Phases. Today is Rare Disease Day. I would like to use this opportunity to explain some of the phenotype science that is critical for rare diseases. In contrast to common disorders, rare diseases face an unusual challenge. Once identified, the overall rareness of these condition poses the question of where phenotypes begin and where they end. For rare genetic disorders, is the phenotype of the first individual identified with a rare disease characteristic, or is there a larger spectrum that we should be aware of? Enter the various approaches to phenotype science that aim to decipher the full depth of clinical features associated with rare diseases. In order to understand the various approaches to rare diseases phenotypes, I would like to suggest a somewhat unusual analogy: phenotypes are like water.
FIRES. As a rare and severe epilepsy syndrome, febrile-infection related epilepsy syndrome (FIRES) is characterized by refractory status epilepticus (RSE) preceded by a febrile illness and often leads to prolonged hospitalizations, cognitive impairment, and intractable epilepsy. There are currently no clear causative etiologies identified in FIRES, and the underlying genetic architecture remains elusive. Here is a brief summary of our recent manuscript on the genetics of FIRES and refractory status epilepticus. This is what we learned about one of the most enigmatic conditions in child neurology.
NaV1.2 Today is International SCN2A Day, 2/24/2023. SCN2A is on the long arm (q arm) of chromosome 2 at position 24.3, hence 2/24. In honor of this day, we wanted to refresh the SCN2A gene page, which was long overdue. Much has been learned since our initial post in 2015, so in addition to the gene page, here are three things to know about SCN2A in 2023.
Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.
Zebra finches. Exactly one year ago, I wrote my last blog post on the genetics of stuttering and thought that it would be time for an update. Here, I would like to explore why stuttering is a truly neglected neurogenetic disorder and why we have made so little progress. In addition, I would like to give a brief update on where we are right now, looking at stuttering from the perspective of the wider pediatric neurogenetics field. In addition, we will unleash the power of EMR genomics to query the medical records of more than 52,000 individuals to find associated genes, and we will discuss a monogenic cause of familial childhood-onset fluency disorders that we did not expect to find. Here is a summary of the last 12 months in stuttering genetics. Continue reading
Precision medicine. This post continues the discussion on how we can make sense of clinical data in the absence of outcomes in the context of precision medicine – a concept that drives much of what we do on a research basis. The fundamental idea is that clinical care in pediatric epilepsies can be personalized and tailored to underlying etiologies. With continual progress in gene curation and variant interpretation alongside clinical knowledge, we typically expect that treatment suggestions are immediately implemented after the discovery of the causative genetic etiology. For example, a child with early onset epileptic encephalopathy is found to have a gain-of-function variant in SCN8A and is almost immediately started on a sodium channel blocker such as Trileptal. However, to what extent is this the case? In the context of precision medicine, how precise are we exactly?
ACMG. Imagine the following scenario: you identify a de novo variant in SCN1A in a young child with the typical clinical features of Dravet Syndrome. However, the lab returns the variant as a variant of uncertain significance. The variant is a missense variant that has never been seen before and the lab argues that they are simply applying the current variant classification criteria. Certainly, either the lab is wrong or the variant classification criteria are deficient. Shouldn’t this variant be a pathogenic variant? Your patient clearly has the typical clinical features that are very unlikely explained by anything but the de novo SCN1A variant. In fact, both assumptions are incorrect, but it is important to know the background. Here is a blog post on why variant classification is distinct from assessing whether variants are explanatory in a clinical context. And please allow me to introduce a neologism: explanatoriness. Continue reading
Zen. This weekend, I finished Robert Pirsig’s Zen and the Art of Motorcycle Maintenance. The unfinished task of reading this book has followed me through my entire academic career. It was initially given to me as a gift for being an anatomy tutor in medical school. Independently, I received it as a gift when I passed my German child neurology boards. I started this book several times, but never finished it, and reading this book took me 25 years. As my professor’s thoughts about various approaches to studying medicine have echoed with me since I was a student tutor, this book deserves its own blog post and an enquiry into values (as Pirsig would say) of anatomy versus physiology. Continue reading
Chromodomain. Today is International CHD2 Awareness Day and we are publishing this blog post in time for our CHD2 webinar where we present the result of a four-week sprint to analyze harmonized clinical data. We also updated our gene page on CHD2, which was long overdue. In addition to becoming a more well-known gene, here are three things to know about CHD2 in 2023. Continue reading