Screening of a large PAX6 cohort identified many novel variants and emphasises the importance of the paired and homeobox domains

Abstract Pathogenic variants within PAX6 are most often associated with aniridia, but have been linked with other phenotypes such as nystagmus, cataracts and foveal hypoplasia. Data are presented from a large cohort of 434 probands referred for PAX6 diagnostic testing. This analysis identified a wide range of pathogenic variants (n = 145) in 254 probands (including 61 novel variants). Excluding missense variants predicted to affect splicing, all 29 of the remaining missense variants were located within the paired (n = 27) or homeobox (n = 2) domains of the PAX6 protein, providing further evidence that these domains are critical to normal PAX6 function. Genotype-phenotype evidence suggests that while aniridia is associated with most variant types, a much broader clinical spectrum is seen in patients harbouring a missense variant, or a frameshift or run-on variant that results in an elongated or extended PAX6 protein.