Smith-Magenis syndrome

Summary

Smith-Magenis syndrome (MONDO:0008434) is a disease caused by RAI1 (GenCC Definitive), with 6 cohort genes and 15 clinical trials. Top therapeutic interventions include tasimelteon.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: RAI1 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 168
• Phenotypes (HPO): 95
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5.35	Europe	Validated
Point prevalence	1-9 / 100 000	4	Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000		Worldwide	Not yet validated
Point prevalence	1-9 / 100 000	5.35	United States	Not yet validated
Prevalence at birth	1-9 / 100 000		United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

95 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000337	Broad forehead	Very frequent (80-99%)
HP:0000403	Recurrent otitis media	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0000664	Synophrys	Very frequent (80-99%)
HP:0000679	Taurodontia	Very frequent (80-99%)
HP:0000680	Delayed eruption of primary teeth	Very frequent (80-99%)
HP:0000733	Abnormal repetitive mannerisms	Very frequent (80-99%)
HP:0000739	Anxiety	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0001609	Hoarse voice	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005607	Abnormal tracheobronchial morphology	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Very frequent (80-99%)
HP:0010804	Tented upper lip vermilion	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0012689	Abnormal pineal melatonin secretion	Very frequent (80-99%)
HP:0100716	Self-injurious behavior	Very frequent (80-99%)
HP:0100729	Large face	Very frequent (80-99%)
HP:0000194	Open mouth	Frequent (30-79%)
HP:0000220	Velopharyngeal insufficiency	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000321	Square face	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000482	Microcornea	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0001169	Broad palm	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Smith-Magenis syndrome
Mondo ID	MONDO:0008434
MeSH	D058496
OMIM	182290
Orphanet	819
DOID	DOID:0060768
ICD-11	989025532
NCIT	C75469
SNOMED CT	401315004
UMLS	C0795864
MedGen	162881
GARD	0008197
NORD	1725
Is cancer (heuristic)	no

Also known as: 17p11.2 microdeletion syndrome · chromosome 17P11.2 deletion syndrome · chromosome 17p11.2 deletion syndrome · Smith Magenis Syndrome · SMITH-Magenis syndrome · Smith-Magenis syndrome · Smith-Magenis syndrome, Isolated cases · SMS

Data availability: 168 ClinVar variants · 5 GenCC gene-disease records · 66 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › Smith-Magenis syndrome

Related subtypes (16): intellectual disability, Buenos-Aires type, intellectual disability, Wolff type, CK syndrome, AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome, 7p22.1 microduplication syndrome, 9p13 microdeletion syndrome, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, Rubinstein-Taybi syndrome, X-linked syndromic intellectual disability, 9q33.3q34.11 microdeletion syndrome, autosomal recessive syndromic intellectual disability, autosomal dominant syndromic intellectual disability, aplasia cutis-enamel dysplasia syndrome, 2p25.3 microduplication syndrome, dyneinopathy

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

168 retrieved; paginated sample, class counts are floors:

