Genomic testing, variant interpretation and counselling

The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the test and its yield: what question is being asked, which test answers it, and what the diagnostic probability is before the sample is sent. The second is the variant and its classification: the ACMG/AMP framework that converts raw sequence data into a probabilistic call, and the distinction between a pathogenic finding that drives management and a VUS that does not. The third is the family: the consent conversation that precedes testing, the disclosure that follows, the cascade testing of relatives, and the re-analysis that keeps the result alive as knowledge grows. [1] [3]

Overview & Definition

Genomic testing in paediatrics encompasses the range of laboratory techniques used to identify genetic variation underlying congenital anomalies, developmental disorders, and inherited diseases. The hierarchy runs from the traditional karyotype, which detects large-scale chromosomal rearrangements visible under a microscope, through chromosomal microarray (CMA), which detects sub-microscopic copy-number variants (CNVs) at far higher resolution, to next-generation sequencing technologies — gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS) — that read the DNA letter by letter and can identify single-nucleotide variants, small insertions and deletions, and some structural rearrangements. [2] [9]

The clinical application of these technologies depends on a structured variant interpretation process that converts millions of sequence differences into a small number of clinically actionable calls. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology published the consensus standards for this process in 2015, establishing a five-tier classification framework — pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign — that every clinical genomics laboratory now applies. This framework, combined with structured pre- and post-test genetic counselling, defines the modern practice of genomic medicine in paediatrics. [1] [10]