Genotype-phenotype relationships in mucopolysaccharidosistype I (MPS I) : insights from the International MPS I Registry

• Autor(a) principal: Clarke, Lorne A.
• Data de Publicação: 2019
• Outros Autores: Giugliani, Roberto, Guffon, Nathalie, Jones, Simon A., Keenan, Hillary, Munõz Rojas, Maria Verônica, Okuyama, Torayuki, Viskochil, David H., Whitley, Chester B., Wijburg, Frits, Muenzer, Joseph
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/201012
• topic: Genótipo; Fenótipo; Doenças por armazenamento dos lisossomos; Mucopolissacaridose I; Variação genética; genotype-phenotype; hurler syndrome; iduronidase; lysosomal storage disease; lysosome; metabolic disease; mucopolysaccharidosis; Scheie syndrome

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resultingfrom pathogenic variants in theα-L-iduronidase (IDUA) gene. Clinical phenotypesrange from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syn-dromes) and vary in age of onset, severity, and rate of progression. Defining the phe-notype at diagnosis is essential for disease management. To date, no systematicanalysis of genotype-phenotype correlation in large MPS I cohorts have been per-formed. Understanding genotype-phenotype is critical now that newborn screeningfor MPS I is being implemented. Data from 538 patients from the MPS I Registry(380 severe, 158 attenuated) who had 2IDUAalleles identified were examined. Inthe 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 wereunique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenu-ated and 22% of patients with severe MPS I had unique genotypes. About 67.6% ofsevere patients had genotypes where both variants identified are predicted toseverely disrupt protein/gene function and 96.1% of attenuated patients had at leastone missense or intronic variant. This dataset illustrates a close genotype/phenotypecorrelation in MPS I but the presence of uniqueIDUAmissense variants remains achallenge for disease prediction.