The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Abstract

Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype-phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

Keywords: developmental and epileptic encephalopathies (DEEs); epileptic encephalopathies (EEs); neurodevelopmental disorders (NDDs); reverse phenotyping; whole-exome sequencing (WES).

Figure 1

Schematic of the diagnostic procedure used in this study. The flow starts with the multidisciplinary team (yellow box) and goes to clinical assessment, molecular tests, and Sanger confirmations and cosegregation analysis (red arrows) and reaches the ending point (diagnosis) through a confirmation path (blue arrows) which includes clinical reassessment using a reverse phenotyping strategy. Abbreviations: SNP: single nucleotide polymorphism; CNV: copy number variation; gnomAD: the Genome Aggregation Database; ExAC: Exome Aggregation Consortium; dbSNP: the Single Nucleotide Polymorphism Database; ACMG: the American College of Medical Genetics and Genomics; P: pathogenic; LP: likely pathogenic; VUS: variant of unknown significance.