Worldwide distribution of common IDUA pathogenic variants

Area of Science:

• Genetics
• Rare Diseases
• Biochemistry

Background:

• Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder.
• It results from deleterious sequence variants in the alpha-L-iduronidase (IDUA) gene.
• Over 200 pathogenic variants are known, but their global frequencies are unanalyzed.

Purpose of the Study:

• To analyze the worldwide frequencies of pathogenic variants in the IDUA gene in MPS I patients.
• To identify population-specific variant distributions.
• To inform the development of genotype-targeted therapies and improve patient management.

Main Methods:

• Systematic review and genotype analysis of MPS I patients from 35 published studies.
• Frequency analysis of pathogenic IDUA variants across different global populations.

Main Results:

• The p.Trp402Ter variant is the most common globally, prevalent in Europe, America, and Australia.
• p.Gln70Ter is frequent in Northern and Eastern Europe.
• p.Pro533Arg is the predominant variant in North Africa, exceeding 90% in Morocco.
• Distinct variants were observed in East Asian populations (e.g., c.1190-1G>A, p.Ala79Val) not found in Western populations, and vice versa for p.Trp402Ter and p.Pro533Arg.

Conclusions:

• p.Trp402Ter, p.Gln70Ter, and p.Pro533Arg are the most frequent pathogenic IDUA variants in MPS I.
• Understanding population-specific genetic backgrounds is vital for developing targeted therapies, accelerating genetic analysis, and enhancing patient care for MPS I.