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Neuropediatrics
DOI: 10.1055/a-2732-4516
Editorial

Function Matters: Variant Mechanisms in the Era of Precision Medicine

Authors

  • Christian M. Boßelmann

    1   Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
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Comment on:

Genetic Variants and Disease Mechanisms: Lessons from Monogenic Childhood EpilepsiesNeuropediatrics eFirst
DOI: 10.1055/a-2731-5130

10.1055/a-2731-5130

The landscape of child neurology is always shifting, constantly being redrawn by advances in our genetic understanding of neurodevelopmental disorders, including epilepsy. By now, more than 1,000 genes have been identified, and the field shows no signs of slowing down since the arrival of next-generation sequencing in the late 2000s.[1] [2] This rapid pace of discovery will only accelerate: genome sequencing can now be done for approximately 500 USD, and same-day results have become feasible.[3] Pilot programmes, such as the Generation Study by Genomics England, are exploring the use of genome sequencing for every newborn to accompany traditional biochemical newborn screening.[4] We have to expect that the number of individuals with positive genetic testing results will increase accordingly. Clearly, there is no better time to become more familiar with epilepsy genetics.

Knowledge of an underlying genetic aetiology has moved from an abstract and academic curiosity to immediately clinically relevant information. Establishing a genetic diagnosis informs disease surveillance, guides clinical management, including precision therapies and clinical trials, and provides prognostic information for genetic counselling.[5] [6] [7] This promise of precision medicine hinges on a conceptual leap: we are no longer looking at mapping syndromes to chromosomal loci, but instead translating specific genetic variants to potentially druggable mechanisms.

In this issue of “Neuropediatrics,” Oberlack and Wagner present a timely and comprehensive overview of clinically relevant developments in epilepsy genetics. They specifically address the clinical implications of gene- and variant-specific functional mechanisms. Most genes associated with epilepsy encode ion channels and transporters.[1] In these genes, classification of variant pathogenicity has to be complemented by assessment of variant functional effect on channel function, broadly classified as gain- or loss-of-function (GOF/LOF). Depending on this functional effect, variants within the same gene can cause entirely different syndromes and necessitate very different treatment approaches.[8] [9] [10] Understanding how these variant effects emerge across all levels (DNA, RNA, protein, cell, and organism) requires specialized knowledge of molecular genetics, in vitro electrophysiology, structure-function relationships, and genotype–phenotype correlations—knowledge summarized here by Oberlack and Wagner.

We live in an era of precision medicine, where variant pathogenicity and functional effect are already used for patient identification and stratification in clinical trials (e.g., ClinicalTrials.gov IDs NCT04442295, NCT05419492) and off-label treatment of individual patients. Here, a misstep in either direction—either falsely assuming a variant of uncertain significance to be pathogenic, or assuming a variant to be GOF instead of LOF and vice versa—can risk the health and safety of these often severely affected individuals. While advanced research labs use patch-clamp recordings and neuronal models to characterize these variant effects, this functional data must seamlessly reach the clinician's desk. Some challenges remain before this insight can be fully translated into clinical use: the availability of genetic testing has outpaced the ability of in vitro electrophysiology to provide direct experimental evidence. Further, while electrophysiology remains the gold standard, it is both expensive and time-consuming and thus not available for clinical use beyond research projects. Oberlack and Wagner highlight the potential of prediction models, but these come with their own challenges and limitations.

The aim is clear: we must work toward integrated diagnostic reports that extend beyond gene names toward functional mechanisms and therapeutic implications. Ideally, these reports will integrate and carefully weigh information from patient phenotype, known and paralogous variants, published experimental evidence, in silico predictions, and disease-specific expert insights from biologists, pediatric neurologists, geneticists, and other stakeholders. The road ahead is long, but it will pave the way for precision medicine.



Publication History

Received: 24 October 2025

Accepted: 24 October 2025

Article published online:
06 November 2025

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