Multi-omics. An emerging avenue of research for investigating the underlying architecture of human disease is the development of multi-omics approaches. Integration and analysis of large-scale data generated from genome sequencing alongside other -omics technologies including transcriptomics, proteomics, and metabolomics, enable a more comprehensive and nuanced insight into biological systems that underlie disease. However, in contrast to genomic data, the generation of multi-omics data remains expensive, time-consuming, and is typically limited in large-scale population studies. In a recent publication, Xu and collaborators developed a model predicting >17,000 multi-omic traits from genomic profiles across 50,000 people. Here is a brief review of their paper, with a focus on the relevance of developing multi-omics resources in 2023.
Category Archives: 2023
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.
Expanding clinical actionability in GLUT1 Deficiency through a blood-based biomarker
GLUT1DS. Disease-causing variants in SLC2A1 are associated with a rare genetic neurometabolic condition known as GLUT1 Deficiency Syndrome (GLUT1DS). While GLUT1DS is typically diagnosed through molecular genetic testing, the diagnostic strategy in some cases includes lumbar puncture to measure cerebrospinal fluid (CSF) glucose to confirm the diagnosis. In a recent study, Mochel and collaborators performed a multicenter validation study of a blood-based biomarker for GLUT1DS. Here is a brief review on their publication and the utility of molecular biomarkers in GLUT1DS and genetic epilepsies 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.
Decoding rare disease through 77,000 genomes
Genome sequencing. Despite continual progress in understanding the genetic etiology of human disease, more than half of rare disorders remain unsolved. Resolving the remaining etiologies in rare disease are a major focus of ongoing efforts in the field, including a shift towards standardized analysis of large-scale genome sequencing data from large patient cohorts. In a recent study, Greene and collaborators aimed to identify associations between genes and rare disease subgroups, leveraging genomes of 77,539 people including 29,741 probands. Here is a brief review on their publication in the context of etiological resolution in rare disease.
Seizure prediction using real world data – a learning health system realized
Neonatal seizures. Neonatal seizures can lead to serious consequences for newborns, including long-term morbidity and mortality. In high-resource neonatal intensive care units, screening for seizures with CEEG has become commonplace and is considered standard of care. Accurate seizure prediction can help optimize the allocation of CEEG resources and improve care for critically ill neonates. In our recent study, we aimed to develop seizure prediction models using data extracted from standardized EEG reports. Here is a brief overview of our findings using real-world data to predict seizures in neonates.
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
The science of data visualization in epilepsy genetics
Language. In the recent years, there has been an emerging focus on the phenotypic characterization of genetic epilepsies and neurodevelopmental disorders. With a rise in large-scale studies leveraging massive and complex genetic and phenotypic datasets, understanding how we make sense of big data becomes critical. However, determining what are clinically meaningful findings and communicating the conclusions we make from these datasets remain a challenge. While we typically think about data in the scope of ‘n’s, probabilities, and p-values, there is understated value in the visualization of information. Here is a different way of how we think about scientific communication and how we can “make data speak in childhood epilepsies.”
