Technology-Driven and Evidence-Based Genomic Analysis for Integrated Pediatric and Prenatal Genetics Evaluation

The first decade since the completion of the Human Genome Project has been marked with rapid development of genomic technologies and their immediate clinical applications. Genomic analysis using oligonucleotide array comparative genomic hybridization (aCGH) or single nucleotide polymorphism (SNP) chips has been applied to pediatric patients with developmental and intellectual disabilities (DD/ID), multiple congenital anomalies (MCA) and autistic spectrum disorders (ASD). Evaluation of analytical and clinical validities of aCGH showed > 99% sensitivity and specificity and increased analytical resolution by higher density probe coverage. Reviews of case series, multi-center comparison and large patient-control studies demonstrated a diagnostic yield of 12%–20%; approximately 60% of these abnormalities were recurrent genomic disorders. This pediatric experience has been extended toward prenatal diagnosis. A series of reports indicated approximately 10% of pregnancies with ultrasound-detected structural anomalies and normal cytogenetic findings had genomic abnormalities, and 30% of these abnormalities were syndromic genomic disorders. Evidence-based practice guidelines and standards for implementing genomic analysis and web-delivered knowledge resources for interpreting genomic findings have been established. The progress from this technology-driven and evidence-based genomic analysis provides not only opportunities to dissect disease-causing mechanisms and develop rational therapeutic interventions but also important lessons for integrating genomic sequencing into pediatric and prenatal genetic evaluation.