syndromic X-linked intellectual disability Snyder type

Summary

syndromic X-linked intellectual disability Snyder type (MONDO:0010664) is a disease caused by SMS (GenCC Strong), with 2 cohort genes and 8 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 43
• Phenotypes (HPO): 66
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0002751	Kyphoscoliosis	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000275	Narrow face	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000324	Facial asymmetry	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001519	Disproportionate tall stature	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003199	Decreased muscle mass	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010511	Long toe	Frequent (30-79%)
HP:0011308	Slender toe	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000029	Testicular atrophy	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000319	Smooth philtrum	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000414	Bulbous nose	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000465	Webbed neck	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000664	Synophrys	Occasional (5-29%)
HP:0000678	Dental crowding	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002757	Recurrent fractures	Occasional (5-29%)
HP:0003698	Difficulty standing	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0007509	Patchy hypo- and hyperpigmentation	Occasional (5-29%)
HP:0007687	Unilateral ptosis	Occasional (5-29%)
HP:0010722	Asymmetry of the ears	Occasional (5-29%)
HP:0011153	Focal motor seizure	Occasional (5-29%)
HP:0045075	Sparse eyebrow	Occasional (5-29%)
HP:0000086	Ectopic kidney	Very rare (<1-4%)
HP:0000232	Everted lower lip vermilion	Very rare (<1-4%)
HP:0000248	Brachycephaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Snyder type
Mondo ID	MONDO:0010664
MeSH	C536678
OMIM	309583
Orphanet	3063
DOID	DOID:0060802
SNOMED CT	702416008
UMLS	C0796160
MedGen	162918
GARD	0005615
NORD	1890
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type, X-linked recessive · intellectual disability, X-linked, Snyder-Robinson type · intellectual disability, X-linked, syndromic, Snyder-Robinson type · mental retardation, X-linked, syndromic, Snyder-Robinson type · MRXSSR · Snyder-Robinson intellectual disability syndrome · Snyder-Robinson mental retardation syndrome · Snyder-Robinson Syndrome · Snyder-Robinson syndrome · SRS · syndromic X-linked intellectual disability Snyder type · X-linked intellectual disability Snyder-Robinson type · X-linked mental retardation Snyder-Robinson type

Data availability: 43 ClinVar variants · 4 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 › syndromic X-linked intellectual disability Snyder 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, 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, intellectual disability, X-linked, syndromic, Houge type, 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

