The story of the missed SCN1A mutations

Dravet Syndrome. In 2011, our EuroEPINOMICS-RES program was in full swing. We had recruited a cohort of 31 patients with Dravet Syndrome who had been previously tested negative for mutations in SCN1A with the aim to identify novel genes for this epileptic encephalopathy. Even though this cohort was crucial in our identification of CHD2, HCN1, and KCNA2 as novel genes for genetic epilepsies, the main finding in this cohort was something that we did not expect. Roughly one third of our 31 patients had mutations in SCN1A, even though they had previously been tested negative. In a recent publication in Molecular Genetics and Genomic Medicine, we tried to understand what had happened and joined forces with other groups who had made the same observation. Here is the story of the missed SCN1A mutations. Continue reading

Karl Marx, Hauts Forneaux, and the impact factor

Porta Nigra. This is part two of our travel diary. After a one hour drive through the rural Eifel mountains, you start a seemingly endless descent upon the Moselle Valley to get to Trier. A former Roman town with old ruins, a former summer residence of local royalty, a cathedral in redevelopment for 1500 years and Germany’s oldest city, Trier is rich with history. We didn’t know any of this as it was simply meant to be our stop on our way to Luxembourg, but it is hard to take a walk through the city without noticing. Yet Trier’s most famous son is a controversial historical figure who left to never return before starting any of his far-reaching work. Here is what we can learn from Karl Marx about the exchange value of scientific work in 2016. Continue reading

Mephistopheles, the intermaxillary bone, and trust in science

Classicism. After completing my rotation as the senior consult resident in adult neurology, I handed over the stroke pager and the consult phone, and on the next day we boarded a plane to Germany for a two-week vacation. During our first week, we paid our annual visit to the Leipzig group and used the opportunity to explore the cradle of German classicism, Weimar, Jena, and Leipzig. Here is what Goethe, the overlord of German classicism, told us about trust, Faust, and the current issues of collaborative genomic science. Continue reading

PCDH19 – what’s new in 2016?

The story of PCDH19. The clinical features and unique inheritance pattern of PCDH19-related epilepsy were first described in 1971, and the clinical entity was coined Epilepsy in Females with Mental Retardation (EFMR), due to the presence of epilepsy and cognitive disability that seemed to be limited to females. Pathogenic PCDH19 variants were identified in females in 2008, and it soon became clear that PCDH19 is a major player in the genetic basis of epilepsy, with more than 100 patients with PCDH19 variants described to date. The inheritance pattern is one of the most striking features of this condition. Heterozygous females are affected, while hemizygous transmitting males are spared. At the cellular level, the disease mechanism seems to be loss of function. However, at the tissue level, the current hypothesis for the underlying mechanism is gain of function, resulting from the co-existence of two different PCDH19-expressing neuronal populations in females and mosaic males. Keep reading to learn more about recent discoveries related to PCDH19. Continue reading

Must love rules: an insider’s guide to variant sciences

Unknown significance. Quite possibly the two most dreaded words in clinical genetics. To some these two words should seldom be used let alone act as qualifiers for testing results. What are the rules of assessment? How do laboratories determine what constitutes enough evidence to say that a variant, previously known as mutation, is of known significance?   Continue reading