A Diagnostic Approach for Neurogenetic Disorders in the Genome Era

Abstract

The unique sensitivity of the brain to perturbations in the human genome has been recognized since the early days of karyotyping when it was clear that developmental delay/intellectual disability (DD/ID) was by far the most common phenotypic manifestation of virtually all major chromosomal aberrations. Unlike many biochemical abnormalities that were erroneously linked to DD/ID due to ascertainment bias, the causal link between chromosomal aberrations and DD/ID was robust even in unbiased antenatally ascertained cases. With the advent of modern molecular karyotyping, which is orders of magnitude more sensitive than regular and even “high-resolution” karyotype, the same pattern persisted and DD/ID remains the most common phenotypic expression of the ensuing list of ever smaller genomic rearrangements. Even at the level of single gene mutations, DD/ID is a major phenotype in the majority of the resulting syndromes. This should not come as a surprise knowing that at least 80% of genes are expressed at some point during development in the brain, a fact that likely reflects the extreme complexity of this organ and, subsequently, its vulnerability to any lesion that perturbs the exquisitely orchestrated network of molecules required for its development and function [1]. Pediatric neurologists, therefore, are at the frontline in the assessment and management of the majority of patients with genetic syndromes, and although there are those who specialize specifically in neurogenetic conditions, all pediatric neurologists should be prepared to provide a first-line assessment of these patients. The goal of this chapter is to provide a pediatric neurologist-friendly strategy to systemically approach patients with suspected neurogenetic phenotypes.