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Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry
被引:49
|作者:
Clarke, Lorne A.
[1
]
Giugliani, Roberto
[2
]
Guffon, Nathalie
[3
]
Jones, Simon A.
[4
]
Keenan, Hillary A.
[5
]
Munoz-Rojas, Maria, V
[5
]
Okuyama, Torayuki
[6
]
Viskochil, David
[7
]
Whitley, Chester B.
[8
,9
]
Wijburg, Frits A.
[10
]
Muenzer, Joseph
[11
]
机构:
[1] Univ British Columbia, BC Childrens Hosp Res Inst, Dept Med Genet, Vancouver, BC, Canada
[2] Fed Univ Rio Grande & Med Genet Serv, Dept Genet, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil
[3] Hop Femme Mere Enfant, Ctr Reference Malad Hereditaires Metab, Bron, France
[4] Manchester Univ NHS Trust, Manchester Ctr Genom Med, Manchester, Lancs, England
[5] Sanofi Genzyme, Cambridge, MA USA
[6] Natl Ctr Child Hlth & Dev, Dept Clin Lab Med, Tokyo, Japan
[7] Univ Utah, Salt Lake City, UT USA
[8] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[9] Univ Minnesota, Expt & Clin Pharmacol, Minneapolis, MN USA
[10] Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands
[11] Univ N Carolina, Chapel Hill, NC 27515 USA
关键词:
genotype-phenotype;
hurler syndrome;
iduronidase;
lysosomal storage disease;
lysosome;
metabolic disease;
mucopolysaccharidosis;
Scheie syndrome;
ALPHA-L-IDURONIDASE;
IDENTIFICATION;
DIAGNOSIS;
D O I:
10.1111/cge.13583
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the alpha-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
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页码:281 / 289
页数:9
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