Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I.

IDUA

Hypomorphic bi-allelic IDUA genotypes (mostly a loss-of-function allele paired with a missense variant) leaving residual α-L-iduronidase activity; mis-splicing of the recurrent missense c.298A>G

This study describes 14 individuals from 12 families with retinitis pigmentosa, later attributed to bi-allelic IDUA genotypes, a gene classically causing mucopolysaccharidosis type I (MPS I). Seven of them, aged 46-73 years at last assessment, showed no features of MPS I despite comprehensive systemic assessment, and leukocyte α-L-iduronidase activity was reduced but not abolished in all 9 individuals tested. None carried bi-allelic null genotypes: most had a loss-of-function allele paired with a missense variant, and cell-based functional assays showed relative specific activity of about 0.5%-1.5% for several missense alleles. The recurrent missense c.298A>G (p.Arg100Gly) had no protein or catalytic effect, but targeted long-read transcript analysis showed predominant mis-splicing with about 1%-2% correctly spliced transcript, explaining residual activity in vivo.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The message is direct for exome/genome interpretation: a bi-allelic IDUA genotype in an adult with isolated retinitis pigmentosa should no longer be dismissed because MPS I is absent. The c.298A>G case shows that a missense variant that looks neutral in an enzyme assay can act through splicing, which only transcript analysis reveals. Leukocyte α-L-iduronidase activity, reduced in every patient tested, provides a simple biochemical argument to settle the question.

Analysis by Dr Thibaut Benquey