Lessons learned from gene identification studies in Mendelian epilepsy disorders

Abstract

Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies.

Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders

“…These genes could be considered critical in the evaluation of individuals with epilepsy and NDD. Of note, the rate of gene discovery for genetic epilepsies has been significant in recent years and additional potentially high‐yield genes have been reported recently (ie, DEPDC5, KCNT1, IQSEC2, KIAA2022 , and SLC6A1 ) . Based on our results and limited published evidence, the CACNB4, EFHC1, SRPX2 , and ATP6AP2 genes appear to be low‐yield and variants in these genes should be reviewed cautiously.…”

“…Of note, the rate of gene discovery for genetic epilepsies has been significant in recent years and additional potentially high-yield genes have been reported recently (ie, DEPDC5, KCNT1, IQSEC2, KIAA2022, and SLC6A1). [29][30][31] Based on our results and limited published evidence, the CACNB4, EFHC1, SRPX2, and ATP6AP2 genes appear to be lowyield and variants in these genes should be reviewed cautiously. When variants are identified in a proband, parental testing should be considered to clarify the clinical significance of the variant and determine recurrence risk for the family.…”

Unexplained Early Infantile Epileptic Encephalopathy in Han Chinese Children: Next-Generation Sequencing and Phenotype Enriching

“…conducted a retrospective cohort study of 110 patients with intractable epilepsy, global developmental delay, and cognitive dysfunction, Detection rate by targeted next-generation sequencing was 12.7% and SCN1A was the most frequently mutated gene accounting for 29% of 14 variants, which we found similar to our results. Hardies k et al 49,. reviewed 35 NGS studies that focused on patients with epilepsy, and cited that genetic factors are thought to have a role in 70% of all epilepsy; also the author reported that NGS findings have additionally increased the recognition of phenotypical and genetic heterogeneity which was demonstrated in our study.…”

Hereditary Diseases and Syndromes Accompanied by Febrile Convulsions: Clinical and Genetic Characteristics and Diagnostic Procedures

“…Его технология позволяет «прочи-тать» единовременно сразу несколько участков генома благодаря беспрецедентной пропускной способности и широте охвата, что является главным отличием от более ранних методов секвенирования. В результа-те использования NGS возможно одновременное те-стирование мутаций в 97 % экзонов и сплайс-зонах, в том числе в генах значительного размера [15].…”