intellectual disability, X-linked, syndromic, Bain type

Summary

intellectual disability, X-linked, syndromic, Bain type (MONDO:0010512) is a disease caused by HNRNPH2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HNRNPH2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		44	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked, syndromic, Bain type
Mondo ID	MONDO:0010512
OMIM	300986
Orphanet	662198
DOID	DOID:0070538
UMLS	C4310814
MedGen	934781
GARD	0013442
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, syndromic, Bain type, X-linked dominant · intellectual disability, X-linked, syndromic, Bain type · mental retardation, X-linked, syndromic, Bain type · MRXSB

Data availability: 17 ClinVar variants · 3 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 › intellectual disability, X-linked, syndromic, Bain 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 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, 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

17 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 4 uncertain significance, 3 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225760	NM_019597.5(HNRNPH2):c.616C>T (p.Arg206Trp)	HNRNPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225761	NM_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)	HNRNPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1098285	NM_019597.5(HNRNPH2):c.340C>T (p.Arg114Trp)	RPL36A-HNRNPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
225759	NM_019597.5(HNRNPH2):c.626C>T (p.Pro209Leu)	RPL36A-HNRNPH2	Pathogenic	criteria provided, single submitter
1708044	NM_019597.5(HNRNPH2):c.613C>T (p.Gln205Ter)	HNRNPH2	Likely pathogenic	criteria provided, single submitter
1708226	NM_019597.5(HNRNPH2):c.460del (p.Glu154fs)	HNRNPH2	Likely pathogenic	criteria provided, single submitter
828178	NM_001257293.2(HNRNPH1):c.340C>T (p.Arg114Trp)	LOC128966623	Likely pathogenic	criteria provided, single submitter
4687982	NM_019597.5(HNRNPH2):c.978_979del (p.Arg326fs)	RPL36A-HNRNPH2	Likely pathogenic	criteria provided, single submitter
807430	NM_019597.5(HNRNPH2):c.85C>T (p.Arg29Cys)	RPL36A-HNRNPH2	Likely pathogenic	criteria provided, single submitter
984808	NM_019597.5(HNRNPH2):c.635G>C (p.Arg212Thr)	RPL36A-HNRNPH2	Likely pathogenic	no assertion criteria provided
217410	NM_000169.3(GLA):c.1055C>G (p.Ala352Gly)	GLA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521005	NM_019597.5(HNRNPH2):c.629A>G (p.Tyr210Cys)	HNRNPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009590	NM_019597.5(HNRNPH2):c.1019A>T (p.Asp340Val)	HNRNPH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432515	NM_019597.5(HNRNPH2):c.737A>G (p.Tyr246Cys)	HNRNPH2	Uncertain significance	criteria provided, single submitter
3238802	NM_019597.5(HNRNPH2):c.1195G>A (p.Gly399Arg)	HNRNPH2	Uncertain significance	criteria provided, single submitter
4056762	NM_019597.5(HNRNPH2):c.312C>T (p.Ser104=)	HNRNPH2	Uncertain significance	criteria provided, single submitter
1285350	NM_019597.5(HNRNPH2):c.1320C>T (p.Asn440=)	RPL36A-HNRNPH2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
HNRNPH2	Strong	X-linked	intellectual disability, X-linked, syndromic, Bain type	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNRNPH2	Orphanet:662198	Neurodevelopmental delay-intellectual disability-skeletal defects syndrome
GLA	Orphanet:324	Fabry disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNRNPH2	HGNC:5042	ENSG00000126945	P55795	Heterogeneous nuclear ribonucleoprotein H2	gencc,clinvar
GLA	HGNC:4296	ENSG00000102393	P06280	Alpha-galactosidase A	clinvar
RPL36A-HNRNPH2	HGNC:48349	ENSG00000257529		RPL36A-HNRNPH2 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNRNPH2	Heterogeneous nuclear ribonucleoprotein H2	This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm.
GLA	Alpha-galactosidase A	Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.

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)
HNRNPH2	Transcription factor	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, Znf_CHHC
GLA	Enzyme (other)	yes	3.2.1.22	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b
RPL36A-HNRNPH2	Other/Unknown	no

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
islet of Langerhans	2
choroid plexus epithelium	1
seminal vesicle	1
monocyte	1
mononuclear cell	1
pancreatic ductal cell	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNRNPH2	295	ubiquitous	marker	choroid plexus epithelium, islet of Langerhans, seminal vesicle
GLA	263	ubiquitous	marker	pancreatic ductal cell, monocyte, mononuclear cell
RPL36A-HNRNPH2	134	ubiquitous	marker	left ovary, right ovary, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPH2	2,073
GLA	1,826
RPL36A-HNRNPH2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLA	P06280	31
HNRNPH2	P55795	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Glycosphingolipid metabolism	1	150.3×	0.041	GLA
Glycosphingolipid catabolism	1	146.4×	0.041	GLA
Sphingolipid metabolism	1	84.0×	0.047	GLA
mRNA Polyadenylation	1	43.9×	0.058	HNRNPH2
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.058	HNRNPH2
mRNA Splicing - Major Pathway	1	27.3×	0.073	HNRNPH2
Dengue Virus-Host Interactions	1	22.8×	0.074	HNRNPH2
Metabolism of lipids	1	15.8×	0.094	GLA
Innate Immune System	1	12.8×	0.102	GLA
Neutrophil degranulation	1	11.5×	0.102	GLA
Immune System	1	6.5×	0.162	GLA
Metabolism	1	5.8×	0.165	GLA

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
negative regulation of nitric-oxide synthase activity	1	4213.0×	0.001	GLA
glycosylceramide catabolic process	1	2808.7×	0.001	GLA
glycoside catabolic process	1	1404.3×	0.002	GLA
glycosphingolipid catabolic process	1	766.0×	0.002	GLA
negative regulation of nitric oxide biosynthetic process	1	495.6×	0.003	GLA
oligosaccharide metabolic process	1	351.1×	0.003	GLA
regulation of RNA splicing	1	109.4×	0.009	HNRNPH2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
GLA	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLA	62	4
HNRNPH2	0	0
RPL36A-HNRNPH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GLA	114	Binding:104, Functional:10
HNRNPH2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLA	3.2.1.22	alpha-galactosidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLA	114

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

30 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)
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLA
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	2	HNRNPH2, RPL36A-HNRNPH2

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)
HNRNPH2	2	—
RPL36A-HNRNPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.