Diagnostic Yield and Cost-Effectiveness of "Dynamic" Exome Analysis in Epilepsy with Neurodevelopmental Disorders: A Tertiary-Center Experience in Northern Italy.

Costanza Varesio,Simone Gana,Elena Tartara,Renato Borgatti,Michela Bagnaschi,Marialuisa Valente,Simona Orcesi,Pierangelo Veggiotti,Alessia Asaro,Cristina Cereda,Valentina De Giorgis,Elena Ballante,Raffaella Fiamma Cabini,Ludovica Pasca,Enza Maria Valente

doi:10.3390/diagnostics11060948

Abstract

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a “dynamic” exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders. Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis. Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps (p < 0.01), between the first and second (p = 0.001), and the first and third (p << 0.001). The cost-effectiveness plane indicated that our exome-based “dynamic” approach was better in terms of cost savings and higher diagnostic rate. Conclusions: Our findings suggested that “dynamic” NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.

Highlights

Childhood-onset epilepsies are known to be associated with various degrees of neurodevelopmental disorders (NDDs) in approximately 25% of cases [1]
As the two mechanisms may play a role in the same individual and a single genetic defect can act through both mechanisms, the term developmental and epileptic encephalopathy (DEE) has been coined to refer to conditions in which epilepsy and NDDs coexist based on these two pathogenic mechanisms [6,7]
Under the reasonable assumption that patients who received a diagnosis in the previous step would have received diagnosis in the following steps, the diagnostic yields were evaluated on the total court of 72 subjects at the first step, and at the second and at the third steps, instead of the restricted sample of non-diagnosed subjects

Summary

Introduction

Childhood-onset epilepsies are known to be associated with various degrees of neurodevelopmental disorders (NDDs) in approximately 25% of cases [1]. The genetic landscape of epilepsy with NDDs and DEE is broad and complex [8] For this reason, there are many options for diagnostic investigations on this topic [9]. Progress in technology development and affordability of next-generation sequencing techniques (NGS) (including gene panels, clinical exome sequencing, whole-exome sequencing, and whole-genome sequencing) led to a significant advance in gene discovery, with several genes implicated in epilepsy with NDD [10]. We aimed to describe diagnostic yields of a “dynamic” exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved

Objectives

Methods

Results

Discussion

Conclusion