Phenotypic overlap and genetic challenges in neurodevelopmental disorders

The bidirectional and temporal relationship between intellectual disability and developmental and epileptic encephalopathies (DEE), as well as causal mechanisms, are still not fully understood. Some common biological mechanisms for epilepsy and comorbid intellectual disability/autistim spectrum disorder (ASD) are suggested from their overlapping prevalence, which may include subgroups of genes that have similar phenotypic manifestations and biological functions. Carvill et al. investigated phenotypically well-defined cohorts of patients with intellectual disability, and DEE to delineate the genetic convergence between epilepsy and intellectual disability. They identified seven genes (CHD2, CDKL5, GRIN2A, SCN1A, SCN2A, SCN8A, STXBP1) that were more likely to be related to epilepsy with intellectual disability rather than intellectual disability only; two genes, GRIN2B and SCN2A, can be involved in intellectual disability only, while the others appear to confer a high risk of epilepsy in individuals with pathogenic variants. As summarized by the authors, the study failed to identify a previously associated DEE gene that was more common in individuals with intellectual disability only. These genes cause both intellectual disability and epilepsy, rather than the intellectual disability being a consequence of seizure activity alone. However, the study once again highlighted the huge phenotypic heterogeneity of DEE-related genes, as well as the genotypic and phenotypic overlap between a broad spectrum of neurodevelopmental disorders (NDDs). These include epilepsy, intellectual disability, ASD, attention-deficit/hyperactivity disorder, and DEEs. In addition to highlighting the clinical heterogeneity of these conditions, the authors raise several clinical issues. Patients are often allocated to ASD/intellectual disability/ developmental delay/epilepsy cohorts depending on the interest of the clinician recruiting for the study (e.g. an epileptologist vs a geneticist). This does not consider the natural history of NDDs which evolves over time, as patients often develop epilepsy and ASD. It should also be noted that it is often difficult to establish how rearrangement of genomic regions can contribute to the broad spectrum of NDDs, especially when the mutations or deletions occur in genes that are not presently identified as susceptibility genes for these disorders. However, for some genes (e.g. SCN1A, SCN2A, SCN8A), the characterization of functional effects (loss-offunction vs gain-of-function) of different variants is improving: the genotype–phenotype correlation and the understanding of the underlying pathophysiology is particularly crucial to direct therapeutic decisions. The research done to identify genetic mutations in individuals with NDDs has indeed several important benefits, in terms of management and prognosis. However, for patients with de novo epileptic encephalopathy, prognosis cannot be drawn solely from gene identification, since within a specific family a mutation in one gene may be linked to both severe and self-limited epilepsies. In these cases, clinical approach and electroencephalogram pattern remain mandatory to determine the best strategy to manage and treat the disorder. Furthermore, they seem to correlate with prognosis better than with the molecular genetic finding. It clearly appears that genetic testing is a valuable strategy to determine aetiology in patients with NDDs. Along with the findings, exome sequencing and chromosomal microarray, which is the first diagnostic test for individuals with unexplained NDDs, have improved the understanding of these disorders. The use of a whole-genome screening approach raises phenotypic and genetic challenges. Collaboration between international research centers, that provide high-quality and homogeneous phenotyping, is necessary to gather enough patients to improve the identification of the genetic bases of NDDs.