Intellectual disability, autosomal dominant 29

Summary

Intellectual disability, autosomal dominant 29 (MONDO:0014482) is a disease caused by SETBP1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SETBP1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 128

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 29
Mondo ID	MONDO:0014482
OMIM	616078
DOID	DOID:0070059
UMLS	C4015141
MedGen	863578
GARD	0013379
NORD	1958
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 29 · autosomal dominant mental retardation 29 · intellectual disability, autosomal dominant type 29 · intellectual disability-expressive aphasia-facial dysmorphism syndrome caused by mutation in SETBP1 · mental retardation, autosomal dominant 29 · mental retardation, autosomal dominant type 29 · MRD29 · SETBP1 disorder · SETBP1 Haploinsufficiency Disorder · SETBP1 intellectual disability-expressive aphasia-facial dysmorphism syndrome · SETBP1 related developmental delay · SETBP1-related complex neurodevelopmental disorder · SETBP1-related disorder · SETBP1-related intellectual disability

Data availability: 128 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual disability, autosomal dominant 29

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

128 retrieved; paginated sample, class counts are floors:

38 pathogenic, 37 uncertain significance, 24 conflicting classifications of pathogenicity, 16 likely pathogenic, 7 benign/likely benign, 3 likely benign, 2 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031	NM_015559.3(SETBP1):c.2612T>C (p.Ile871Thr)	SETBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032	NM_015559.3(SETBP1):c.2602G>A (p.Asp868Asn)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1035	NM_015559.3(SETBP1):c.2608G>A (p.Gly870Ser)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1164030	NM_015559.3(SETBP1):c.1777C>T (p.Gln593Ter)	SETBP1	Pathogenic	no assertion criteria provided
1302004	NM_015559.3(SETBP1):c.632del (p.Gln211fs)	SETBP1	Pathogenic	criteria provided, single submitter
1320239	NM_015559.3(SETBP1):c.3731dup (p.Ala1245fs)	SETBP1	Pathogenic	criteria provided, single submitter
157555	NM_015559.3(SETBP1):c.2464del (p.Ile822fs)	SETBP1	Pathogenic	no assertion criteria provided
157556	NM_015559.3(SETBP1):c.1596G>A (p.Trp532Ter)	SETBP1	Pathogenic	no assertion criteria provided
157557	NM_015559.3(SETBP1):c.3032C>G (p.Ser1011Ter)	SETBP1	Pathogenic	no assertion criteria provided
157558	NM_015559.3(SETBP1):c.427del (p.Arg143fs)	SETBP1	Pathogenic	no assertion criteria provided
157559	NM_015559.3(SETBP1):c.1873C>T (p.Arg625Ter)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
157560	NM_015559.3(SETBP1):c.1876C>T (p.Arg626Ter)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1805460	NM_015559.3(SETBP1):c.623del (p.Pro208fs)	SETBP1	Pathogenic	criteria provided, single submitter
1805990	NM_015559.3(SETBP1):c.2087dup (p.Glu697fs)	SETBP1	Pathogenic	criteria provided, single submitter
212152	NM_015559.3(SETBP1):c.1821del (p.Ser608fs)	SETBP1	Pathogenic	criteria provided, single submitter
2429955	NM_015559.3(SETBP1):c.1588C>T (p.Arg530Ter)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2578403	NM_015559.3(SETBP1):c.2812del (p.His938fs)	SETBP1	Pathogenic	no assertion criteria provided
280223	NM_015559.3(SETBP1):c.1568del (p.His523fs)	SETBP1	Pathogenic	criteria provided, single submitter
3254903	NM_015559.3(SETBP1):c.1119del (p.Ala374fs)	SETBP1	Pathogenic	criteria provided, single submitter
3337997	NM_015559.3(SETBP1):c.2762del (p.His921fs)	SETBP1	Pathogenic	criteria provided, single submitter
3366957	NM_015559.3(SETBP1):c.2183del (p.Gly728fs)	SETBP1	Pathogenic	criteria provided, single submitter
3376129	NM_015559.3(SETBP1):c.334del (p.Arg112fs)	SETBP1	Pathogenic	criteria provided, single submitter
3383975	NM_015559.3(SETBP1):c.1593del (p.Arg531fs)	SETBP1	Pathogenic	criteria provided, single submitter
375633	NM_015559.3(SETBP1):c.2016_2017insT (p.Lys673Ter)	SETBP1	Pathogenic	criteria provided, single submitter
4077415	NM_015559.3(SETBP1):c.2435del (p.Ser812fs)	SETBP1	Pathogenic	criteria provided, single submitter
4077416	NM_015559.3(SETBP1):c.4596_4602del (p.Pro1533fs)	SETBP1	Pathogenic	criteria provided, single submitter
4533245	NM_015559.3(SETBP1):c.712del (p.Ser238fs)	SETBP1	Pathogenic	criteria provided, single submitter
489124	NM_015559.3(SETBP1):c.821G>A (p.Trp274Ter)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
520830	NM_015559.3(SETBP1):c.1408del (p.Lys469_Met470insTer)	SETBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
521296	NM_015559.3(SETBP1):c.2572G>A (p.Glu858Lys)	SETBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
SETBP1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 29	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SETBP1	Orphanet:436151	Intellectual disability-expressive aphasia-facial dysmorphism syndrome
SETBP1	Orphanet:798	Schinzel-Giedion syndrome
ZBTB7A	Orphanet:694956	Intellectual disability-lymphoid hypertrophy-macrocephaly syndrome

