GeneBe

IDS

protein-coding

iduronate 2-sulfatase, the group of Sulfatases

Gene summary

This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

Previous symbols:
  • SIDS

MANE transcript

NM_000202.8

Inheritance

XL, XLR

ClinVar variants

P:797U:274B:278

Top phenotype

Mucopolysaccharidosis type II

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:149,476,988-149,521,096

External References & Databases

Ensembl (ENSG00000010404)NCBI Gene (3423)OMIM (300823)HGNC:5389GenCCUniProt (P22304)AlphaFoldClinVar (IDS)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~44.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 2DEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010674

Submitter: Natera

mucopolysaccharidosis type 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: ClinGen

*IDS* was first reported in relation to X-linked mucopolysaccharidosis type 2, also known as Hunter syndrome, in 1991 (Wilson et al., PMID: 1901826). *IDS* encodes iduronate 2-sulfatase, a lysosomal enzyme involved in the degradation pathway of the glycosaminoglycans dermatan sulfate and heparan sulfate. IDS deficiency leads to progressive accumulation of the two glycosaminoglycans in lysosomes, and a wide spectrum of clinical phenotypes in affected males. The neuronopathic (severe) phenotype is characterized by progressive deterioration with intellectual disability, and cardio respiratory impairment that leads to death in the first or second decade of life. In patients with the non-neuronopathic (attenuated) phenotype, the central nervous system is minimally or not affected, but the effects on other organ systems can be severe. Carrier females are typically unaffected, but on rare occasions they can manifest findings. Over 300 *IDS* pathogenic variants have been described in patients with mucopolysaccharidosis type 2. Eighteen variants (missense, nonsense, frameshift, splice) that have been reported in 19 probands in six publications (PMIDs: 1639384, 8940265, 9501270, 9950361, 12794697, 27246110) are included in this curation. The mechanism of pathogenicity is loss of function. Findings in mouse models are consistent with clinical manifestations in human patients. In summary, there is definitive evidence supporting the relationship between *IDS* and X-linked mucopolysaccharidosis type 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 21, 2018 (SOP Version 5).

mucopolysaccharidosis type 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: G2P

mucopolysaccharidosis type 2, attenuated formSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0016316

Submitter: Orphanet

mucopolysaccharidosis type 2, severe formSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0016315

Submitter: Orphanet

mucopolysaccharidosis type 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: PanelApp Australia

mucopolysaccharidosis type 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010674

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type IIXL

Manifestation: Biochemical; Cardiovascular

Intervention: Biochemical

Rationale: Enzyme replacement therapy is available and may positively influence biochemical parameters and some outcomes (such as height and endurance), but there is not evidence that the outcome would be positively affected with earlier (genetic) diagnosis, and replacement may not affect neurologic (CNS) manifestations; Awareness of multisystemic involvement, including cardiac manifestations, may allow early and beneficial management of sequelae such as cardiac valvular disease; BMT has been reported

Refs: 4622960; 1901826; 1906048; 1303211; 8111411; 7581397; 8940265; 9660053; 9762601; 9501270; 9921913; 10399096; 16912578; 17185020; 18038146; 19901005; 19748810; 20301451; 21502868; 23497636; 23537841; 25541100; 28595941Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IDS variants in ClinVar

11 Conditions Cataloged
Mucopolysaccharidosis, MPS-IITotal: 1354
not providedTotal: 152
Inborn genetic diseasesTotal: 102
Mucopolysaccharidosis, MPS-III-ATotal: 70
not specifiedTotal: 61
IDS-related disorderTotal: 45
Mucopolysaccharidosis type 2, severe formTotal: 2
Mucopolysaccharidosis, type II, mild formTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000202.8. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
15
clinvar
199
clinvar
11
clinvar
 229
missense
95
clinvar
234
clinvar
245
clinvar
63
clinvar
5
clinvar
 642
nonsense
86
clinvar
13
clinvar
2
clinvar
 101
start loss
2
clinvar
1
clinvar
 3
frameshift
248
clinvar
54
clinvar
1
clinvar
 303
splice donor/acceptor (+/-2bp)
47
clinvar
13
clinvar
11
clinvar
 71
Total478319274262161349

Highest pathogenic variant AF is 0.000008967001

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000202.8RefSeqNP_000193.19MANE Select
ENST00000340855.11EnsemblENSP00000339801.69MANE Select
NM_001166550.4RefSeqNP_001160022.18Standard
NM_006123.5RefSeqNP_006114.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
idsDanio rerio

Structure: atrioventricular valve

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Glycosaminoglycan degradation - Homo sapiens (human)
  • Metabolism of carbohydrates
  • HS-GAG degradation
  • Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

  • glycosaminoglycan catabolic process
  • chondroitin sulfate catabolic process

Molecular Function

  • iduronate-2-sulfatase activity
  • sulfuric ester hydrolase activity
  • metal ion binding

Cellular Component

  • lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000340855
Coding exons
9
Length
56950
Individuals with no LoFs
125740
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125742
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.581622290.7060.00001843590
Missense (PolyPhen)4091.6730.436331445
Synonymous-0.21410097.31.030.000008311109
Loss of Function3.77016.60.000.00000116275

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000360.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Required for the lysosomal degradation of heparan sulfate and dermatan sulfate.;
Disease
DISEASE: Mucopolysaccharidosis 2 (MPS2) [MIM:309900]: An X-linked lysosomal storage disease characterized by intracellular accumulation of heparan sulfate and dermatan sulfate and their excretion in urine. Most children with MPS2 have a severe form with early somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration. A prominent feature is neurological damage that presents as developmental delay and hyperactivity but progresses to mental retardation and dementia. They die before 15 years of age, usually as a result of obstructive airway disease or cardiac failure. In contrast, those with a mild form of MPS2 may survive into adulthood, with attenuated somatic complications and often without mental retardation. {ECO:0000269|PubMed:10215411, ECO:0000269|PubMed:10220152, ECO:0000269|PubMed:10447264, ECO:0000269|PubMed:10671065, ECO:0000269|PubMed:10838181, ECO:0000269|PubMed:11015461, ECO:0000269|PubMed:11683780, ECO:0000269|PubMed:11731225, ECO:0000269|PubMed:12655569, ECO:0000269|PubMed:12794697, ECO:0000269|PubMed:1284597, ECO:0000269|PubMed:1303211, ECO:0000269|PubMed:16699754, ECO:0000269|PubMed:7581397, ECO:0000269|PubMed:7599640, ECO:0000269|PubMed:7728156, ECO:0000269|PubMed:7866405, ECO:0000269|PubMed:7887413, ECO:0000269|PubMed:7981716, ECO:0000269|PubMed:8281149, ECO:0000269|PubMed:8566953, ECO:0000269|PubMed:8664909, ECO:0000269|PubMed:8830188, ECO:0000269|PubMed:8940265, ECO:0000269|PubMed:9222763, ECO:0000269|PubMed:9266380, ECO:0000269|PubMed:9375851, ECO:0000269|PubMed:9452044, ECO:0000269|PubMed:9501270, ECO:0000269|PubMed:9660053, ECO:0000269|PubMed:9762601, ECO:0000269|PubMed:9875019, ECO:0000269|PubMed:9921913, ECO:0000269|PubMed:9950361}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.254

Intolerance Scores

RVIS EVS
0.38
RVIS percentile EVS
75.51

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0204

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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