Reference. Today, the human pangenome was announced, the first reference of the human genome that systematically includes a cohort of genetically diverse individuals. The human genome, once thought to be a linear reference, is now a graph with nodes and edges. I came across the pangenome publications when I was thinking about a comment that I made earlier this week, when I was asked whether people on our team have their own flavor of variant interpretation. Let me share with you how both topics connect. Continue reading
Author Archives: Ingo Helbig
Five novel concepts in epilepsy genetics you need to know in 2023
Framework. Neurogenetics is evolving, and so is the way we think about the connection between genes and seizures. Over the last few years, several new frameworks of thinking have entered the epilepsy genetics sphere that allow us to think about epilepsy genetics with more nuance. This blog post is dedicated to five known or emerging concepts that are evolving alongside our increased understanding of genetic epilepsies. Continue reading
Love For Liam and the true driving force in epilepsy genetics
Fundraiser. Last Friday, our epilepsy genetics team participated in the Annual Love for Liam fundraiser, which was a golf tournament at the Northhampton Country Club, in Richboro, Pennsylvania. The Love For Liam Foundation was initiated by Heather and Kyle Johnson in memory of their baby boy, Liam, who passed away from a likely genetic epileptic encephalopathy. During the fundraiser, Heather gave one of the most passionate and powerful speeches in support of epilepsy genetics that I have ever heard. I had carried around a sense of “bittersweetness” all day that I had a hard time putting into words. And after Heather’s speech, it clicked: maybe we got it all wrong, maybe we should think about the real driving force in epilepsy genetics slightly differently.
Neurogenetics, neurodiversity, and self-advocacy – the stuttering perspective
Perspective. This blog post is about a topic that I had planned to write about for a while – the intersection of neurogenetics and self-advocacy. This is a potentially loaded topic in many disease areas, and I had held off on writing this for a while. However, when I put together my prior blog post on the different perspectives on stuttering, it occurred to me that I could use stuttering genetics as a vehicle to get these thoughts across. Stuttering genetics is relatively underdeveloped, and I feel that I can speak to the intersection of self-advocacy and genetic research as pediatric neurologist involved in neurogenetics research and as a person who stutters. However, this post is not only about stuttering, it is about how neurogenetics and self-advocacy may be synergistic, adding nuance to both perspectives.
The I and the Why – stuttering and the infinity of neurogenetics
Dysfluency. I typically reserve my more contemplative blog posts for our summer beach vacation, but there are some thoughts that I had during this Spring Break that I wanted to share. In brief, I read Life on Delay by John Hendrickson and started reading The Beginning of Infinity by David Deutsch. At first glance, these two books couldn’t be any more different – a story about bullying, depression, isolation, and other issues that people who stutter face on a daily basis, and a wide-ranging narrative about the cosmic power of the search for good, scientific explanations. Then something occurred to me: there are two ways to spell dysfluency/disfluency. Hendrickson spells dysfluency with an “I,” while the scientific literature often prefers the “Y”. And this ambivalence may actually tell us something about the nature of neurogenetics more broadly.
FIRES, NORSE, Omics, and Urgency
FIRES. Febrile infection-related epilepsy syndrome (FIRES) is characterized by refractory status epilepticus following a non-specific febrile illness. FIRES is a subtype of New Onset Refractory Status Epilepticus (NORSE) without a clear cause in individuals without active epilepsy. The cause of FIRES and NORSE is unclear, and it is not even clear whether both conditions share a joint mechanism or represent distinct entities. In a recent publication, we contributed to a review of the state-of-the-art in NORSE and FIRES research and suggested a very first step to understand these conditions better – standardized biosamples. This blog post is about the intersection of omics and urgency, long-term strategies and scientific principles.
Revisiting the genetics of cerebral palsy
CP. Over the last few years, a range of high-impact publications have revolutionized our understanding of the genetics of cerebral palsy (CP). While CP is traditionally thought of as an exclusively acquired disorder, massive parallel sequencing studies have suggested causative genetic etiologies in up to 30% of individuals. Here is an overview of the emerging genetics of CP through the lens of neurodevelopmental disorders, questioning some of the assumptions that are typically made when comparing both disease groups. Continue reading
KCNA6 – a novel potassium gene in childhood epilepsy
Potassium. The channelopathies are the largest group of genetic epilepsies, and disease-causing variants in genes for neuronal sodium channels, calcium channels, and potassium channels are among the most common causes of genetic epilepsies. However, amongst the various ion channel families, potassium channels stand out due to sheer number. There are more than 70 potassium channel genes encoded in the human genome, and the combination of various subtypes and auxiliary units generates an enormous combinatorial potential. In a recent publication, de novo variants in KCNA6, the gene for the voltage-gated potassium channel Kv1.6, were identified in childhood-onset neurodevelopmental disorders. Here is the somewhat unusual story of the most recent potassium channel gene implicated in human epilepsy. Continue reading
CLDN5, the blood brain barrier, and alternating hemiplegia of childhood
AHC. Amongst the various episodic neurological disorders of childhood, alternating hemiplegia of childhood (AHC) is one of the most mysterious conditions. AHC is characterized by transient hemiplegic attacks and a wide range of other neurological features including dystonic attacks, seizures, neurodevelopmental features, and autonomic symptoms. Recurrent de novo variants in ATP1A3 represent the most common cause of AHC, even though a small subset of individuals have disease-causing variants in other genes. In a recent paper, de novo variants in CLDN5 were identified. In contrast to known causes of AHC, CLDN5 implicates an entirely new disease mechanism – disruptions of the blood-brain barrier. Continue reading
EuroEPINOMICS and the golden age of epilepsy gene discovery
Exome era. When a consortium disappears, where does it go and what does it leave behind? I realized last week that exactly 10 years ago, the EuroEPINOMICS Rare Epilepsy Syndrome (RES) consortium pushed the button for the second round of trio exome sequencing, a pivotal event in the history of epilepsy genetics that led to the discovery of more than a dozen genes for developmental and epileptic encephalopathies. The fact that this critical juncture in the history of epilepsy gene discovery went largely unnoticed lies within the nature of research consortia – they form, they work, and they disperse. However, as EuroEPINOMICS was formative for me as a junior researcher, I wanted to dedicate this blog post to the research consortia of the early 2010s and the golden era of epilepsy gene discovery, when I was a EuroEPINOMICS kid.