intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Summary

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (MONDO:0014336) is a disease caused by SETD5 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SETD5 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 243

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
Mondo ID	MONDO:0014336
OMIM	615761
Orphanet	404440
DOID	DOID:0070053
UMLS	C3810406
MedGen	816736
GARD	0017673
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 23 · intellectual developmental disorder, autosomal dominant 23 · intellectual disability, autosomal dominant 23 · intellectual disability, autosomal dominant type 23 · intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency · mental retardation, autosomal dominant 23 · mental retardation, autosomal dominant type 23 · MRD23

Data availability: 243 ClinVar variants · 4 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-facial dysmorphism syndrome due to SETD5 haploinsufficiency

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, 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 29, 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

243 retrieved; paginated sample, class counts are floors:

73 pathogenic, 65 uncertain significance, 51 likely pathogenic, 27 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 7 likely benign, 4 not provided, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031046	NM_001080517.3(SETD5):c.1459G>T (p.Glu487Ter)	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032602	NM_001080517.3(SETD5):c.1390C>T (p.Gln464Ter)	SETD5	Pathogenic	criteria provided, multiple submitters, no conflicts
1032603	NM_001080517.3(SETD5):c.1495del (p.Asp499fs)	SETD5	Pathogenic	criteria provided, single submitter
1064598	NM_001080517.3(SETD5):c.960-5C>G	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075980	NM_001080517.3(SETD5):c.3631+1G>A	SETD5	Pathogenic	criteria provided, multiple submitters, no conflicts
1254037	NM_001080517.3(SETD5):c.1525-1G>C	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127102	NM_001080517.3(SETD5):c.1195A>T (p.Lys399Ter)	SETD5	Pathogenic	no assertion criteria provided
127103	NM_001080517.3(SETD5):c.2177_2178del (p.Thr726fs)	SETD5	Pathogenic	no assertion criteria provided
127104	NM_001080517.3(SETD5):c.3001C>T (p.Arg1001Ter)	SETD5	Pathogenic	criteria provided, multiple submitters, no conflicts
127105	NM_001080517.3(SETD5):c.3771dup (p.Ser1258fs)	SETD5	Pathogenic	no assertion criteria provided
127106	NM_001080517.3(SETD5):c.3856del (p.Ser1286fs)	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301864	NM_001080517.3(SETD5):c.2182del (p.Asp728fs)	SETD5	Pathogenic	criteria provided, single submitter
1323579	NM_001080517.3(SETD5):c.889_890del (p.Leu297fs)	SETD5	Pathogenic	criteria provided, single submitter
1325818	NM_001080517.3(SETD5):c.1689del (p.Glu564fs)	SETD5	Pathogenic	criteria provided, single submitter
1343149	NM_001080517.3(SETD5):c.890_897delinsC (p.Leu297fs)	SETD5	Pathogenic	criteria provided, single submitter
1343278	NM_001080517.3(SETD5):c.1028dup (p.Gly344fs)	SETD5	Pathogenic	criteria provided, single submitter
1527877	NM_001080517.3(SETD5):c.489dup (p.Val164fs)	SETD5	Pathogenic	criteria provided, single submitter
1679232	NM_001080517.3(SETD5):c.1967del (p.Ser655_Leu656insTer)	SETD5	Pathogenic	criteria provided, single submitter
1679238	NM_001080517.3(SETD5):c.1612C>T (p.Gln538Ter)	SETD5	Pathogenic	criteria provided, single submitter
1679259	NM_001080517.3(SETD5):c.2521G>T (p.Glu841Ter)	SETD5	Pathogenic	criteria provided, single submitter
1686177	NM_001080517.3(SETD5):c.1082G>C (p.Arg361Pro)	SETD5	Pathogenic	criteria provided, single submitter
1708229	NM_001080517.3(SETD5):c.2438dup (p.Asn814fs)	SETD5	Pathogenic	criteria provided, single submitter
1710028	NM_001080517.3(SETD5):c.2003C>G (p.Ser668Ter)	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1801347	NM_001080517.3(SETD5):c.3556C>T (p.Arg1186Ter)	SETD5	Pathogenic	criteria provided, single submitter
1805789	NM_001080517.3(SETD5):c.588_591del (p.Gln196fs)	SETD5	Pathogenic	criteria provided, single submitter
1992342	NM_001080517.3(SETD5):c.1416dup (p.Val473fs)	SETD5	Pathogenic	criteria provided, single submitter
2002358	NM_001080517.3(SETD5):c.3361C>T (p.Arg1121Ter)	SETD5	Pathogenic	criteria provided, multiple submitters, no conflicts
219198	NM_001080517.3(SETD5):c.2302C>T (p.Arg768Ter)	SETD5	Pathogenic	criteria provided, multiple submitters, no conflicts
219199	NM_001080517.3(SETD5):c.547_567+60del	SETD5	Pathogenic	no assertion criteria provided
2441815	NM_001080517.3(SETD5):c.2168T>A (p.Leu723Ter)	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SETD5	Definitive	Autosomal dominant	intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability

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
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	gencc,clinvar
LHFPL4	HGNC:29568	ENSG00000156959	Q7Z7J7	LHFPL tetraspan subfamily member 4 protein	clinvar
LHFPL3	HGNC:6589	ENSG00000187416	Q86UP9	LHFPL tetraspan subfamily member 3 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.
LHFPL4	LHFPL tetraspan subfamily member 4 protein	Plays a role in the regulation of inhibitory synapse formation and function by being involved in maintening gamma-aminobutyric acid receptors (GABAARs) clustering and their associated scaffold proteins at inhibitory synaptic sites.

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)
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf
LHFPL4	Other/Unknown	no		LHFPL
LHFPL3	Other/Unknown	no		LHFPL

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
colonic epithelium	1
sural nerve	1
cerebellar vermis	1
cortical plate	1
postcentral gyrus	1
dorsal plus ventral thalamus	1
lateral nuclear group of thalamus	1
subthalamic nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve
LHFPL4	109	broad	yes	cerebellar vermis, cortical plate, postcentral gyrus
LHFPL3	123	tissue_specific	marker	lateral nuclear group of thalamus, dorsal plus ventral thalamus, subthalamic nucleus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETD5	1,865
LHFPL4	1,366
LHFPL3	1,089

Intra-cohort edges

A	B	Sources
LHFPL4	SETD5	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LHFPL4	Q7Z7J7	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LHFPL3	Q86UP9	88.73
SETD5	Q9C0A6	47.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 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 3 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 inhibitory synapse assembly	1	5617.3×	0.002	LHFPL4
sensory perception of sound	2	67.3×	0.002	LHFPL4, LHFPL3
negative regulation of transcription by RNA polymerase III	1	1123.5×	0.002	SETD5
gamma-aminobutyric acid receptor clustering	1	1123.5×	0.002	LHFPL4
regulation of DNA-templated transcription elongation	1	936.2×	0.002	SETD5
regulation of chromatin organization	1	510.7×	0.004	SETD5
neurotransmitter receptor localization to postsynaptic specialization membrane	1	267.5×	0.006	LHFPL4
regulation of synapse assembly	1	234.1×	0.006	SETD5
cognition	1	95.2×	0.013	SETD5
methylation	1	56.7×	0.019	SETD5
regulation of DNA-templated transcription	1	10.5×	0.092	SETD5

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
SETD5	0	0
LHFPL4	0	0
LHFPL3	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	SETD5, LHFPL4, LHFPL3

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)
SETD5	0	—
LHFPL4	0	—
LHFPL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.