Clinical, genetic and biochemical signatures of -related ocular malformations.

BACKGROUND

The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in (), encoding a serum retinol-specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC).

METHODS

We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous variants, of whom we performed biochemical analyses.

RESULTS

For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes, depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal genotypes on phenotypical expression in dominant forms, suggesting that maternal genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that retinol-binding protein blood dosage in patients could provide a biological signature crucial for classifying variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in mutational spectrum.

CONCLUSION

Dominant missense variants in are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.