One region, three disorders. The following blogpost serves as a partner to this week’s earlier post on the genomic idiosyncrasies of the 15q11-13 region. We hope that the discussion of the clinical aspects of disorders rooted in this region will further illustrate the vast complexity of the genome. Below we describe the three clinical syndromes associated with this region.
Cytogenetics. 15q11-13 can be an intimidating region, even for many seasoned genetics professionals. Several factors contribute to this, including a complex genomic architecture, genomic imprinting, an acrocentric chromosome, and several genes critical to neurological function. For today’s blog post, we’ll try to unravel some of its complexity to make interpretation of copy number variants (CNVs) in this area clearer.
Copy numbers. When we think about genetic causes of neurodevelopmental disorders and the epilepsies, we typically discuss single genes and de novo variants. Over the last few years, exome and genome data of hundreds of thousands of people have been analyzed, creating large-scale resources to understand genetic variation in health and disease. However, there has been one resource that has always been larger by at least one order of a magnitude – information on copy number variation derived from SNP arrays and array CHG. Now, a recent publication pulls all the existing information together and performs a meta-analysis of rare copy-number variants in nearly one million people. Here is what this study tells us about neurodevelopmental genes and how we can use mismatches between CNV and exome data to answer old questions and find novel genes. Continue reading
CNV. There are different forms of genetic variation and historically, our ability to query the entire exome or genome is a relatively recent development. However, the first type of genetic variation that could be assessed in the epilepsies in large cohorts were copy number variations (CNV), small gains or losses of chromosomal materials. In a recent study, the entire Epi25 cohort was analyzed for CNVs, giving a long-needed update on the role of the structural genomic variations in various forms of epilepsies and highlighting that the overall landscape of CNVs in the epilepsies is well understood and delineated. With up to 3% of individuals with epilepsies carrying some of the recurrent CNVs, this type of genomic variation remains a rare, but important source of genetic morbidity in the epilepsies. Continue reading
Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading
A productive week in epilepsy genetics. Scientists and editors were certainly busy this week reporting novel variants and deletions as well the experimental and statistical advances for their interpretation.
A de novo GRIN2A missense mutation in early-onset epileptic encephalopathy. We and others have associated variants affecting the GRIN2A gene with a range of childhood focal epilepsy syndromes. Continue reading
New Year – new papers. The United Nations has declared 2014 the International Year of Family Farming and Crystallography.
But for epilepsy genetics it will be the year of genotyping and sequencing. Hopefully, these studies will translate into with major insights in epilepsy genetics.
Back from Israel. This week I will send you on holidays with a lot of interesting papers for the the time off. Hopefully you will find time to read some of these papers and won’t get overwhelmed by the amount of studies this week. Here we go:
Variations on Copy Numbers. In the third issue of our series on the papers of the week I will focus on the detection and annotation of the most common form of structural variation encountered in genomes. Deletions, duplications and inversions are frequent events, which are surprisingly hard to deal with using sequencing-based tools. Hence, this is an area of active development.
GEFS+, meet CNV. Microduplications at 17q12 have been identified in various neurodevelopmental disorders and in some unaffected individuals, a pattern familiar from other structural genomic variants such as microdeletions at 16p13.11 and 15q11.2. In contrast to the corresponding microdeletion, most 17q12 microduplications are inherited. This suggests that the microduplication is a risk factor, but does not fully explain the phenotype. In a recent paper in Neurology, Hardies and collaborators look at the families of 17q12 microduplication carriers with epilepsy. And this is when they noticed something strange. Continue reading