DDD. It’s probably the most impressive of all exome sequencing studies of 2014 and I almost missed it. Late December last year, the Deciphering Developmental Disorders study was published in Nature, reporting the genetic findings in more than 1,000 patient-parent trios, which were collected in a systematic nation-wide approach in the United Kingdom and Ireland. The analysis of more than 1,600 de novo mutations in this cohort provides another fascinating view into the genetics of neurodevelopmental disorders, independently confirming the role of DNM1 and pointing out several genes that act through either activating or dominant-negative mutations. Let me guide you through a study that comes to the sobering conclusion that even entire nations are too small to understand the genetics of neurodevelopmental disease. Continue reading
Category Archives: Papers
ESES and the postsynapse – CNKSR2 in genetic epilepsies
Structure. Despite tremendous advances in understanding its genetic underpinnings in the last few years, electrical status epilepticus during slow-wave sleep (ESES) is a poorly understood neurodevelopmental disorder and to a certain extent the prototype of an epileptic encephalopathy. Slow-wave sleep in affected children is entirely replaced by epileptiform activity, leading to significant neurocognitive impairment with an emphasis on speech impairment. In a recent publication in Annals of Neurology, alterations in CNKSR2 are identified in families with a more severe course of ESES, highlighting the postsynapse as a possible player in ESES pathogenesis. Continue reading
AP4S1 in fever-associated epilepsies and spastic paraplegia
Peds vs. adult. Sometimes it makes a fundamental difference in diagnosis whether a patient is seen in a pediatric setting or by an adult specialist later in life. Here is the most recent example from our consortium, which was just published in Human Molecular Genetics: what initially looked like recessive inheritance with intellectual disability and a peculiar fever-associated epilepsy syndrome eventually turned out to be the second reported family of the novel spastic paraplegia gene AP4S1. This raises the question of how much we are missing if we are looking at the wrong point in time. Let’s have a look at how genetics can help us see an overlap of diseases where we usually don’t have a chance to. Continue reading
Beyond recessive – KCNC1 mutations in progressive myoclonus epilepsy
PME. The progressive myoclonus epilepsies (PME) are a particular subtype of seizure disorders characterized by progressive myoclonus, generalized seizures and cognitive deterioration. Known causes of PME include recessive mutations in several well-known genes, but the genetic cause is unknown in a significant proportion of patients. Now, in a recent paper in Nature Genetics, de novo mutations in KCNC1 are identified as a novel cause of progressive myoclonus epilepsies. In addition to elucidating the genetic basis in a significant subset of patients with PME, the authors demonstrate that de novo mutations play an important role in a group of diseases usually thought to be recessive. Continue reading
PURA mutations and when diverse phenotypes become a single syndrome
Reverse. With the increasing amount of genetic information available in patients with various neurodevelopmental syndromes, some genes will be observed more than once in patients. In a recent study in the Journal of Medical Genetics, the authors trace back the phenotypes of individuals carrying de novo mutations in PURA. However, there seems to be a wide range of clinical features with a seemingly inverse genotype-phenotype correlation. 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
SETBP1, ZMYND11, and the power of joint exome and CNV analysis
Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. Continue reading
The common variants in our genome that predispose to epilepsy – the ILAE GWAS
ILAE GWAS. This is one of the rare occasions when I can write on behalf of the ILAE Genetics Commission and discuss a recent publication. Earlier this week, the ILAE Consortium on complex epilepsies came online in Lancet Neurology. This study is a large meta-analysis of almost 9,000 patients and 26,000 controls looking at common genetic variants predisposing to common epilepsies, including the Idiopathic/Genetic Generalized Epilepsies and focal epilepsies. In a nutshell, when looking for common variants predisposing to the epilepsies, the answer is surprisingly simple. Continue reading
Typical versus atypical: exome sequencing in pediatric epilepsies
Exome mining. Trio exome sequencing is both easy and difficult at the same time. If you manage to identify a plausible de novo mutation, the job is pretty much done. However, if no plausible de novo is found, things can become complex very quickly. Some of the known genes for recessive disorders are quite variable and therefore difficult to interpret. Also, we know little about the overall spectrum of the recessive disorders and the plausibility of atypical cases. A recent paper in Clinical Genetics takes a comprehensive approach to the genetic basis of pediatric epilepsies by exome sequencing. The authors include the analysis of recessive and compound heterozygous variants, and they follow up on some of the biomarkers that establish the diagnosis. There are some surprising findings. Continue reading
Critical brain-expressed exons and de novo mutations in autism
Selection. De novo mutations in neurodevelopmental disorders including autism, schizophrenia, and intellectual disability raise an important question: are the mutations identified in patients pathogenic or are they simply genomic noise? A recent study in Nature Genetics tries to answer this question by looking at expression of particular exons in the brain and the overall mutational burden in these exons. They come up with critical exons, which seem to be particularly vulnerable in Autism Spectrum Disorder. Continue reading
