Pediatric genetic testing in the genomics era

Abstract

The revolutionary advances in genetic testing technologies of the past decade have allowed detailed analysis of a patient ́s whole genome with increased precision, speed and cost-effectiveness, substantially improving diagnostic rates. High-throughput genome-scale tests commonly used in pediatric care include chromosome microarray analysis (CMA) and whole exome sequencing (WES). CMA assesses genome-wide copy number variations (CNVs) and has been well established in clinical practice as the first-tier test in children with developmental delay/ intellectual disability, autism spectrum disorder or multiple congenital anomalies, with diagnostic yields ranging from 12 to 28%.1 WES is more recent and takes advantage of next-generation-sequencing (NGS) technology to analyze the protein coding regions of known genes (approximately 20.000) for sequence variants and can additionally screen for CNVs. WES is particularly useful in the etiological investigation of unspecific genetic conditions with multiple differential diagnoses and in disorders with genetic heterogeneity such as epilepsy, developmental delay/intellectual disability, sensorineural hearing loss or retinitis pigmentosa. The diagnostic yields of WES range from 15% to 50% and can be enhanced with trio analyses (proband and both parents).2