intellectual disability, X-linked 61

Summary

intellectual disability, X-linked 61 (MONDO:0010506) is a disease caused by RLIM (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: RLIM (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 61
Mondo ID	MONDO:0010506
OMIM	300978
DOID	DOID:0112042
UMLS	C4283894
MedGen	924419
GARD	0022695
Is cancer (heuristic)	no

Also known as: intellectual disability, X-linked 61 · intellectual disability, X-linked type 61 · mental retardation, X-linked 61 · mental retardation, X-linked type 61 · MRX61 · non-syndromic X-linked intellectual disability caused by mutation in RLIM · RLIM non-syndromic X-linked intellectual disability · Tonne-Kalscheuer syndrome

Data availability: 31 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 › non-syndromic intellectual disability › non-syndromic X-linked intellectual disability › intellectual disability, X-linked 61

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked 63, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 99, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 102, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, FRAXE intellectual disability, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

31 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
156224	NM_016120.4(RLIM):c.1067A>G (p.Tyr356Cys)	RLIM	Pathogenic	criteria provided, single submitter
253087	NM_016120.4(RLIM):c.1760C>G (p.Pro587Arg)	RLIM	Pathogenic	no assertion criteria provided
253088	NM_016120.4(RLIM):c.1159C>T (p.Arg387Cys)	RLIM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253089	NM_016120.4(RLIM):c.1795C>T (p.Arg599Cys)	RLIM	Pathogenic	no assertion criteria provided
585243	NM_016120.4(RLIM):c.1792G>A (p.Asp598Asn)	RLIM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585244	NM_016120.4(RLIM):c.1093C>T (p.Arg365Cys)	RLIM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184531	NM_016120.4(RLIM):c.992G>A (p.Gly331Glu)	RLIM	Likely pathogenic	no assertion criteria provided
585245	NM_016120.4(RLIM):c.1831C>T (p.Arg611Cys)	RLIM	Likely pathogenic	criteria provided, single submitter
598940	NM_016120.4(RLIM):c.1729T>C (p.Tyr577His)	RLIM	Likely pathogenic	criteria provided, single submitter
979167	NM_016120.4(RLIM):c.1262A>G (p.Tyr421Cys)	RLIM	Likely pathogenic	criteria provided, single submitter
2435439	NM_016120.4(RLIM):c.826T>C (p.Ser276Pro)	RLIM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547086	NM_016120.4(RLIM):c.223C>G (p.Pro75Ala)	RLIM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992873	NM_016120.4(RLIM):c.131A>G (p.Tyr44Cys)	RLIM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2734069	NM_000537.4(REN):c.241_243dup (p.Tyr81_Met82insTyr)	REN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030534	NM_016120.4(RLIM):c.736A>G (p.Ile246Val)	RLIM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333443	NM_016120.4(RLIM):c.1490A>G (p.Asn497Ser)	RLIM	Uncertain significance	criteria provided, single submitter
1709208	NM_016120.4(RLIM):c.1311G>A (p.Met437Ile)	RLIM	Uncertain significance	criteria provided, single submitter
2435437	NM_016120.4(RLIM):c.507A>C (p.Glu169Asp)	RLIM	Uncertain significance	criteria provided, single submitter
2435438	NM_016120.4(RLIM):c.1401_1412del (p.Ser473_Ser476del)	RLIM	Uncertain significance	criteria provided, single submitter
2444076	NM_016120.4(RLIM):c.1115G>A (p.Arg372Gln)	RLIM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500702	NM_016120.4(RLIM):c.74G>T (p.Arg25Leu)	RLIM	Uncertain significance	criteria provided, single submitter
2585183	NM_016120.4(RLIM):c.1358G>A (p.Ser453Asn)	RLIM	Uncertain significance	criteria provided, single submitter
2663272	NM_016120.4(RLIM):c.1508C>T (p.Ser503Leu)	RLIM	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362724	NM_016120.4(RLIM):c.1529G>A (p.Arg510Gln)	RLIM	Uncertain significance	criteria provided, multiple submitters, no conflicts
3775614	NM_016120.4(RLIM):c.1045A>G (p.Thr349Ala)	RLIM	Uncertain significance	criteria provided, single submitter
4079880	NM_016120.4(RLIM):c.1566A>T (p.Glu522Asp)	RLIM	Uncertain significance	criteria provided, single submitter
4279732	NM_016120.4(RLIM):c.221G>A (p.Gly74Asp)	RLIM	Uncertain significance	criteria provided, single submitter
4292448	NM_016120.4(RLIM):c.1114C>T (p.Arg372Trp)	RLIM	Uncertain significance	criteria provided, single submitter
4687991	NM_016120.4(RLIM):c.1357AGT[1] (p.Ser455del)	RLIM	Uncertain significance	criteria provided, single submitter
635529	NM_016120.4(RLIM):c.1364C>A (p.Ser455Tyr)	RLIM	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
RLIM	Definitive	X-linked	non-syndromic X-linked intellectual disability	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RLIM	Orphanet:528084	Non-specific syndromic intellectual disability
REN	Orphanet:217330	REN-related autosomal dominant tubulointerstitial kidney disease
REN	Orphanet:97369	Renal tubular dysgenesis of genetic origin

