Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

Summary

Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (MONDO:0014455) is a disease caused by IARS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IARS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000399	Prelingual sensorineural hearing impairment	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000408	Progressive sensorineural hearing impairment	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000519	Developmental cataract	Very frequent (80-99%)
HP:0000824	Decreased response to growth hormone stimulation test	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0002827	Hip dislocation	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0002571	Achalasia	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002655	Spondyloepiphyseal dysplasia	Very frequent (80-99%)
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0003162	Fasting hypoglycemia	Very frequent (80-99%)
HP:0003416	Spinal canal stenosis	Very frequent (80-99%)
HP:0005659	Thoracic kyphoscoliosis	Very frequent (80-99%)
HP:0007470	Periarticular subcutaneous nodules	Very frequent (80-99%)
HP:0008445	Cervical spinal canal stenosis	Very frequent (80-99%)
HP:0008619	Bilateral sensorineural hearing impairment	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
Mondo ID	MONDO:0014455
OMIM	616007
Orphanet	436174
UMLS	C4014942
MedGen	863379
GARD	0017727
Is cancer (heuristic)	no

Also known as: CAGSSS · cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia

Data availability: 27 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › hereditary endocrine growth disease › cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

Related subtypes (7): growth hormone insensitivity syndrome, permanent congenital hypothyroidism, congenital adrenal hyperplasia, non-acquired pituitary hormone deficiency, inherited primary ovarian failure, Zerres Rietschel Majewski syndrome, microdontia hypodontia short stature

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

27 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 5 conflicting classifications of pathogenicity, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1393654	NM_018060.4(IARS2):c.1942_1945dup (p.Lys649delinsIleTer)	IARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768372	NM_018060.4(IARS2):c.280dup (p.Ser94fs)	IARS2	Pathogenic	criteria provided, single submitter
638569	NM_018060.4(IARS2):c.680T>C (p.Phe227Ser)	IARS2	Pathogenic	no assertion criteria provided
638570	NM_018060.4(IARS2):c.2450G>A (p.Arg817His)	IARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638571	NM_018060.4(IARS2):c.2725C>T (p.Pro909Ser)	IARS2	Pathogenic	no assertion criteria provided
638572	NM_018060.4(IARS2):c.2282A>G (p.His761Arg)	IARS2	Pathogenic	no assertion criteria provided
4813835	NM_018060.4(IARS2):c.890G>A (p.Trp297Ter)	IARS2	Likely pathogenic	criteria provided, single submitter
638568	NM_018060.4(IARS2):c.2620G>A (p.Gly874Arg)	IARS2	Likely pathogenic	criteria provided, single submitter
156551	NM_018060.4(IARS2):c.1821G>A (p.Trp607Ter)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156552	NM_018060.4(IARS2):c.2122G>A (p.Glu708Lys)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156553	NM_018060.4(IARS2):c.2726C>T (p.Pro909Leu)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1987468	NM_018060.4(IARS2):c.991G>A (p.Val331Ile)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3252888	NM_018060.4(IARS2):c.1A>C (p.Met1Leu)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032019	NM_018060.4(IARS2):c.1016C>T (p.Ser339Phe)	IARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032783	NM_018060.4(IARS2):c.601C>T (p.Arg201Cys)	IARS2	Uncertain significance	criteria provided, single submitter
1489126	NM_018060.4(IARS2):c.1163C>T (p.Thr388Met)	IARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2083859	NM_018060.4(IARS2):c.2102C>T (p.Ala701Val)	IARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2556610	NM_018060.4(IARS2):c.2186C>T (p.Thr729Ile)	IARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3384176	NM_018060.4(IARS2):c.1562G>A (p.Cys521Tyr)	IARS2	Uncertain significance	criteria provided, single submitter
3391175	NM_018060.4(IARS2):c.349T>C (p.Tyr117His)	IARS2	Uncertain significance	criteria provided, single submitter
3580457	NM_018060.4(IARS2):c.34G>A (p.Ala12Thr)	IARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3766935	NM_018060.4(IARS2):c.1244T>C (p.Leu415Pro)	IARS2	Uncertain significance	criteria provided, single submitter
4078955	NM_018060.4(IARS2):c.1A>G (p.Met1Val)	IARS2	Uncertain significance	criteria provided, single submitter
587501	NM_018060.4(IARS2):c.1504A>C (p.Ile502Leu)	IARS2	Uncertain significance	criteria provided, single submitter
801624	NM_018060.4(IARS2):c.1255G>A (p.Asp419Asn)	IARS2	Uncertain significance	criteria provided, single submitter
1277932	NM_018060.4(IARS2):c.1328-5dup	IARS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1556751	NM_018060.4(IARS2):c.268-8del	IARS2	Benign	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
IARS2	Strong	Autosomal recessive	cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IARS2	Orphanet:436174	Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
IARS2	Orphanet:506	Leigh syndrome

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
IARS2	HGNC:29685	ENSG00000067704	Q9NSE4	Isoleucine–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IARS2	Isoleucine–tRNA ligase, mitochondrial	Aminoacyl-tRNA synthetase that catalyzes the specific attachment of isoleucine to its cognate tRNA (tRNA(Ile)).

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IARS2	Transcription factor	no	6.1.1.5	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Ile-tRNA-ligase

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
diaphragm	1
parietal pleura	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IARS2	293	ubiquitous	marker	diaphragm, parietal pleura, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IARS2	3,442

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IARS2	Q9NSE4	89.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.009	IARS2
tRNA Aminoacylation	1	285.5×	0.009	IARS2
Mitochondrial protein degradation	1	114.2×	0.015	IARS2
Translation	1	62.1×	0.020	IARS2
Metabolism of proteins	1	12.4×	0.081	IARS2

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
isoleucyl-tRNA aminoacylation	1	8426.0×	4e-04	IARS2
tRNA aminoacylation for protein translation	1	842.6×	0.002	IARS2
mitochondrial translation	1	173.7×	0.006	IARS2

Therapeutics

Drug target analysis

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

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
IARS2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIMASERTIB	2	IARS2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
IARS2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IARS2	6.1.1.5	isoleucine-tRNA ligase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
PIMASERTIB	2	IARS2

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	1	IARS2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.