Over 300 IDS pathogenic variants have been described in patients with MPSII. Findings in mouse models are consistent with clinical manifestations in human patients.
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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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