Genomic Diagnosis for Neurodevelopmental Disorders: Revolution, Evolution, and Current Reflections on the “Rational Diagnostic Evaluation”

Neurodevelopmental disorders (NDDs) are a class of childhood-onset conditions that affect brain development and function. NDDs have a heterogeneous etiology, a wide genetic and clinical variability and generally lead to impaired cognition, communication, psychomotor skills, and adaptive behavior. These disorders include intellectual disability (ID), autism spectrum disorder (ASD), and developmental and epileptic encephalopathies that manifest during childhood. Over the past 2 decades, genetic research has discovered more than 1,500 genes in different signaling pathways that are involved in NDDs, including many transcriptional regulators such as DNA/histone modifiers and chromatin-regulatory protein complexes. These same investigations have led to the accessibility and availability of next-generation sequencing in the assessment of children with NDDs in the clinical setting. The advances have dramatically altered the approach to the genetic diagnostic assessment of the child with NDDs and have increased the diagnostic yield of genetic testing in the pediatric setting. The purpose of this review is to provide the historical background to the rational assessment of child with an NDD and present a perspective on the current evaluation given the modern repertoire available to the pediatric practitioner facing this challenge in the clinical setting.