Bohring-Opitz syndrome is a clinically heterogeneous developmental condition characterized by feeding difficulties, severe developmental delays, a smaller than average head circumference, and distinctive facial features and posture. It is estimated that around half of the individuals affected have de novo truncating mutations in the additional sex combs like 1 (ASXL1) gene. The ASXL gene family is composed of three evolutionarily conserved transcriptional regulators, ASXL1, ASXL2 and ASXL3 that are known to play key roles in development.

In a study recently published in Genome Medicine, and highlighted in a Nature News piece, Matthew Bainbridge and colleagues report de novo truncating mutations in the ASXL3 gene that are associated with a clinical syndrome with features partially overlapping with Bohring-Opitz. This finding, made possible by next generation sequencing analysis of the patients and their parents, has important implications for clinical diagnosis, since it suggests that the diverse clinical presentations observed in Bohring-Opitz patients might be partly due to underlying genetic heterogeneity.

As pointed out by John Graham and Bianca Russell in the accompanying research highlight, we might be moving towards the molecular definition of distinct clinical syndromes associated with different members of the ASXL gene family, as more patients are analyzed for ASXL mutations. Another interesting aspect, which should become evident as the number of reported patients increases, is whether ASXL genes play a dual role in development and tumorigenesis. This will add to the list of genes where germline mutations cause developmental syndromes and somatic mutations can lead to tumor development and would require monitoring.