Medical Genetics seminars

The presentation will provide an overview of the expanding role of genetic factors in epilepsy. It will delve into the fundamentals of this field and elucidate how digital tools and resources can aid in the re-evaluation of genetic test results. In the initial segment of the presentation, Dr. Lal will examine the advancements made over the past two decades regarding the genetic architecture of various epilepsy types. Additionally, he will present research studies in which he has actively participated, offering concrete examples. Subsequently, during the second part of the talk, Dr. Lal will share the ongoing research projects that focus on epilepsy genetics, bioinformatics, and health record data science.

Focal Cortical Dysplasia (FCD) is the most common focal cortical malformation leading to intractable childhood focal epilepsy. In recent years, we and others have shown that FCD type II is caused by mosaic mutations in genes within the PI3K-AKT-mTOR-signaling pathway. Hyperactivation of the mTOR pathway accounts for neuropathological abnormalities and seizure occurrence in FCD. We further showed from human surgical FCDII tissue that epileptiform activity correlates with the density of mutated dysmorphic neurons, supporting their pro-epileptogenic role. The level of mosaicism, as defined by variant allele frequency (VAF) is thought to correlate with the size and regional brain distribution of the lesion such that when a somatic mutation occurs early during the cortical development, the dysplastic area is smaller than if it occurs later. Novel approaches based on the detection of cell-free DNA from the CSF and from trace tissue adherent to SEEG electrodes promise future opportunities for genetic testing during the presurgical evaluation of refractory epilepsy patients or in those that are not eligible for surgery. In utero-based electroporation mouse models allow to express somatic mutation during neurodevelopment and recapitulate most neuropathological and clinical features of FCDII, establishing relevant preclinical mouse models for developing precision medicine strategies.

Whilst epilepsy may be a consequence of an acquired insult including trauma, stroke, and brain tumours, the genetic component to epilepsies has been greatly under-estimated. Considerable progress has recently occurred in the understanding of epilepsy genetics, both at a clinical genetic level and in the basic science of epilepsies. The clinical evidence for genetic components will be first briefly discussed including data from population studies, twin analyses and multiplex family studies. Initial molecular discoveries occurred via classical methods of linkage and gene identification. Recent large-scale hypothesis-free whole exome studies searching for rare variants and genome-wide association studies detecting common variants have been very rewarding. These discoveries have now impacted on clinical practice, especially in severe childhood epilepsies but increasingly so in adult patients. The “genetic background” of patients has long been posited as part of the reason that some patients have epilepsy, or perhaps why some have more severe epilepsy. This has been unmeasurable but now, with the development of polygenic risk scores, the “background” is now in the research foreground. The current and future impact of polygenic risk scores will be explored.

There are no effective disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis or Huntington’s disease. Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the world’s most common genetic dementia. I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA (Tabrizi et al Neuron 2019), the cause of HD pathogenesis, and the translational pathway from bench to clinic for a HTT targeting antisense oligonucleotide (Tabrizi et al New England Journal of Medicine 2019, Tabrizi, Science 2020) which is now in phase 3 studies. In my talk I will also review some of the genetic approaches in development for other CNS diseases. I will talk a bit about my journey as a clinician scientist and share some of my learnings for young scientists on how to survive a career in science.