Allele definition

How to define PGx alleles

PGx alleles are defined as collections of one or more SNPs, INDELs or structural variants. When a patient is sequenced by next generation sequencing (NGS) we may typically observe more variants than those which are included in any individual PGx allele definitions. miniatyr|The 16 possible haplotypes for a four loci, decomposed variant calling This means that

• Patients may have a large, ambiguous number of matching PGx alleles
• Patients may have additional variants that may modify the effect of a known PGx allele

We illustrate some of the problems that we encountered when trying to make robust PGx allele definitions, by an imagined four loci PGx gene

The SNP array method

miniatyr|PGx alleles defined as collections of variants, with no requirement on loci that are not part of the definition, will assign the same PGx allele to several different haplotypes This definition only requires matches for variants explicitly included in PGx allele definitions.

This means that

• Several PGx alleles may match the patient
• But the presence of additional variants will have no effect on reported PGx alleles

The PharmCAT method

This definition require matches also for variants not explicitly included in PGx allele definitions. miniatyr|PGx alleles defined as complete haplotypes classifies the patient uniquely This means that

• Only one PGx allele can exist simultaneously for the same patient
• But whenever we have additional variants, no PGx alleles will be reported

Which definition should we stick to?

Method	Advantages	Disadvantages
SNP array method	Compatible with previous SNP array methods. Assigns PGx alleles to the maximum number of patients	Multiple PGx alleles are possible
PharmCAT method	One PGx allele per patient	Less compatible with previous SNP array methods. Many patients are not assigned to a known PGx allele