6AP2, MED14, NYX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP6AP2	0	—
MED14	0	—
NYX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.