The identification of two families with homozygous APP variants (Tomiyama et al., 2008 and now Di Fede et al., 2009) is interesting, but the linkage analysis in neither pedigree is sufficient for us to be sure that the mutations are pathogenic, let alone sufficient for us to tell whether they act in a co-dominant or recessive fashion. The homozygosity in both families is almost certainly caused by unrecognized consanguinity and this is common even in ostensibly outbred populations (Nalls et al., 2009). Thus, in both cases it is still possible that the variants are simply harmless polymorphisms or that they additively increase risk of disease. In both families, it might be informative to carry out whole genome genotyping to see which other loci are homozygous. Interpretation of these variants as recessive is premature.

View all comments by John Hardy

I recommend the primary paper.

View all comments by J. Lucy Boyd