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<p>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&#xa0;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.</p>

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‘Missing’ disease-causing variants in Alport syndrome

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Judy Savige,
  • Adam M. Bournazos,
  • Tomoko Horinouchi,
  • Bryony A. Thompson,
  • Yanqin Zhang,
  • Julia Hoefele,
  • Mary Huang

摘要

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.