Oligogenic inheritance in severe adult obesity

Abstract The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity but, even when pathogenic mutations are present, there may be variable penetrance. Here, we present a family where initial discovery of a proband with a mutation in SH2B1 could have led to inaccurate genetic counselling. Whole exome sequencing (WES) of the parents revealed an apparently oligogenic mode of inheritance, with rare mutations in POGZ and MBD5 also segregating in this trio. Subsequent reanalysis of WES data from 91 unrelated adults with severe obesity revealed two other patients who carried more than one rare, predicted-deleterious mutation. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance. We caution clinicians and researchers to avoid confining their analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.