The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

Abstract

Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders

“…Particularly because ES is also increasingly suitable for the detection of CNVs (in our cohort 26 CNVs, including small and complex alternations like translocations, were identified through NGS), which provides an alternative to chromosomal microarrays. 24,38–40 In case of inconclusive results in first tier ES, genetic examinations could be extended accordingly to entities possibly not covered, such as translocations, repeat disorders (fragile X syndrome) or mitochondrial disorders.…”

“…The decision to put a child at risk 45 for imaging with sedation and contrast agent could be influenced by the outcome of prioritized genetic testing since imaging results rarely lead to diagnosis in individuals with NDD. 46 A quickly established molecular diagnosis can also affect therapy and further medical interventions 15,24,36,47 , have an impact on family planning 14,18 , and contribute to the psychological well-being of the parents. 16…”

“…20 Next Generation Sequencing (NGS) outperforms traditional genetic diagnostics, as it can achieve a diagnostic yield between 30% and 47% in NDD and epilepsy cohorts combined with speed-up through a single test. 18,21–24 Thus, the question remains 25 whether first-line initiation of exome sequencing (ES) could save costs and time, reduce the risks associated with thereby obsolete extensive or even invasive diagnostic procedures, and allow families to make earlier reproductive decisions.…”

A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2

“…Variants in the index cases were identified by trio exome sequencing (ES) as described previously 20,21 . We used an Excel based questionnaire for retrospective phenotyping of the individuals described here and for review of published cases.…”

2022 Overview of Metabolic Epilepsies

“…[17] 38 patients with progressive myoclonic epilepsies 62.5% ES [22] 150 adult and elderly patients with intellectual disability and epilepsy 18% TruSight One panel, Illumina/ES ES-exome sequencing.…”