GABRB3, 15q dups, and CNVs from exomes

GABAergic. Let’s start out with a provocative statement. There is a single gene that may explain more cases of Lennox-Gastaut Syndrome (LGS) and Infantile Spasms (IS) than you would expect, rivalling SCN1A for the most common gene found in this group of patients. It’s a gene that you are probably aware of but that you may think to be a very rare finding. In a recent publication in Annals of Neurology, the Epi4K consortium published their recent analysis of copy number variations that were derived from exome data. Combining de novo mutations and copy number variations points to GABRB3 as a major player in LGS and IS, explaining probably more than 2% of patients. Let’s find out about the twilight zone, strategies to obtain structural variants from exomes, and the re-emergence of the 15q duplication syndrome. Continue reading

What is the genomic blind spot?

Beneath the surface. Even though the comprehensiveness of next generation sequencing technologies may suggest that we can capture all the variation in the human genome, there is an entire gray zone of small rearrangements that current technologies are blind to. In a recent publication in the American Journal of Human Genetics, Brand and collaborators now use a novel technology to explore the twilight zone of genomics, the realm of small deletions, duplication, inversions and cryptic complex rearrangements. 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

The 16p11.2 microdeletion: assessing the phenotypic range

The 16p11.2 story. Among the various microdeletion and microduplication syndromes located on human chromosome 16, the 16p11.2 microdeletion has unique position. Historically, this microdeletion was the first of the “neurodels” to be identified through association studies in autism, where it can be identified in 0.5% of patients. However, there is more to the phenotypes of the 16p11.2 microdeletion, which is now addressed in a recent paper assessing the full phenotypes in 72 microdeletion carriers. 16p11.2 therefore represents one of the best-investigated microdeletions to date. Continue reading

Close encounters of the third kind – rare genetic variants in families

A new beast. Rare genetic variants probably account for a significant fraction of the genetic liability to many common and rare disorders. Rare variants occupy the liability space between monogenic variants and common genetic variants. Their existence has often been postulated, and genetic investigations looking at copy number variants have elucidated some examples of rare variants. These rare variants appear to carry particular properties that are quite unexpected including the way that these variants run in families. Now, in a recent paper in the European Journal of Human Genetics, we have developed a model of the way rare variants behave in families. And there is a lot of misbehaving. Continue reading

15q11.2 – the microdeletion spectre

Genetic mirage. We look at genetic variants all the time. There are few genetic variants that stare back at us. 15q11.2 is one these variants, facing us with the constant question how we define and perceive genetic risk. Not because of its pathogenicity, but because of the confusion that it causes. Continue reading

Double Impact

Second hits. Genomic disorders are genetic disorders due to recurrent microdeletions or microduplications, i.e. small losses or gains of genomic material that happen again and again due to existing breakpoints in the human genome. Intriguingly, additional large microdeletions or microduplications can be identified in some patients with genomic disorders. A recent study in the New England Journal of Medicine tries to explain why. Continue reading