H syndrome

Summary

H syndrome (MONDO:0011273) is a disease caused by SLC29A3 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC29A3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 519
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0030053	Stiff skin	Very frequent (80-99%)
HP:0100324	Scleroderma	Very frequent (80-99%)
HP:0100727	Histiocytosis	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0012385	Camptodactyly	Frequent (30-79%)
HP:0000027	Azoospermia	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000105	Enlarged kidney	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000204	Cleft upper lip	Occasional (5-29%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000141	Amenorrhea	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000534	Abnormal eyebrow morphology	Occasional (5-29%)
HP:0000771	Gynecomastia	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0008064	Ichthyosis	Occasional (5-29%)
HP:0001084	Corneal arcus	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001822	Hallux valgus	Occasional (5-29%)
HP:0001935	Microcytic anemia	Occasional (5-29%)
HP:0001954	Recurrent fever	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002110	Bronchiectasis	Occasional (5-29%)
HP:0002155	Hypertriglyceridemia	Occasional (5-29%)
HP:0002257	Chronic rhinitis	Occasional (5-29%)
HP:0002619	Varicose veins	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0002757	Recurrent fractures	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0003765	Psoriasiform dermatitis	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0007380	Facial telangiectasia	Occasional (5-29%)
HP:0009125	Lipodystrophy	Occasional (5-29%)
HP:0011025	Abnormality of cardiovascular system physiology	Occasional (5-29%)
HP:0012724	Upper eyelid edema	Occasional (5-29%)
HP:0100776	Recurrent pharyngitis	Occasional (5-29%)
HP:0100790	Hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	H syndrome
Mondo ID	MONDO:0011273
MeSH	C535391, C538322
OMIM	602782
Orphanet	168569
DOID	DOID:0111278
ICD-11	107155297
SNOMED CT	711159002
UMLS	C1864445
MedGen	400532
GARD	0010239
Is cancer (heuristic)	no

Also known as: Asrar Facharzt Haque syndrome · H syndrome · HJCD · SLC29A3 spectrum disorder

Data availability: 519 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › upper respiratory tract disorder › laryngeal disorder › H syndrome

Related subtypes (19): spasmodic dystonia, laryngostenosis, laryngitis, laryngeal abductor paralysis, congenital laryngomalacia, larynx atresia, congenital laryngeal web, primary laryngeal lymphangioma, congenital laryngeal palsy, congenital subglottic stenosis, congenital laryngeal cyst, laryngocele, laryngeal diphtheria, laryngeal granuloma, laryngeal neoplasm, polyp of vocal cord, voice disorders, acquired laryngomalacia, idiopathic subglottic stenosis

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

519 retrieved; paginated sample, class counts are floors:

218 uncertain significance, 197 likely benign, 33 pathogenic, 22 conflicting classifications of pathogenicity, 21 benign, 11 likely pathogenic, 10 benign/likely benign, 6 pathogenic/likely pathogenic, 1 benign; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
2086492	NM_018344.6(SLC29A3):c.382_383del (p.Arg128fs)	LOC105378353	Pathogenic	criteria provided, single submitter
30947	NM_018344.6(SLC29A3):c.308_309del (p.Tyr102_Phe103insTer)	LOC105378353	Pathogenic	criteria provided, single submitter
1069036	NM_018344.6(SLC29A3):c.269_275del (p.Thr90fs)	SLC29A3	Pathogenic	criteria provided, single submitter
1071023	NC_000010.10:g.(?73079047)(73079087_?)del	SLC29A3	Pathogenic	criteria provided, single submitter
130338	NM_018344.6(SLC29A3):c.1228C>T (p.Gln410Ter)	SLC29A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
130339	NM_018344.6(SLC29A3):c.300+1G>A	SLC29A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1354691	NM_018344.6(SLC29A3):c.963del (p.Ile322fs)	SLC29A3	Pathogenic	criteria provided, single submitter
1366169	NM_018344.6(SLC29A3):c.101_104dup (p.Leu36fs)	SLC29A3	Pathogenic	criteria provided, single submitter
1390366	NM_018344.6(SLC29A3):c.443del (p.Val148fs)	SLC29A3	Pathogenic	criteria provided, single submitter
1451137	NM_018344.6(SLC29A3):c.300+2T>C	SLC29A3	Pathogenic	criteria provided, single submitter
1693224	NM_018344.6(SLC29A3):c.400C>T (p.Arg134Cys)	SLC29A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1993275	NM_018344.6(SLC29A3):c.1294del (p.Leu432fs)	SLC29A3	Pathogenic	criteria provided, single submitter
1993276	NM_018344.6(SLC29A3):c.1295del (p.Leu432fs)	SLC29A3	Pathogenic	criteria provided, single submitter
2426462	NC_000010.10:g.(?73115818)(73116020_?)del	SLC29A3	Pathogenic	criteria provided, single submitter
2426463	NC_000010.10:g.(?73121691)(73122365_?)del	SLC29A3	Pathogenic	criteria provided, single submitter
2426464	NC_000010.10:g.(?73111299)(73122365_?)del	SLC29A3	Pathogenic	criteria provided, single submitter
2721497	NM_018344.6(SLC29A3):c.1077_1084del (p.Asp359fs)	SLC29A3	Pathogenic	criteria provided, single submitter
2750513	NM_018344.6(SLC29A3):c.919dup (p.Ser307fs)	SLC29A3	Pathogenic	criteria provided, single submitter
2760413	NM_018344.6(SLC29A3):c.67_70del (p.Leu24fs)	SLC29A3	Pathogenic	criteria provided, single submitter
2783465	NM_018344.6(SLC29A3):c.59_60dup (p.Ser21fs)	SLC29A3	Pathogenic	criteria provided, single submitter
2788367	NM_018344.6(SLC29A3):c.777C>A (p.Tyr259Ter)	SLC29A3	Pathogenic	criteria provided, single submitter
30948	NM_018344.6(SLC29A3):c.1088G>A (p.Arg363Gln)	SLC29A3	Pathogenic	criteria provided, multiple submitters, no conflicts
30949	NM_018344.6(SLC29A3):c.1087C>T (p.Arg363Trp)	SLC29A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244862	NC_000010.10:g.(?73103946)(73104068_?)del	SLC29A3	Pathogenic	criteria provided, single submitter
3727523	NM_018344.6(SLC29A3):c.273_277dup (p.Asp93fs)	SLC29A3	Pathogenic	criteria provided, single submitter
427021	NM_018344.6(SLC29A3):c.300+1G>C	SLC29A3	Pathogenic	criteria provided, multiple submitters, no conflicts
4797550	NM_018344.6(SLC29A3):c.201dup (p.Trp68fs)	SLC29A3	Pathogenic	criteria provided, single submitter
563	NM_018344.6(SLC29A3):c.1279G>A (p.Gly427Ser)	SLC29A3	Pathogenic	criteria provided, multiple submitters, no conflicts
564	NM_018344.6(SLC29A3):c.1330G>T (p.Glu444Ter)	SLC29A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565	NM_018344.6(SLC29A3):c.1309G>A (p.Gly437Arg)	SLC29A3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SLC29A3	Strong	Autosomal recessive	H syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC29A3	Orphanet:168569	H syndrome
SLC29A3	Orphanet:1782	Dysosteosclerosis

