Somatic mosaicism of SLC35A2 in focal epilepsy: an emerging common genetic mechanism

Somatic mosaicism in focal epilepsy. Recent findings highlighted the role of somatic parental mosaicism in epileptic encephalopathies. However, somatic mosaicism has also emerged over the last few years as a prominent mechanism in the pathogenesis of lesional focal epilepsies, including focal cortical dysplasia (FCD) type 2 and hemimegalencephaly. Previous studies have identified the role of mosaicism of genes such as MTOR, TSC1/TSC2, and genes encoding components of the PI3K/AKT pathway in patients with epilepsy secondary to brain malformations. A recent study in Annals of Neurology has identified a new unrelated genetic cause of refractory non-lesional focal epilepsy, which leads us to wonder what role mosaicism may be playing in focal epilepsies without obvious findings on MRI.
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Not only de novo after all: the role of parental mosaicism in genetic epilepsies

Conventional wisdom. Trio whole exome sequencing has been successful over the last five years in identifying underlying genetic etiologies in nearly 50% of patients with epileptic encephalopathies, which is largely owing to the genetic architecture of these conditions. The vast majority of these genetic epilepsies are caused by apparent de novo variants that are present in the patient but not in the mother or father. The conventional wisdom is that the recurrence risk in future pregnancies for parents of an affected child is low to non-existent and traditionally we have quoted a ~1% recurrence risk for future pregnancies. However, a new study published in the New England Journal of Medicine turns this conventional wisdom on its head, identifying detectable somatic mosaicism in approximately 10% of parents tested, which has implications for how we counsel families of children with epileptic encephalopathies – and potentially other genetic conditions due to de novo variants as well. Continue reading

The mosaic brain – single neuron copy number variations in humans

Variability. It has been rumored for quite some time, but only now is solid evidence present to show this phenomenon: the high degree of genomic diversity of human neurons. In a recent paper in Science, the genomic diversity among frontal brain neurons is explored on a cell-by-cell basis. The results are breathtaking: up to 40% of frontal cortex neurons have altered genomic material affected by large deletions or duplications. This study provides the linchpin for a plethora of new investigations aiming to understand the impact of this phenomenon in health and disease. Continue reading