Figure 1:

Genome sequencing process. Middle panel was adapted from “Whole Genome Sequencing” by BioRender.com (2021); retrieved from https://app.biorender.com/biorender-templates. Note: Variants in the KDM6A gene are linked to Kabuki syndrome. After appropriate pretest counselling, including review of possible results, a DNA sample is obtained from the patient, usually via a blood draw. Samples from biological parents are often sequenced at the same time to give additional context regarding inheritance. DNA is fragmented into small pieces and run on a high-throughput sequencing machine to generate millions of “nucleotide reads.” Reads are aligned to a reference genome, like puzzle pieces being assembled by looking at the image pictured on the box. The average number of reads covering a given genomic position (the “read depth”) is typically 30–40. Variants (differences) from that reference are annotated using sophisticated bioinformatics tools and large-scale databases of genomic variation. These variants are filtered and reviewed by a genome analyst to identify 1 or more that might be causal for the observed clinical presentation.