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
SLC29A3	HGNC:23096	ENSG00000198246	Q9BZD2	Equilibrative nucleoside transporter 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC29A3	Equilibrative nucleoside transporter 3	Uniporter that mediates the facilitative transport of nucleoside across lysosomal and mitochondrial membranes.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC29A3	Other/Unknown	no		Eqnu_transpt

Expression context

Cohort genes with no expression data: 0.

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
olfactory bulb	1
primordial germ cell in gonad	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC29A3	219	ubiquitous	yes	olfactory bulb, type B pancreatic cell, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC29A3	864

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC29A3	Q9BZD2	82.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective SLC29A3 causes histiocytosis-lymphadenopathy plus syndrome (HLAS)	1	11420.0×	9e-04	SLC29A3
Ribavirin ADME	1	1038.2×	0.004	SLC29A3
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	951.7×	0.004	SLC29A3
Transport of vitamins, nucleosides, and related molecules	1	271.9×	0.008	SLC29A3
Drug ADME	1	228.4×	0.008	SLC29A3
SLC transporter disorders	1	203.9×	0.008	SLC29A3
Disorders of transmembrane transporters	1	139.3×	0.010	SLC29A3
SLC-mediated transmembrane transport	1	59.2×	0.021	SLC29A3
Transport of small molecules	1	25.1×	0.044	SLC29A3
Disease	1	13.1×	0.076	SLC29A3

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
pyrimidine nucleobase transmembrane transport	1	8426.0×	4e-04	SLC29A3
nucleoside transport	1	5617.3×	4e-04	SLC29A3
guanine transmembrane transport	1	5617.3×	4e-04	SLC29A3
uracil transmembrane transport	1	5617.3×	4e-04	SLC29A3
cytidine transport	1	4213.0×	4e-04	SLC29A3
inosine transport	1	4213.0×	4e-04	SLC29A3
obsolete serotonin transport	1	3370.4×	4e-04	SLC29A3
nucleobase transport	1	3370.4×	4e-04	SLC29A3
adenosine transport	1	3370.4×	4e-04	SLC29A3
uridine transmembrane transport	1	2808.7×	4e-04	SLC29A3
nucleoside transmembrane transport	1	2808.7×	4e-04	SLC29A3
purine nucleobase transmembrane transport	1	2808.7×	4e-04	SLC29A3
obsolete norepinephrine transport	1	1872.4×	6e-04	SLC29A3
obsolete dopamine transport	1	1532.0×	7e-04	SLC29A3
xenobiotic metabolic process	1	149.1×	0.007	SLC29A3

Therapeutics

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
SLC29A3	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
SLC29A3	2	Binding:2

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	SLC29A3

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)
SLC29A3	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06742073	Not specified	RECRUITING	Histiocytosis and Inflammatory Manifestations in Patients with H Syndrome