42 pathogenic, 40 uncertain significance, 33 conflicting classifications of pathogenicity, 21 likely pathogenic, 14 benign/likely benign, 11 benign, 4 pathogenic/likely pathogenic, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
183386	chr17:g.(AC027266_AL353996)_(AC015726-AC087393)del		Pathogenic	no assertion criteria provided
1703565	GRCh37/hg19 17p11.2(chr17:16651292-20286898)	AKAP10	Pathogenic	no assertion criteria provided
1703566	GRCh37/hg19 17p11.2(chr17:17151140-20187953)	AKAP10	Pathogenic	no assertion criteria provided
625730	GRCh37/hg19 17p11.2(chr17:16842991-20217316)	AKAP10	Pathogenic	criteria provided, single submitter
1047863	GRCh37/hg19 17p11.2(chr17:17145361-20137943)	ALDH3A1	Pathogenic	criteria provided, single submitter
1321231	NM_030665.4(RAI1):c.-148-13952_-148-10583del	LOC112529899	Pathogenic	criteria provided, single submitter
243061	Single allele	MIR33B	Pathogenic	criteria provided, single submitter
1047930	NM_030665.4(RAI1):c.3179_3180del (p.Leu1060fs)	RAI1	Pathogenic	no assertion criteria provided
1098289	NM_030665.4(RAI1):c.4525del (p.Gln1509fs)	RAI1	Pathogenic	criteria provided, single submitter
1184965	NM_030665.4(RAI1):c.868C>T (p.Gln290Ter)	RAI1	Pathogenic	criteria provided, single submitter
1330239	NM_030665.4(RAI1):c.4271del (p.Phe1424fs)	RAI1	Pathogenic	criteria provided, single submitter
143197	NM_030665.4(RAI1):c.2273G>A (p.Trp758Ter)	RAI1	Pathogenic	no assertion criteria provided
167563	NM_030665.4(RAI1):c.4678C>T (p.Arg1560Ter)	RAI1	Pathogenic	criteria provided, multiple submitters, no conflicts
1679394	NM_030665.4(RAI1):c.13C>T (p.Arg5Ter)	RAI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709995	NM_030665.4(RAI1):c.1785dup (p.Arg596fs)	RAI1	Pathogenic	criteria provided, single submitter
1802191	NM_030665.4(RAI1):c.848_851del (p.Gln283fs)	RAI1	Pathogenic	criteria provided, single submitter
1805893	NM_030665.4(RAI1):c.4317dup (p.Thr1440fs)	RAI1	Pathogenic	criteria provided, single submitter
2230823	NM_030665.4(RAI1):c.2763_2764del (p.Glu923fs)	RAI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2430023	NM_030665.4(RAI1):c.4810C>T (p.Arg1604Ter)	RAI1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501674	NM_030665.4(RAI1):c.2329del (p.Asp777fs)	RAI1	Pathogenic	criteria provided, single submitter
2505268	NM_030665.4(RAI1):c.219_226del (p.Ala74fs)	RAI1	Pathogenic	criteria provided, single submitter
2682235	NM_030665.4(RAI1):c.5626dup (p.His1876fs)	RAI1	Pathogenic	criteria provided, single submitter
2946	NM_030665.4(RAI1):c.5265del (p.Arg1756fs)	RAI1	Pathogenic	no assertion criteria provided
2947	NM_030665.4(RAI1):c.1449del (p.Glu484fs)	RAI1	Pathogenic	no assertion criteria provided
2948	NM_030665.4(RAI1):c.2773_2801del (p.Val925fs)	RAI1	Pathogenic	no assertion criteria provided
2950	NM_030665.4(RAI1):c.4685A>G (p.Gln1562Arg)	RAI1	Pathogenic	no assertion criteria provided
2951	NM_030665.4(RAI1):c.3801del (p.Thr1268fs)	RAI1	Pathogenic	no assertion criteria provided
2952	NM_030665.4(RAI1):c.253_271del (p.Leu85fs)	RAI1	Pathogenic	no assertion criteria provided
3381888	NM_030665.4(RAI1):c.1810C>T (p.Gln604Ter)	RAI1	Pathogenic	criteria provided, single submitter
3383141	NM_030665.4(RAI1):c.2809_2830delinsCACATGAAG (p.Lys937fs)	RAI1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
RAI1	Definitive	Autosomal dominant	Smith-Magenis syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAI1	Orphanet:1713	17p11.2 microduplication syndrome
RAI1	Orphanet:477817	PMP22-RAI1 contiguous gene duplication syndrome
RAI1	Orphanet:819	Smith-Magenis syndrome
SMS	Orphanet:3063	X-linked intellectual disability, Snyder type

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAI1	HGNC:9834	ENSG00000108557	Q7Z5J4	Retinoic acid-induced protein 1	gencc,clinvar
SMS	HGNC:11123	ENSG00000102172	P52788	Spermine synthase	clinvar
DRC3	HGNC:25384	ENSG00000171962	Q9H069	Dynein regulatory complex subunit 3	clinvar
MIR33B	HGNC:32791	ENSG00000207839		microRNA 33b	clinvar
AKAP10	HGNC:368	ENSG00000108599	O43572	A-kinase anchor protein 10, mitochondrial	clinvar
ALDH3A1	HGNC:405	ENSG00000108602	P30838	Aldehyde dehydrogenase, dimeric NADP-preferring	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAI1	Retinoic acid-induced protein 1	Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C.
SMS	Spermine synthase	Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM).
DRC3	Dynein regulatory complex subunit 3	Component of the nexin-dynein regulatory complex (N-DRC) a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.
AKAP10	A-kinase anchor protein 10, mitochondrial	Differentially targeted protein that binds to type I and II regulatory subunits of protein kinase A and anchors them to the mitochondria or the plasma membrane.
ALDH3A1	Aldehyde dehydrogenase, dimeric NADP-preferring	ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · 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)	2	4.0×	0.249
Transcription factor	1	1.4×	0.758
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAI1	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
SMS	Enzyme (other)	yes	2.5.1.22	Spermine_synthase_animal, SAM-dependent_MTases_sf, PABS_CS
DRC3	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, Cilia_flagella_integrity
MIR33B	Other/Unknown	no
AKAP10	Other/Unknown	no		RGS, RGS_sf, AKAP10_AKB_dom
ALDH3A1	Enzyme (other)	yes	1.2.1.5	Aldehyde_DH_NAD(P), Aldehyde_DH_dom, Ald_DH_CS_CYS

