Fifty times more data. Not fifty times more insight.

Exome sequencing, WES for whole exome sequencing, reads only the protein-coding regions of the genome, around one to two per cent. Whole genome sequencing, WGS, reads everything: coding and non-coding regions plus the mitochondrial DNA. The point is not the volume of data, though. Those one to two per cent contain roughly 85 per cent of the disease-causing variants known today, because a change in the protein itself has the most direct effect. WGS additionally finds four classes of finding that remain closed to the exome: structural variants, regulatory variants, mitochondrial DNA at full depth, and complete pharmacogenetic interpretation.

Not in general, but for particular questions. WGS reads roughly fifty times as many bases, but the share of that which can be interpreted with clinical confidence today does not grow in the same proportion. For the typical questions of a preventive examination, meaning hereditary cancer risk, lipid metabolism, haemochromatosis and core pharmacogenetics, WES delivers the findings. WGS is the better choice where structural variants are suspected, where complete pharmacogenetics is wanted, and where a targeted prior investigation left something unexplained. More data also means more variants of uncertain significance, meaning more findings nobody can interpret.

Pure sequencing costs have fallen for years, and the price difference between exome and genome is considerably smaller today than five years ago. What drives the cost difference now is not the reading but the interpretation: more data means more bioinformatic compute, more storage and above all more physician curation work, because more variants of uncertain significance have to be assessed. At YEARS the question is commercially defused, because the Ultimate programme runs both methods and the price of 16,900 euros covers the entire programme rather than sequencing as a line item.

The clinical question decides, and that arises from your family history and your existing findings, not from a catalogue. Three examples. Where breast or bowel cancer occurred early in the family, the route runs via a targeted panel or the exome, because the relevant genes are coding. Where you take several medications and tolerance is unclear, complete pharmacogenetic interpretation from WGS delivers more. Where a panel or the exome has already returned no finding and family history still points to a hereditary cause, WGS is the next step. Making exactly this assignment is the content of the pre-test medical consultation.

Because the question cannot be reopened after the blood draw. If no explanatory finding emerges from the exome, the next step would be full sequencing, and that means a new sample, a new waiting period and a new appointment. The marginal cost of additional interpretation from one sample is lower than that of a second run months later. Parallel interpretation also allows a plausibility check: a finding that appears in both methods is more robust than one from a single method. At YEARS both are part of the Ultimate programme and cannot be booked separately.

Those generally work with an SNP array, not with sequencing. An array tests individual predefined positions in the genome, typically a few hundred thousand to a million. That is fundamentally different from reading: an array only finds what was asked in advance, and cannot see a rare variant at a position it does not query. For polygenic risk scores that is sufficient, for clarifying a familial cancer risk it is not. On top of that comes the legal framework: in Germany a predictive genetic examination may only be ordered by a physician, with genetic counselling before and after the test.