ClinGen Dosage Sensitivity Curation Page

IDS

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22976768 Pollard et al (2013) describe 218 cases of mucopolysaccharidosis type II (MPSII / Hunter syndrome) patients tested for variants in IDS. The variant spectrum is diverse and includes intergenic inversions and multi-exon deletions. 121 different sequence IDS variants were detected, as well as a common pathogenic inversion and exonic deletions in an additional 15 cases. Testing 102 mothers of MPSII patients showed that 22.5 % of IDS variants were de novo. All coding exons +/- 25bp were PCR amplified and Sanger sequenced. If no variant was detected, allele-specific PCR and/or MLPA were used. The allele-specific PCR detects a common pathogenic inversion between intron 7 of the IDS gene and a region near exon 3 of the IDSP1 pseudogene. MLPA detects CNVs. Reported variants include: 8 stop variants: c.79G>T p.E27* c.361C>T p.Q121* c.495T>G p.Y165* c.1010G>A p.W337* c.1035G>A p.W345* c.1266C>A p.C422* c.1470T>A p.Y490* c.429dupT p.(Asn144*) 20 frameshift variants: c.128_129delTC p.(Ile43Serfs*3) c.219delC p.(Phe74Serfs*56) c.601_602delAG p.(Ser201Hisfs*2) c.632delA p.(Lys211Argfs*2) c.798delC p.(Trp267Glyfs*13) c.817delC p.(Arg273Glyfs*7) c.996delC p.(Ser333Argfs*7) c.1274delC p.(Pro425Leufs*15) c.1377delA p.(Glu459Aspfs*2) c.1411_1412delGA p.(Asp471Hisfs*7) c.314_317dupTCAA p.(Ser107Glnfs*39) c.753dupC p.(Asp252Argfs*6) c.812_813insA p.(Gln272Alafs*70) c.976_979dupAGCA p.(Thr327Lysfs*16) c.1025dupA p.(His342Glnfs*11) c.1141dupC p.(Leu381Profs*5) c.1186_1187insTGCCT p.(Gln396Leufs*46) c.1294_1298dupTGCAG p.(Arg433Serfs*9) c.1362_1365dupTGGT p.(Asn456Trpfs*2) c.514_516delCGAins13 p.(Arg172Glyfs*2) 4 splicing variants: c.104-1G>A c.880-2A>C c.1007-2A>C c.1006+2T>A 15 exonic deletions were also reported, although it is not clear how many of these only involve IDS due to the limitations of MLPA.
24125893 Brusius-Facchin et al (2014) describe 103 South American MPSII patients, tested by Sanger, single-strand conformation polymorphism (SSCP) & PCR amplification. All 103 cases had IDS variants. Sixty-three variants were observed in families with multiple affected individuals. Fifteen of the variants were de novo. 3 whole gene deletions were described, but these were contiguous with other genes. 4 partial gene deletions were also described: exons [5,6,7]x2, [5,6,7,8] & [5,6,7,8,9]. The extent of the last one is unknown, therefore at least 3 deletions include IDS alone. Other described variants include: 4 stop variants: c.241C>T p.Q81* c.327G>A p.W109* c.715C>T p.Q239* c.1608T>A p.Y536* 3 splice variants: c.418G>C c.709-2A>T c.1007G>T 5 frameshift variants: c.155delG p.(Gly52Alafs*8) c.1349_1364del16 p.(Asp450Valfs*6) c.805_808dupGACA p.(Ile270Argfs*73) c.1134_1152dup19 p.(Asp385Profs*7) c.1300_1306dupGAAGGCA p.(Lys436Argfs*13)

Haploinsufficiency phenotype comments:

Loss of function variants in IDS cause Mucopolysaccharidosis type II (Hunter syndrome), including frameshift, nonsense, splicing, and deletion variants. 9% of all variants are deletions involving one or more exons (Gene Reviews). Males are always affected. Female carriers are usually asymptomatic, but there have been rare reports of symptomatic females due to skewed X-inactivation. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy, and, in most patients, neurologic decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Enzyme replacement therapy may mitigate some of these features.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.