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
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	gencc,clinvar
ZBTB7A	HGNC:18078	ENSG00000178951	O95365	Zinc finger and BTB domain-containing protein 7A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZBTB7A	Zinc finger and BTB domain-containing protein 7A	Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
ZBTB7A	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type

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)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
caput epididymis	1
ventricular zone	1
nipple	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
ZBTB7A	281	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, nipple

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETBP1	2,077
ZBTB7A	1,737

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZBTB7A	O95365	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SETBP1	Q9Y6X0	43.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
regulation of transcription regulatory region DNA binding	1	2106.5×	0.008	ZBTB7A
double-strand break repair via classical nonhomologous end joining	1	842.6×	0.008	ZBTB7A
obsolete regulation of DNA-binding transcription factor activity	1	766.0×	0.008	ZBTB7A
regulation of glycolytic process	1	601.9×	0.008	ZBTB7A
negative regulation of androgen receptor signaling pathway	1	468.1×	0.008	ZBTB7A
erythrocyte maturation	1	421.3×	0.008	ZBTB7A
negative regulation of Notch signaling pathway	1	216.1×	0.014	ZBTB7A
protein localization to nucleus	1	175.5×	0.015	ZBTB7A
regulation of alternative mRNA splicing, via spliceosome	1	122.1×	0.017	ZBTB7A
DNA-templated transcription	1	112.3×	0.017	ZBTB7A
B cell differentiation	1	109.4×	0.017	ZBTB7A
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.017	ZBTB7A
fat cell differentiation	1	90.6×	0.017	ZBTB7A
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.017	ZBTB7A
chromatin organization	1	49.6×	0.028	ZBTB7A
regulation of apoptotic process	1	41.7×	0.031	ZBTB7A
chromatin remodeling	1	36.5×	0.034	ZBTB7A
regulation of DNA-templated transcription	1	15.8×	0.069	SETBP1
negative regulation of DNA-templated transcription	1	15.8×	0.069	ZBTB7A
negative regulation of transcription by RNA polymerase II	1	8.9×	0.115	ZBTB7A
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZBTB7A

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
SETBP1	0	0
ZBTB7A	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
ZBTB7A	2	Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SETBP1, ZBTB7A

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)
SETBP1	0	—
ZBTB7A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.