Researchers at the Greenwood Genetic Center (GGC) have identified an unexpected association between retinitis pigmentosa (RP), an inherited retinal disorder characterized by progressive loss of vision, and variants in the alpha-L-iduronidase (IDUA) gene. The gene is traditionally associated with mucopolysaccharidosis type I (MPS I), a rare lysosomal storage disorder caused by deficient alpha-L-iduronidase activity.
The international study, published in The American Journal of Human Genetics, investigated 14 individuals from 12 unrelated families who presented with RP. Genetic testing identified biallelic, or disease-associated variants affecting both copies, of the IDUA gene in all individuals. The findings expand the recognized phenotypic spectrum associated with IDUA variants and identify RP as a retinal-predominant presentation that can occur in the absence of the typical syndromic features of MPS I.
MPS I results from impaired degradation of glycosaminoglycans because of deficient alpha-L-iduronidase activity. The disorder can produce a broad range of systemic manifestations, including skeletal abnormalities, cardiovascular disease, organ involvement, airway disease, hearing impairment and, in more severe forms, developmental and neurological complications. Traditionally, individuals with biallelic pathogenic IDUA variants are evaluated for these multisystem features.
However, the clinical presentation of the individuals in this study was notably different. Seven of the 14 individuals had no features consistent with MPS I despite comprehensive systemic assessments. These individuals were between 46 and 73 years of age, indicating that a retinal-predominant presentation can persist into later adulthood without the development of recognizable systemic manifestations of MPS I. Progressive retinal degeneration was instead the principal clinical feature.
The researchers investigated whether differences in the functional effects of individual IDUA variants could explain this unusual phenotype. Their analysis focused on the activity of the alpha-L-iduronidase enzyme and demonstrated that the variants associated with this presentation were hypomorphic, meaning that they reduced gene or protein function but did not completely abolish it. Some variants retained measurable residual enzyme activity, although at substantially reduced levels.
This residual activity may help explain why affected individuals developed retinal disease without the broader manifestations typically associated with MPS I. The findings suggest that the degree of residual enzyme function may influence the clinical expression of IDUA-related disease, contributing to substantial variation in the phenotype.
The study provides an important example of why genetic testing alone may not be sufficient to establish the clinical significance of a variant. Functional studies, including biochemical assessment of enzyme activity, can provide additional information about how particular variants affect protein function and may help explain why individuals carrying variants in the same gene can develop markedly different clinical presentations.
The findings also have implications for the diagnosis of inherited retinal disease. The researchers propose that IDUA should be considered when evaluating individuals with RP or other inherited retinal disorders, including those who do not show the characteristic systemic manifestations of MPS I. The study has already influenced genetic disease resources, with IDUA added to the Genomics England Retinal Disorders Panel as a biallelic gene associated with RP and attenuated MPS I.
The study highlights the value of combining genomic analysis, clinical assessment and functional biochemical testing to establish genotype–phenotype relationships and recognize atypical presentations of genetic disease. The findings could ultimately improve diagnostic evaluation for individuals with unexplained inherited retinal degeneration. Recognizing IDUA as a potential cause may help identify patients who would otherwise remain undiagnosed because they lack the systemic features traditionally used to recognize MPS I.
References
- Lin S, Yu SH, Browning AC, Sangermano R, Poplawski AB, Stepien KM, et al. Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I. Am J Hum Genet. 2026.