The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable.
The 16p13.11 microdel. We have discussed the 16p13.11 microdeletion various times on this blog and the “16p13.11 microdeletion” is the single most frequent search term that leads readers to our blog. The 16p13.11 microdeletion is the result of the duplication architecture of the human genome that has resulted in two virtually identical short genomic stretches upstream and downstream of the microdeletion, so-called low-copy repeats (LCR). As a result, during meiosis, the replication machinery sometimes mixes up the upstream and downstream LCR, which results in a deletion or duplication of the genomic region between both LCRs. This is the mechanism resulting in the so-called canonical 16p13.11 microdeletion or microduplication. Related mechanisms may result in the generation of slightly smaller or larger variants in this region. 16p13.11 microdeletions were first described in patients with intellectual disability and multiple congenital anomalies. Soon after, they were found to represent relatively common genetic risk factors for the Idiopathic Generalized Epilepsies.
The big picture. Tropeano and colleagues investigate more than 10,000 cases and 11,000 controls for microdeletions in the 16p13.11 region. Cases represent patients with a broad range of neurodevelopmental disorders who underwent array comparative hybridization for clinical studies. The authors identify 46 cases and 17 controls with structural genomic variants in this region, confirming previous estimates regarding the relative risk conferred by variants in this genomic region. The authors confirm an odds ratio of ~4 for deletions and also find that microduplications in this region are significantly more frequent in cases than in controls.
The male bias. Interestingly, the authors find that the frequency of microdeletions is only significantly elevated in males, while the frequency in females is not different from controls. This points towards a higher penetrance of this microdeletion in male carriers. The authors find that deletions and duplications are 3-4 times more frequent in male patients. Given the fact that 16p13.11 microdeletions are relatively rare events, this study is the first to report such a bias for this microdeletion. It will be interesting to see whether this finding is confirmed in further studies and how this will affect clinical counseling in deletion carriers.
The ohnologs. No, this is not typo. Ohnologs are genes that are the result of a whole-genome duplication. While many of these duplicated genes lose their function over time and are removed from the genome, the persistence of duplicated genes may point towards an essential role of these genes. Accordingly, identifying ohnologs amongst a number of genes in a microdeletion might help pick out the genes that are responsible for the phenotype. Using computational methods, Tropeano and colleagues identify NDE1, MYH11, ABCC1 and ABCC6 as ohnologs. These four genes are also part of the critical region of the 16p13.11 microdeletion that can be determined by looking at the overlap of various deletions in cases. In summary, the authors present converging evidence that these four genes might contribute to the phenotype of 16p13.11 microdeletion carriers.
Lessons for EuroEPINOMICS. The paper by Tropeano and colleagues provides an interesting view on the phenotypic spectrum of 16p13.11 microdeletion and microduplication carriers and the genomic variability of the underlying structural variants. Particularly, the increased penetrance in males is a phenomenon that requires a large sample size. Their study proves that even after the initial discovery, there can be quite a few surprises regarding the phenotype and other characteristics of these variants.