Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome

Summary

Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome (MONDO:0014559) is a disease caused by SLC6A17 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC6A17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 23
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000742	Self-mutilation	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002378	Hand tremor	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0045025	Narrow palpebral fissure	Frequent (30-79%)
HP:0000073	Ureteral duplication	Occasional (5-29%)
HP:0000574	Thick eyebrow	Occasional (5-29%)
HP:0000748	Inappropriate laughter	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0003002	Breast carcinoma	Occasional (5-29%)
HP:0005580	Duplication of renal pelvis	Occasional (5-29%)
HP:0012114	Endometrial carcinoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome
Mondo ID	MONDO:0014559
OMIM	616269
Orphanet	457212
DOID	DOID:0081212
UMLS	C4225395
MedGen	895952
GARD	0017798
Is cancer (heuristic)	no

Also known as: intellectual disability, autosomal recessive 48 · intellectual disability, autosomal recessive type 48 · mental retardation, autosomal recessive 48 · mental retardation, autosomal recessive type 48 · MRT48

Data availability: 23 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

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

23 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 4 benign, 2 pathogenic, 2 benign/likely benign, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
187769	NM_001010898.4(SLC6A17):c.484G>A (p.Gly162Arg)	SLC6A17	Pathogenic	no assertion criteria provided
187770	NM_001010898.4(SLC6A17):c.1898C>G (p.Pro633Arg)	SLC6A17	Pathogenic	no assertion criteria provided
723416	NM_001010898.4(SLC6A17):c.286+10A>G	SLC6A17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033374	NM_018255.4(ELP2):c.1321C>G (p.Leu441Val)	ELP2	Uncertain significance	criteria provided, single submitter
1031719	NM_001010898.4(SLC6A17):c.754-4G>A	SLC6A17	Uncertain significance	criteria provided, single submitter
1031720	NM_001010898.4(SLC6A17):c.852G>A (p.Met284Ile)	SLC6A17	Uncertain significance	criteria provided, single submitter
1034370	NM_001010898.4(SLC6A17):c.1957G>A (p.Val653Met)	SLC6A17	Uncertain significance	criteria provided, single submitter
1034371	NM_001010898.4(SLC6A17):c.29G>A (p.Arg10His)	SLC6A17	Uncertain significance	criteria provided, single submitter
1709501	NM_001010898.4(SLC6A17):c.351G>T (p.Glu117Asp)	SLC6A17	Uncertain significance	criteria provided, single submitter
1709502	NM_001010898.4(SLC6A17):c.374G>A (p.Arg125His)	SLC6A17	Uncertain significance	criteria provided, single submitter
3062084	NM_001010898.4(SLC6A17):c.895C>T (p.Arg299Trp)	SLC6A17	Uncertain significance	criteria provided, single submitter
3064781	NM_001010898.4(SLC6A17):c.1129T>C (p.Tyr377His)	SLC6A17	Uncertain significance	criteria provided, single submitter
3892491	NM_001010898.4(SLC6A17):c.784G>A (p.Val262Met)	SLC6A17	Uncertain significance	criteria provided, single submitter
436763	NM_001010898.4(SLC6A17):c.824G>A (p.Arg275Gln)	SLC6A17	Uncertain significance	criteria provided, multiple submitters, no conflicts
436764	NM_001010898.4(SLC6A17):c.1105G>A (p.Glu369Lys)	SLC6A17	Uncertain significance	criteria provided, multiple submitters, no conflicts
436766	NM_001010898.4(SLC6A17):c.1723G>A (p.Val575Met)	SLC6A17	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333111	NM_001010898.4(SLC6A17):c.168T>C (p.Asp56=)	SLC6A17	Benign	criteria provided, multiple submitters, no conflicts
1333112	NM_001010898.4(SLC6A17):c.169G>A (p.Ala57Thr)	SLC6A17	Benign	criteria provided, multiple submitters, no conflicts
2585674	NM_001010898.4(SLC6A17):c.1581G>A (p.Ser527=)	SLC6A17	Benign	criteria provided, single submitter
2585675	NM_001010898.4(SLC6A17):c.1816-10C>T	SLC6A17	Benign	criteria provided, single submitter
376873	NM_001010898.4(SLC6A17):c.2036A>G (p.Lys679Arg)	SLC6A17	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
436762	NM_001010898.4(SLC6A17):c.525G>A (p.Pro175=)	SLC6A17	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
436765	NM_001010898.4(SLC6A17):c.1287C>T (p.Asp429=)	SLC6A17	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
SLC6A17	Strong	Autosomal recessive	progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A17	Orphanet:457212	Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior 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
SLC6A17	HGNC:31399	ENSG00000197106	Q9H1V8	Sodium-dependent neutral amino acid transporter SLC6A17	gencc,clinvar
ELP2	HGNC:18248	ENSG00000134759	Q6IA86	Elongator complex protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A17	Sodium-dependent neutral amino acid transporter SLC6A17	Synaptic vesicle transporter with apparent selectivity for neutral amino acids.
ELP2	Elongator complex protein 2	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A17	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
ELP2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

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
pancreatic ductal cell	1
prefrontal cortex	1
right frontal lobe	1
calcaneal tendon	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A17	154	broad	marker	right frontal lobe, prefrontal cortex, pancreatic ductal cell
ELP2	253	ubiquitous	marker	left ovary, calcaneal tendon, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELP2	2,023
SLC6A17	1,459

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ELP2	Q6IA86	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC6A17	Q9H1V8	81.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HATs acetylate histones	1	79.3×	0.013	ELP2

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
alanine transport	1	1203.7×	0.004	SLC6A17
L-leucine transport	1	766.0×	0.004	SLC6A17
glycine transport	1	702.2×	0.004	SLC6A17
regulation of receptor signaling pathway via JAK-STAT	1	702.2×	0.004	ELP2
proline transport	1	648.1×	0.004	SLC6A17
tRNA wobble uridine modification	1	601.9×	0.004	ELP2
neutral amino acid transport	1	443.5×	0.005	SLC6A17
transcription elongation by RNA polymerase II	1	221.7×	0.008	ELP2
neurotransmitter transport	1	210.7×	0.008	SLC6A17
protein catabolic process	1	118.7×	0.012	SLC6A17
regulation of translation	1	109.4×	0.012	ELP2
sodium ion transmembrane transport	1	101.5×	0.012	SLC6A17
transport across blood-brain barrier	1	89.6×	0.013	SLC6A17
brain development	1	39.8×	0.027	SLC6A17
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ELP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
SLC6A17	0	0
ELP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SLC6A17, ELP2

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)
SLC6A17	0	—
ELP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.