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<p>“Alport spectrum disorder” describes a phenotypically and genotypically multifaceted disease entity encompassing classic autosomal recessive and X-linked Alport syndrome (AS) but also more heterogenous and typically milder, yet not benign, hematuric phenotypes like autosomal dominant AS, formerly also known as thin basement membrane nephropathy (TBMN). Alport spectrum disorder is associated with disease-causing variants in the type IV collagen genes <i>COL4A3</i>, <i>COL4A4</i> and <i>COL4A5</i>. Variants and genotypes, reported by a genetic diagnostics lab between 2009 and 2014, of 91 index cases with the clinical tentative diagnosis of AS (66/91), TBMN (21/91), or AS/TBMN (not specified further; 4/91), were reassessed based on 2015 ACMG (American College of Medical Genetics and Genomics) criteria and current amendments. 80 different variants, all originally reported as “mutations”, and their genotypes have been reassessed (<i>COL4A3</i>: 21/80, <i>COL4A4</i>: 15/80, <i>COL4A5</i>: 44/80). In 10/80 variants, classification changed from disease-causing to variant of uncertain significance (VUS). 69/91 (76%) index cases included in the analysis could be classified as solved. 22/91 (24%) index cases had an ambiguous result either on variant, genotype, or both variant and genotype level. VUS cases had a significantly more limited phenotype (e.g., isolated microscopic hematuria) compared to non-downgraded cases (e.g., additional extrarenal manifestations). Reassessment of variants/genotypes in this study showed a significant reduction in unequivocal genetic diagnoses highlighting variant and genotype interpretation as a dynamic process. Genetic reports of individuals with suspected Alport spectrum disorder, especially those obtained in the pre-ACMG criteria era, should therefore be critically evaluated.</p>

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Systematic reassessment of reported variants in individuals with suspicion of Alport spectrum disorder reveals a high rate of ambiguous results

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Korbinian M. Riedhammer,
  • Patrick Richthammer,
  • Dominik S. Westphal,
  • Jasmina Ćomić,
  • Roman Günthner,
  • Matthias C. Braunisch,
  • Anja K. Büscher,
  • Hanns-Georg Klein,
  • Stefanie Weber,
  • Julia Hoefele

摘要

“Alport spectrum disorder” describes a phenotypically and genotypically multifaceted disease entity encompassing classic autosomal recessive and X-linked Alport syndrome (AS) but also more heterogenous and typically milder, yet not benign, hematuric phenotypes like autosomal dominant AS, formerly also known as thin basement membrane nephropathy (TBMN). Alport spectrum disorder is associated with disease-causing variants in the type IV collagen genes COL4A3, COL4A4 and COL4A5. Variants and genotypes, reported by a genetic diagnostics lab between 2009 and 2014, of 91 index cases with the clinical tentative diagnosis of AS (66/91), TBMN (21/91), or AS/TBMN (not specified further; 4/91), were reassessed based on 2015 ACMG (American College of Medical Genetics and Genomics) criteria and current amendments. 80 different variants, all originally reported as “mutations”, and their genotypes have been reassessed (COL4A3: 21/80, COL4A4: 15/80, COL4A5: 44/80). In 10/80 variants, classification changed from disease-causing to variant of uncertain significance (VUS). 69/91 (76%) index cases included in the analysis could be classified as solved. 22/91 (24%) index cases had an ambiguous result either on variant, genotype, or both variant and genotype level. VUS cases had a significantly more limited phenotype (e.g., isolated microscopic hematuria) compared to non-downgraded cases (e.g., additional extrarenal manifestations). Reassessment of variants/genotypes in this study showed a significant reduction in unequivocal genetic diagnoses highlighting variant and genotype interpretation as a dynamic process. Genetic reports of individuals with suspected Alport spectrum disorder, especially those obtained in the pre-ACMG criteria era, should therefore be critically evaluated.