Riley-Day syndrome

Summary

Riley-Day syndrome (MONDO:0009131) is a disease caused by ELP1 (GenCC Definitive), with 1 cohort gene and 12 clinical trials. Top therapeutic interventions include carbidopa anhydrous, dronabinol, and phosphatidyl serine.

At a glance

• Prevalence: 1-5 / 10 000 (Specific population) [Orphanet-validated]
• Causal gene: ELP1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,192
• Phenotypes (HPO): 37
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	18.5	Specific population	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000522	Alacrima	Very frequent (80-99%)
HP:0000615	Abnormal pupil morphology	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001278	Orthostatic hypotension	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002047	Malignant hyperthermia	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0200020	Corneal erosion	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001100	Heterochromia iridis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002103	Abnormality of the pleura	Occasional (5-29%)
HP:0002585	Abnormality of the peritoneum	Occasional (5-29%)
HP:0002757	Recurrent fractures	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0010885	Avascular necrosis	Occasional (5-29%)
HP:0100820	Glomerulopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Riley-Day syndrome
Mondo ID	MONDO:0009131
MeSH	D004402
OMIM	223900
Orphanet	1764
DOID	DOID:11589
ICD-10-CM	G90.1
ICD-11	831377479
NCIT	C84706
SNOMED CT	29159009
UMLS	C0013364
MedGen	41678
GARD	0007581
MedDRA	10039179
NORD	1069
Is cancer (heuristic)	no

Also known as: Dysautonomia, Familial · dysautonomia, familial · familial dysautonomia · hereditary sensory and autonomic neuropathy 3 · hereditary sensory and autonomic neuropathy type 3 · hereditary sensory and autonomic neuropathy type III · hereditary sensory neuropathy type 3 · HSAN 3 · HSAN III · HSAN3 · HSN 3 · neuropathy, hereditary sensory and autonomic, type 3 · neuropathy, hereditary sensory and autonomic, type III · Riley Day syndrome · Riley-Day syndrome

Data availability: 1,192 ClinVar variants · 2 GenCC gene-disease records · 40 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › neurocristopathy › Riley-Day syndrome

Related subtypes (15): paraganglioma, neuroblastoma, piebaldism, DiGeorge syndrome, CHARGE syndrome, craniofrontonasal syndrome, craniofacial microsomia, multiple endocrine neoplasia, Hirschsprung disease, neurofibromatosis type 1, Axenfeld-Rieger syndrome, cutaneous neuroendocrine carcinoma, Waardenburg-Shah syndrome, melanocytic neoplasm, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

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

600 retrieved; paginated sample, class counts are floors:

300 uncertain significance, 109 likely pathogenic, 59 pathogenic/likely pathogenic, 51 likely benign, 39 conflicting classifications of pathogenicity, 23 benign, 16 benign/likely benign, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069416	NM_003640.5(ELP1):c.707_711dup (p.Ala238fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069538	NM_003640.5(ELP1):c.572G>A (p.Trp191Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070946	NM_003640.5(ELP1):c.64C>T (p.Gln22Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071336	NM_003640.5(ELP1):c.990G>A (p.Trp330Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071639	NM_003640.5(ELP1):c.2859T>A (p.Cys953Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074489	NM_003640.5(ELP1):c.3424C>T (p.Arg1142Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074533	NM_003640.5(ELP1):c.307G>T (p.Glu103Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074683	NM_003640.5(ELP1):c.737G>A (p.Trp246Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076972	NM_003640.5(ELP1):c.1339C>T (p.Gln447Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299758	NM_003640.5(ELP1):c.138dup (p.Val47fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353787	NM_003640.5(ELP1):c.3382_3385del (p.Thr1128fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361491	NM_003640.5(ELP1):c.2020C>T (p.Gln674Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378924	NM_003640.5(ELP1):c.3408del (p.Lys1136fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380716	NM_003640.5(ELP1):c.3822G>A (p.Trp1274Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386347	NM_003640.5(ELP1):c.1289T>A (p.Leu430Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391877	NM_003640.5(ELP1):c.3378dup (p.Gln1127fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410635	NM_003640.5(ELP1):c.1884T>A (p.Cys628Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426685	NM_003640.5(ELP1):c.3688G>T (p.Glu1230Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430990	NM_003640.5(ELP1):c.3343G>T (p.Glu1115Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451893	NM_003640.5(ELP1):c.2322_2325del (p.Asp775fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452982	NM_003640.5(ELP1):c.3291C>G (p.Tyr1097Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453211	NM_003640.5(ELP1):c.969G>A (p.Trp323Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454132	NM_003640.5(ELP1):c.3595A>T (p.Lys1199Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455335	NM_003640.5(ELP1):c.1053G>A (p.Trp351Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457413	NM_003640.5(ELP1):c.1615_1618del (p.Asp539fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459836	NM_003640.5(ELP1):c.3714dup (p.Ile1239fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460164	NM_003640.5(ELP1):c.1361-1G>T	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705187	NC_000009.11:g.(111644468_111651611)(111696613?)del	ELP1	Pathogenic	criteria provided, single submitter
1724014	NM_003640.5(ELP1):c.882G>A (p.Trp294Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725667	NM_003640.5(ELP1):c.252_255del (p.Cys84fs)	ELP1	Pathogenic/Likely pathogenic	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
ELP1	Definitive	Autosomal recessive	Riley-Day syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ELP1	Orphanet:1764	Familial dysautonomia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ELP1	HGNC:5959	ENSG00000070061	O95163	Elongator complex protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELP1	Elongator complex protein 1	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: 0 · 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	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELP1	Scaffold/PPI	no		Elp1, WD40/YVTN_repeat-like_dom_sf, Beta-prop_ELP1_1st

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELP1	291	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELP1	2,733

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ELP1	O95163	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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	ELP1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation	1	5617.3×	5e-04	ELP1
tRNA wobble uridine modification	1	1203.7×	0.001	ELP1
regulation of translation	1	218.9×	0.005	ELP1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Albuterol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Dexmedetomidine.

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ELP1	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
ELP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	ELP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ELP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	5
Not specified	4
PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01212484	PHASE3	COMPLETED	Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
NCT01987219	PHASE3	COMPLETED	The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia
NCT06128356	PHASE2	ACTIVE_NOT_RECRUITING	Pilot Study of Dexmedetomidine Sublingual Film for the Ambulatory Treatment of Hyperadrenergic Autonomic Crisis in Patients With Familial Dysautonomia
NCT06148311	PHASE2	ENROLLING_BY_INVITATION	Dexmedetomidine Sublingual Film for the Ambulatory Treatment of Hyperadrenergic Autonomic Crisis in Patients With Familial Dysautonomia
NCT02276716	PHASE2	COMPLETED	The Nutritional Supplement Phosphatidylserine in Patients With Familial Dysautonomia
NCT02553265	PHASE2	COMPLETED	Carbidopa for the Treatment of Excessive Blood Pressure Variability
NCT02608931	PHASE2	WITHDRAWN	The Safety, Tolerability and Efficacy of Dronabinol, for the Treatment of Nausea and Vomiting in Familial Dysautonomia
NCT02274051	PHASE1	COMPLETED	The Safety and Tolerability of Kinetin, in Patients With Familial Dysautonomia
NCT03920774	Not specified	RECRUITING	The Natural History of Familial Dysautonomia
NCT01999257	Not specified	COMPLETED	Efficacy Study of an Online Educational Module Before Carrier Genetic Screening in Persons of Ashkenazi Jewish Descent.
NCT03013777	Not specified	COMPLETED	A Trial of Cognitive Behavioral Therapy in Familial Dysautonomia
NCT03911063	Not specified	WITHDRAWN	Telemedicine Clinical Trial for Cognitive Behavioral Therapy in Familial Dysautonomia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CARBIDOPA ANHYDROUS	4	6
DRONABINOL	4	1
PHOSPHATIDYL SERINE	2	1
KINETIN	0	1