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
nipple	1
palpebral conjunctiva	1
pigmented layer of retina	1
cortical plate	1
ganglionic eminence	1
placenta	1
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	1
olfactory segment of nasal mucosa	1
skeletal muscle tissue	1
buccal mucosa cell	1
calcaneal tendon	1
lower esophagus mucosa	1
nasal cavity epithelium	1
trachea	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAI1	264	ubiquitous	marker	pigmented layer of retina, nipple, palpebral conjunctiva
SMS	134	ubiquitous	marker	cortical plate, placenta, ganglionic eminence
DRC3	200	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
MIR33B	79		yes	sural nerve, olfactory segment of nasal mucosa, skeletal muscle tissue
AKAP10	287	ubiquitous	marker	buccal mucosa cell, sural nerve, calcaneal tendon
ALDH3A1	204	broad	marker	nasal cavity epithelium, trachea, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH3A1	3,940
SMS	2,005
RAI1	1,979
AKAP10	1,644
DRC3	1,312
MIR33B	0

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH3A1	P30838	7
SMS	P52788	2
AKAP10	O43572	2
DRC3	Q9H069	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAI1	Q7Z5J4	39.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of polyamines	1	219.6×	0.041	SMS
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	73.2×	0.041	RAI1
Phase I - Functionalization of compounds	1	54.9×	0.041	ALDH3A1
Heme signaling	1	53.9×	0.041	RAI1
Biological oxidations	1	32.4×	0.055	ALDH3A1
Metabolism	2	5.8×	0.059	SMS, ALDH3A1
Metabolism of amino acids and derivatives	1	16.9×	0.066	SMS
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.066	AKAP10
Hemostasis	1	9.0×	0.107	AKAP10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
spermine biosynthetic process	1	2106.5×	0.006	SMS
polyamine metabolic process	1	842.6×	0.006	SMS
L-methionine metabolic process	1	702.2×	0.006	SMS
aldehyde metabolic process	1	324.1×	0.009	ALDH3A1
negative regulation of multicellular organism growth	1	280.9×	0.009	RAI1
circadian regulation of gene expression	1	58.5×	0.037	RAI1
xenobiotic metabolic process	1	37.3×	0.049	ALDH3A1
skeletal system development	1	31.4×	0.051	RAI1
intracellular protein localization	1	26.2×	0.054	AKAP10
lipid metabolic process	1	22.9×	0.056	ALDH3A1
positive regulation of DNA-templated transcription	1	7.0×	0.160	RAI1
signal transduction	1	4.0×	0.246	AKAP10
regulation of transcription by RNA polymerase II	1	2.9×	0.302	RAI1

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Tasimelteon	Approved (phase 4)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAI1	0	0
SMS	0	0
DRC3	0	0
MIR33B	0	0
AKAP10	0	0
ALDH3A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ALDH3A1	42	Binding:38, ADMET:4
SMS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMS	2.5.1.22	spermine synthase
ALDH3A1	1.2.1.5	aldehyde dehydrogenase [NAD(P)+]

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	2	SMS, ALDH3A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RAI1, DRC3, MIR33B, AKAP10

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RAI1	0	—
SMS	1	—
DRC3	0	—
MIR33B	0	—
AKAP10	0	—
ALDH3A1	42	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2/PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02231008	PHASE2/PHASE3	COMPLETED	Evaluating the Effects of Tasimelteon vs Placebo on Sleep Disturbances in SMS
NCT02776215	PHASE1	COMPLETED	Study of the Pharmacokinetics and Safety of Tasimelteon in Children and Adolescents
NCT00013559	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study of Smith-Magenis Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT05116904	Not specified	RECRUITING	Smith Magenis Syndrome and Autism Spectrum Disorders
NCT07510971	Not specified	NOT_YET_RECRUITING	mHealth Intervention for Improving Vaccination Coverage in Bangladesh
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT01837121	Not specified	COMPLETED	a Trial of Using SMS Reminder Among Diabetic Retinopathy Patients in Rural China
NCT02180451	Not specified	UNKNOWN	Observational Study to Investigate the Melatonin and Cortisol Circadian Rhythms of Individuals With Smith-Magenis Syndrome (SMS)
NCT02400671	Not specified	COMPLETED	Mobile Strategies for Women’s and Children’s Health: Optimizing Adherence and Efficacy of PMTCT/ART
NCT03346616	Not specified	COMPLETED	Text4Peds: Short Message Service Evaluating Medical Student Education
NCT03379467	Not specified	COMPLETED	Use of SMS and Interactive Reminders to Improve Timely Immunization Coverage
NCT03492970	Not specified	COMPLETED	Melatonin in Adults With SMS
NCT04768803	Not specified	UNKNOWN	Ghrelin in Patients With a Rare Disease Associated With Intellectual Disability, and Hyperphagia, and/or Overweight, and/or Obesity
NCT06247852	Not specified	COMPLETED	Persistent Pain After Cesarean Delivery - A Danish Multicenter Cohort Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TASIMELTEON	4	2