It is common practice to halt mutation screening in a heterogeneous disease after the identification of a single pathogenic mutation. In Axenfeld Rieger Syndrome, an ocular and craniofacial morphogenesis disorder associated with two genes encoding developmental transcription factors, one usually starts with the screening of the PITX2 gene and continues with the more laborious screening of the FOXC1 gene only if no mutation could be identified in PITX2.
In this issue, Kelberman et al. (Hum Mutat 32:1144–1152, 2011) demonstrate how important it can be to analyze both PITX2 and FOXC1 in Axenfeld Rieger Syndrome, as they identified a family who segregate mutations in both genes. Strikingly, if both mutations are present, they cause a more severe phenotype than in individuals carrying only one of the two mutations. Moreover, the functional studies on transcription activation very convincingly support the long-standing hypothesis that FOXC1 and PITX2 act in a common genetic pathway.
As a consequence of their findings, the question arises whether a mutation screening should always be performed for both genes when analyzing patients with Axenfeld Rieger Syndrome. Both genes have a broad and complex mutation spectrum comprising not only single nucleotide variants but also (sub)microscopic deletions or duplications. To perform a complete mutation screening for both genes is quite laborious. However, in cases with high intrafamilial phenotypic variability, digenic inheritance should be considered. Certainly more cases with digenic inheritance will be identified in the foreseeable future, now that Kelberman et al. have proven the existence of this mechanism in Axenfeld Rieger Syndrome.