'Missing' disease-causing variants in Alport syndrome

Up to 20% of people with clinically suspected Alport syndrome do not have a disease-causing variant identified with genetic testing. Disease-causing changes are 'missing' because the identified variant is of uncertain significance or no suspicious change has been found. A variant of uncertain significance might be resolved after a clinician-laboratory consultation, family segregation studies, functional assays, evidence from large case-control cohorts or review after further genetic and experimental information becomes available. Other explanations for a lack of disease-causing variants include the presence of phenocopies such as IgA nephropathy, technical issues associated with whole-exome sequencing and difficulties in identifying and computationally assessing non-canonical splicing variants, including deep intronic and synonymous changes. Candidate splicing variants might be identified using whole-exome, whole-genome or long-read sequencing, prioritized bioinformatically, and validated with targeted RNA sequencing or splicing assays. People with suspected Alport syndrome but no identified disease-causing variant should be managed as for Alport syndrome while awaiting confirmation of their diagnosis. Missing disease-causing variants are also common in other genetic kidney diseases, and the methods used for their resolution are the same. Our current inability to detect all disease-causing variants means that the contribution of genetic disease is underestimated for kidney phenotypes.