Papers of the week – SCN1B, ATP1A3, NGLY1, and ontologies

Filling in. As Dennis is current fully engaged in the Helsinki meeting, I am filling in for him to present the most relevant publications in the field published in the last two weeks. This week’s publications were about functional studies, phenotype delineations, and novel gene findings. Continue reading

GABRA1 and STXBP1 as novel genes for Dravet Syndrome

Beyond SCN1A. Dravet Syndrome is a severe fever-associated epileptic encephalopathy. While the large majority of patients with Dravet Syndrome carry mutations in the SCN1A gene, the genetic basis is unknown in up to 20% of patients. Some female patients with Dravet-like epilepsies have mutations in PCDH19, but other than this, no additional major gene for typical Dravet Syndrome is known. In a recent paper in Neurology, de novo mutations in GABRA1 and STXBP1 are identified as novel causes for Dravet Syndrome. In addition, several SCN1A-negative patients were shown to have mutations in SCN1A that were initially missed. Continue reading

From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

The two faces of SCN1A. Even though the range of phenotypes associated with mutations in SCN1A can be conceptualized as a continuum, there are usually two distinct entities in clinical practice: the severe, epileptic encephalopathy of Dravet Syndrome due to de novo mutations and the usually mild fever-related epilepsies in autosomal dominant GEFS+ families. While Dravet Syndrome can also be seen in some families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), this is a rare phenomenon; there is usually little overlap between Dravet Syndrome and GEFS+. Within the Israel Epilepsy Family Project, we came across such a family with overlapping phenotypes. This recently published large GEFS+ family probably has the widest phenotypic range reported to date. Continue reading

Are there incidental findings in exomes that require immediate action?

Guidelines. High throughput sequencing generates an unprecedented amount of genetic data. Most exomes are generated in a specific context, i.e. the genetic data is screened for variations in specific candidate genes or screened for de novo mutations. However, these approaches only use a small fraction of the genetic data generated per individual. High-throughput sequencing may also reveal clues towards possibly relevant diseases, and there is an ongoing debate if and how incidental findings should be returned to individuals undergoing high-throughput sequencing. Now, a recent paper in the American Journal of Human Genetics uses a very stringent clinical approach to assess the frequency of medically actionable findings in exome data. The results are not what you would think, and there is an urgent need to fix the existing databases. Continue reading

Temperature rising: 17q12 microduplications and GEFS+

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

Eyelid myoclonia with absences meets GEFS+

Running in the family. Eyelid myoclonia with absences (EMA) is a rare generalized epilepsy syndrome characterized by brief episodes of myoclonic jerks that are often accompanied by an upward deviation of the eyeballs and an extension of the head. The EEG shows generalized spike-wave discharges during these episodes, and most patients are highly photosensitive. Therefore, it would be natural to think of EMA as related to other classical generalized epilepsies including Childhood Absence Epilepsy or Juvenile Myoclonic Epilepsy. Now, a recent paper in Epilepsia shows that the families of patients with EMA tell a slightly different story. Continue reading

The Hippocampus Conspiracy

Slightly misleading. The green and blue histological staining that has become the EuroEPINOMICS logo features a human hippocampus, a part of the human brain that is particularly important in human epilepsy. Temporal Lobe Epilepsy (TLE) is the most common epilepsy in adults and involves the hippocampal region. Ironically, TLE is the human epilepsy that has always been at odds with genetic research. Let’s review what we know about the genetics of TLE and “hippocampal genetics”. Continue reading