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
RLIM	HGNC:13429	ENSG00000131263	Q9NVW2	E3 ubiquitin-protein ligase RLIM	gencc,clinvar
KCTD11	HGNC:21302	ENSG00000213859	Q693B1	BTB/POZ domain-containing protein KCTD11	clinvar
REN	HGNC:9958	ENSG00000143839	P00797	Renin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RLIM	E3 ubiquitin-protein ligase RLIM	E3 ubiquitin-protein ligase that acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/…
KCTD11	BTB/POZ domain-containing protein KCTD11	Plays a role as a marker and a regulator of neuronal differentiation; Up-regulated by a variety of neurogenic signals, such as retinoic acid, epidermal growth factor/EGF and NGFB/nerve growth factor.
REN	Renin	Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retenti…

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
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RLIM	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, RING_finger_E3_ligase
KCTD11	Other/Unknown	no		T1-type_BTB, SKP1/BTB/POZ_sf, KCTD11/21_C
REN	Protease	yes	3.4.23.15	Aspartic_peptidase_A1, Aspartic_peptidase_AS, Aspartic_peptidase_N

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
adrenal tissue	1
cartilage tissue	1
middle temporal gyrus	1
esophagus mucosa	1
lower esophagus mucosa	1
tibial nerve	1
adult mammalian kidney	1
decidua	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RLIM	256	ubiquitous	marker	middle temporal gyrus, cartilage tissue, adrenal tissue
KCTD11	132	ubiquitous	marker	lower esophagus mucosa, tibial nerve, esophagus mucosa
REN	126	tissue_specific	marker	decidua, adult mammalian kidney, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
REN	3,244
RLIM	2,059
KCTD11	420

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
REN	P00797	91
RLIM	Q9NVW2	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCTD11	Q693B1	85.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Metabolism of Angiotensinogen to Angiotensins	1	317.2×	0.016	REN
Class I MHC mediated antigen processing & presentation	1	35.0×	0.071	RLIM
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.082	RLIM
Adaptive Immune System	1	14.9×	0.082	RLIM
Immune System	1	6.5×	0.148	RLIM

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
response to cGMP	1	2808.7×	0.006	REN
renin-angiotensin regulation of aldosterone production	1	1872.4×	0.006	REN
juxtaglomerular apparatus development	1	1872.4×	0.006	REN
neuroblast differentiation	1	702.2×	0.009	KCTD11
mesonephros development	1	510.7×	0.009	REN
amyloid-beta metabolic process	1	510.7×	0.009	REN
angiotensin maturation	1	432.1×	0.009	REN
negative regulation of neuroblast proliferation	1	401.2×	0.009	KCTD11
protein ubiquitination	2	27.6×	0.009	RLIM, KCTD11
drinking behavior	1	330.4×	0.009	REN
random inactivation of X chromosome	1	312.1×	0.009	RLIM
response to immobilization stress	1	244.2×	0.011	REN
response to cAMP	1	170.2×	0.013	REN
regulation of MAPK cascade	1	151.8×	0.013	REN
negative regulation of smoothened signaling pathway	1	151.8×	0.013	KCTD11
cell maturation	1	147.8×	0.013	REN
hormone-mediated signaling pathway	1	133.8×	0.013	REN
regulation of neurogenesis	1	133.8×	0.013	RLIM
neuroblast proliferation	1	122.1×	0.014	KCTD11
cellular response to xenobiotic stimulus	1	80.2×	0.020	REN
regulation of blood pressure	1	73.9×	0.021	REN
positive regulation of neuron differentiation	1	66.1×	0.022	KCTD11
smoothened signaling pathway	1	60.4×	0.023	KCTD11
male gonad development	1	52.0×	0.025	REN
kidney development	1	46.8×	0.027	REN
response to lipopolysaccharide	1	41.6×	0.029	REN
protein homooligomerization	1	40.7×	0.029	KCTD11
neuron differentiation	1	33.4×	0.034	KCTD11
ubiquitin-dependent protein catabolic process	1	24.8×	0.044	RLIM
proteolysis	1	11.4×	0.091	REN

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
REN	CAPTOPRIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
REN	13	4
RLIM	0	0
KCTD11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPTOPRIL	4	REN
ALISKIREN	4	REN
ALISKIREN FUMARATE	4	REN
SITOKIREN	3	REN
ZANKIREN	2	REN
DITEKIREN	2	REN
PEPSTATIN	2	REN
ENALKIREN	2	REN
REMIKIREN	2	REN
IMARIKIREN HYDROCHLORIDE	2	REN
IMARIKIREN	2	REN
TERLAKIREN	2	REN
VTP-27999	1	REN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
REN	541	Binding:472, Functional:68, ADMET:1
KCTD11	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
REN	3.4.23.15	renin

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
REN	541

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

13 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)
CAPTOPRIL	4	REN
ALISKIREN	4	REN
ALISKIREN FUMARATE	4	REN
SITOKIREN	3	REN
ZANKIREN	2	REN
DITEKIREN	2	REN
PEPSTATIN	2	REN
ENALKIREN	2	REN
REMIKIREN	2	REN
IMARIKIREN HYDROCHLORIDE	2	REN
IMARIKIREN	2	REN
TERLAKIREN	2	REN
VTP-27999	1	REN

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	REN
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	RLIM, KCTD11

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)
RLIM	0	—
KCTD11	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.