43 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 11 pathogenic, 8 likely pathogenic, 4 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
11623	NM_004595.5(SMS):c.329+5G>A	SMS	Pathogenic	no assertion criteria provided
11624	NM_004595.5(SMS):c.166G>A (p.Gly56Ser)	SMS	Pathogenic	criteria provided, multiple submitters, no conflicts
11625	NM_004595.5(SMS):c.395T>G (p.Val132Gly)	SMS	Pathogenic	no assertion criteria provided
2248418	NM_004595.5(SMS):c.700C>T (p.Arg234Ter)	SMS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366861	NM_004595.5(SMS):c.661-13A>C	SMS	Pathogenic	criteria provided, single submitter
4813567	NM_004595.5(SMS):c.954T>G (p.Cys318Trp)	SMS	Pathogenic	criteria provided, single submitter
626916	NM_004595.5(SMS):c.908_911del (p.Met303fs)	SMS	Pathogenic	criteria provided, single submitter
65677	NM_004595.5(SMS):c.200G>A (p.Gly67Glu)	SMS	Pathogenic	criteria provided, single submitter
65679	NM_004595.5(SMS):c.443A>G (p.Gln148Arg)	SMS	Pathogenic	no assertion criteria provided
816629	NM_004595.5(SMS):c.388C>T (p.Arg130Cys)	SMS	Pathogenic	criteria provided, single submitter
827761	NM_004595.5(SMS):c.608G>A (p.Gly203Asp)	SMS	Pathogenic	criteria provided, multiple submitters, no conflicts
88767	NM_004595.5(SMS):c.983A>G (p.Tyr328Cys)	SMS	Pathogenic	no assertion criteria provided
1526148	NM_004595.5(SMS):c.865+2T>C	SMS	Likely pathogenic	criteria provided, single submitter
2444331	NM_004595.5(SMS):c.335C>A (p.Pro112Gln)	SMS	Likely pathogenic	criteria provided, single submitter
2500736	NM_004595.5(SMS):c.674T>C (p.Val225Ala)	SMS	Likely pathogenic	criteria provided, single submitter
4279691	NM_004595.5(SMS):c.442C>G (p.Gln148Glu)	SMS	Likely pathogenic	criteria provided, single submitter
4819344	NM_004595.5(SMS):c.608G>T (p.Gly203Val)	SMS	Likely pathogenic	criteria provided, single submitter
916028	NM_004595.5(SMS):c.410A>G (p.Asp137Gly)	SMS	Likely pathogenic	criteria provided, single submitter
973506	NM_004595.5(SMS):c.328C>G (p.Arg110Gly)	SMS	Likely pathogenic	no assertion criteria provided
981630	NM_004595.5(SMS):c.587T>C (p.Ile196Thr)	SMS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028274	NM_004595.5(SMS):c.1019A>G (p.Glu340Gly)	SMS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1175812	NM_004595.5(SMS):c.335C>T (p.Pro112Leu)	SMS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1210218	NM_004595.5(SMS):c.152A>G (p.Tyr51Cys)	SMS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344965	NM_004595.5(SMS):c.329G>A (p.Arg110Gln)	SMS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
915295	NM_004595.5(SMS):c.13C>G (p.Arg5Gly)	LOC130068040	Uncertain significance	criteria provided, single submitter
1331593	NM_004595.5(SMS):c.997G>C (p.Gly333Arg)	SMS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436209	NM_004595.5(SMS):c.113C>T (p.Ser38Leu)	SMS	Uncertain significance	criteria provided, single submitter
2436210	NM_004595.5(SMS):c.289A>G (p.Met97Val)	SMS	Uncertain significance	criteria provided, single submitter
2436212	NM_004595.5(SMS):c.1061+2T>C	SMS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436213	NM_004595.5(SMS):c.261C>G (p.Asp87Glu)	SMS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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	Strong	X-linked	syndromic X-linked intellectual disability Snyder type	10
SMS	Strong	X-linked	syndromic X-linked intellectual disability Snyder type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMS	Orphanet:3063	X-linked intellectual disability, Snyder type
RAI1	Orphanet:1713	17p11.2 microduplication syndrome
RAI1	Orphanet:477817	PMP22-RAI1 contiguous gene duplication syndrome
RAI1	Orphanet:819	Smith-Magenis 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
SMS	HGNC:11123	ENSG00000102172	P52788	Spermine synthase	gencc,clinvar
RAI1	HGNC:9834	ENSG00000108557	Q7Z5J4	Retinoic acid-induced protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMS	Spermine synthase	Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM).
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.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMS	Enzyme (other)	yes	2.5.1.22	Spermine_synthase_animal, SAM-dependent_MTases_sf, PABS_CS
RAI1	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD

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
cortical plate	1
ganglionic eminence	1
placenta	1
nipple	1
palpebral conjunctiva	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMS	134	ubiquitous	marker	cortical plate, placenta, ganglionic eminence
RAI1	264	ubiquitous	marker	pigmented layer of retina, nipple, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMS	2,005
RAI1	1,979

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMS	P52788	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAI1	Q7Z5J4	39.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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 polyamines	1	439.2×	0.011	SMS
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.015	RAI1
Heme signaling	1	107.7×	0.015	RAI1
Metabolism of amino acids and derivatives	1	33.8×	0.037	SMS
Metabolism	1	5.8×	0.165	SMS

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
spermine biosynthetic process	1	4213.0×	0.002	SMS
polyamine metabolic process	1	1685.2×	0.002	SMS
L-methionine metabolic process	1	1404.3×	0.002	SMS
negative regulation of multicellular organism growth	1	561.7×	0.004	RAI1
circadian regulation of gene expression	1	117.0×	0.014	RAI1
skeletal system development	1	62.9×	0.021	RAI1
positive regulation of DNA-templated transcription	1	14.0×	0.080	RAI1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	RAI1

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
SMS	0	0
RAI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SMS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMS	2.5.1.22	spermine synthase

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	1	SMS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RAI1

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)
SMS	1	—
RAI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	3
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT03915106	Not specified	RECRUITING	Quality of Life (HRQoL) of AIS Patients Who Require Bracing or Surgery Using SRS-22 Questionnaire
NCT06466720	Not specified	ACTIVE_NOT_RECRUITING	Measuring and Mapping Cognitive Decline After Brain Radiosurgery
NCT06852001	Not specified	NOT_YET_RECRUITING	Efficacy of the RayerKnife X Stereotactic Radiotherapy System in the Treatment of Brain Metastases
NCT07405112	Not specified	COMPLETED	Impact of Curve Magnitude on Pain and Body Image in Patients With Adolescents Idiopathic Scoliosis