A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

Abstract

Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.

Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome

“…Given that the phenotype of these individuals is similar to the heterozygous individuals, (Table 2), and complete absence of SETD1B is lethal in several species 10,34,35 , we speculate that the combined action of both alleles in bi-allelic cases results in a phenotype similar to that observed in heterozygous cases by reducing the remaining SETD1B activity below a required threshold. A small subset of genes that typically harbor de novo variants has already been associated with recessive inheritance 36 . Further investigations remain necessary to establish causality of these variants, and the possibility of recessive inheritance of the SETD1B -related disorder.…”

Free as a BRD4: Bromodomain Inhibition Ameliorates Disease Phenotypes in a Model of MECP2 Deficiency and Is a Potential Therapy for Rett Syndrome

“…Such research would be beneficial for the epilepsy field more broadly as many of the more commonly implicated genes in the pediatric epilepsies are on the X-chromosome, including PCDH19, ARX, NEXMIF, and SMC1A. 12 The rationale for selecting JQ1 as a candidate therapeutic agent was not apparent in the present study. JQ1 is a potent inhibitor of all members of the BET family of bromodomain families and has been used in preclinical studies on cancer.…”

“…Such research would be beneficial for the epilepsy field more broadly as many of the more commonly implicated genes in the pediatric epilepsies are on the X-chromosome, including PCDH19 , ARX , NEXMIF , and SMC1A. 12 …”

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

“…Even after whole-genome sequencing, a substantial fraction of DEE cases remains unsolved. Possible causes of such unsolved cases include oligogenic inheritance and epigenetic abnormalities [ 203 ]. Inherited variants may lead to DEE through the synergistic effects of distinct deleterious variants involving common or distinct biological pathways [ 204 ].…”