Why Predicting the Phenotypic Effect of Mutations is Hard

By now, we’re probably all  familiar with Niels Bohr’s famous quote that “prediction is very difficult, especially about the future”. Although Bohr’s experience was largely in quantum physics, the same problem is true in human genetics. Despite a plethora of genetic variants associated with disease – with frequencies ranging from ultra-rare to commonplace, and effects ranging from protective to catastrophic – variants where we can accurately predict the severity, onset and clinical implications are still few and far between. Phenotypic heterogeneity is the norm even for many rare Mendelian variants, and despite the heritable nature of many common diseases, genomic prediction is rarely good enough to be clinically useful.

The breadth of genomic complexity was really brought home to me a few weeks ago while listening to a range of fascinating talks at the Genomic Disorders 2013 conference. Set against a policy backdrop that includes the recent ACMG guidelines recommending opportunistic screening of 57 genes, and ongoing rumblings in the UK about the 100,000 NHS genomes, the lack of predictability in genomic medicine is rather sobering...