intellectual disability, X-linked, syndromic, Houge type

Summary

intellectual disability, X-linked, syndromic, Houge type (MONDO:0030909) is a disease caused by CNKSR2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CNKSR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 59

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked, syndromic, Houge type
Mondo ID	MONDO:0030909
OMIM	301008
DOID	DOID:0080242
UMLS	C4538788
MedGen	1624740
GARD	0015282
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, syndromic, Houge type · intellectual disability, X-linked, syndromic, Houge type · mental retardation, X-linked, syndromic, HOUGE type · mental retardation, X-linked, syndromic, Houge type · MRXSHG · syndromic X-linked mental retardation Hough type

Data availability: 59 ClinVar variants · 2 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, Houge 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, 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, 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

59 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 15 pathogenic, 11 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 likely benign, 2 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065349	NM_014927.5(CNKSR2):c.1235T>A (p.Leu412Ter)	CNKSR2	Pathogenic	no assertion criteria provided
1236202	NM_014927.5(CNKSR2):c.2041C>T (p.Gln681Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
1299341	NM_014927.5(CNKSR2):c.2336C>G (p.Ser779Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
157605	NM_014927.5(CNKSR2):c.453dup (p.Asp152fs)	CNKSR2	Pathogenic	no assertion criteria provided
1697306	NM_014927.5(CNKSR2):c.548_551del (p.Lys183fs)	CNKSR2	Pathogenic	criteria provided, single submitter
1802631	NM_014927.5(CNKSR2):c.1198C>T (p.Arg400Ter)	CNKSR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805928	NM_014927.5(CNKSR2):c.2024_2027del (p.Glu675fs)	CNKSR2	Pathogenic	criteria provided, single submitter
2502319	NM_014927.5(CNKSR2):c.2185C>T (p.Arg729Ter)	CNKSR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3341078	NM_014927.5(CNKSR2):c.187C>T (p.Gln63Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
3359078	NM_014927.5(CNKSR2):c.1979G>A (p.Trp660Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
3370293	NM_014927.5(CNKSR2):c.573_576del (p.Ser192fs)	CNKSR2	Pathogenic	criteria provided, single submitter
3370477	NM_014927.5(CNKSR2):c.1684C>T (p.Arg562Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
3376274	NM_014927.5(CNKSR2):c.423G>A (p.Trp141Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
3773734	NM_014927.5(CNKSR2):c.742-1G>A	CNKSR2	Pathogenic	criteria provided, single submitter
446716	NM_014927.5(CNKSR2):c.2134C>T (p.Arg712Ter)	CNKSR2	Pathogenic	criteria provided, multiple submitters, no conflicts
634608	NM_014927.5(CNKSR2):c.1734G>A (p.Trp578Ter)	CNKSR2	Pathogenic	criteria provided, single submitter
976388	NM_014927.5(CNKSR2):c.1988_1989del (p.Arg663fs)	CNKSR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1324091	NM_014927.5(CNKSR2):c.1564C>T (p.Gln522Ter)	CNKSR2	Likely pathogenic	criteria provided, single submitter
2574118	NM_014927.5(CNKSR2):c.1090A>G (p.Arg364Gly)	CNKSR2	Likely pathogenic	criteria provided, single submitter
2671822	NM_014927.5(CNKSR2):c.1657+1G>A	CNKSR2	Likely pathogenic	criteria provided, single submitter
3382012	NM_014927.5(CNKSR2):c.1394-13_1423del	CNKSR2	Likely pathogenic	criteria provided, single submitter
3602104	NM_014927.5(CNKSR2):c.57G>A (p.Trp19Ter)	CNKSR2	Likely pathogenic	criteria provided, single submitter
3764721	NM_014927.5(CNKSR2):c.1312C>T (p.Arg438Ter)	CNKSR2	Likely pathogenic	criteria provided, single submitter
4081252	NM_014927.5(CNKSR2):c.170del (p.Val57fs)	CNKSR2	Likely pathogenic	criteria provided, single submitter
4291827	NM_014927.5(CNKSR2):c.2019_2022del (p.Glu675fs)	CNKSR2	Likely pathogenic	criteria provided, single submitter
4293977	NM_014927.5(CNKSR2):c.2366del (p.Leu789fs)	CNKSR2	Likely pathogenic	criteria provided, single submitter
4795124	NM_014927.5(CNKSR2):c.1873dup (p.Ile625fs)	CNKSR2	Likely pathogenic	criteria provided, single submitter
996895	NM_014927.5(CNKSR2):c.1615C>T (p.Gln539Ter)	CNKSR2	Likely pathogenic	criteria provided, single submitter
1315360	NM_014927.5(CNKSR2):c.2758A>C (p.Ser920Arg)	CNKSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2440157	NM_014927.5(CNKSR2):c.3010A>G (p.Thr1004Ala)	CNKSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
CNKSR2	Definitive	X-linked	X-linked complex neurodevelopmental disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNKSR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CNKSR2	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CNKSR2	HGNC:19701	ENSG00000149970	Q8WXI2	Connector enhancer of kinase suppressor of ras 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNKSR2	Connector enhancer of kinase suppressor of ras 2	May function as an adapter protein or regulator of Ras signaling pathways.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CNKSR2	Scaffold/PPI	no		PDZ, SAM, PH_domain

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
cerebellar cortex	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNKSR2	226	broad	marker	Brodmann (1909) area 23, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CNKSR2	1,194

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNKSR2	Q8WXI2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	CNKSR2
MAP2K and MAPK activation	1	285.5×	0.005	CNKSR2
Signaling by RAF1 mutants	1	278.5×	0.005	CNKSR2
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	CNKSR2
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	CNKSR2
Signaling downstream of RAS mutants	1	253.8×	0.005	CNKSR2
Signaling by BRAF and RAF1 fusions	1	170.4×	0.006	CNKSR2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
postsynaptic specialization organization	1	5617.3×	5e-04	CNKSR2
regulation of signal transduction	1	267.5×	0.006	CNKSR2
intracellular signal transduction	1	38.1×	0.026	CNKSR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CNKSR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CNKSR2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	CNKSR2

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)
CNKSR2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.