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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG
Judy Savige1, Helen Storey2, Elizabeth Watson3
1Department of Medicine (MH and NH), The University of Melbourne, Parkville, VIC, Australia. jasavige@unimelb.edu.au.
Insights
Screening for Alport syndrome gene variants (COL4A3-5) now includes broader kidney conditions beyond the typical phenotype. Variant assessment criteria were refined, identifying key mutation sites and challenges in interpreting rare genetic variants.
Area of Science:
- Genetics and Genomics
- Nephrology
- Molecular Biology
Background:
- Alport syndrome is a genetic kidney disease caused by variants in COL4A3, COL4A4, and COL4A5 genes.
- Current screening guidelines focus on classical phenotypes like haematuria and renal failure, potentially missing other affected individuals.
- Standardized variant assessment criteria are crucial for accurate genetic diagnosis.
Purpose of the Study:
- To extend screening indications for pathogenic variants in COL4A3-5 genes.
- To refine the American College of Medical Genetics and Genomics (ACMG) criteria for variant assessment in Alport syndrome genes.
- To identify challenges in variant interpretation, particularly for hypomorphic variants.
Main Methods:
- A collaborative meeting (Alport Variant Collaborative) reviewed and extended screening criteria.
- ACMG criteria were refined, incorporating 'mutational hotspots' (PM1) and specific residue analyses (PP3).
- The utility of functional assays (PS3, BS3), sequencing, and minigene assays for variant confirmation was evaluated.
Main Results:
- Screening indications expanded to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis, and unexplained end-stage kidney failure.
- Key 'mutational hotspots' were identified in collagen IV chains, including Glycine residues in Gly-X-Y repeats and Cysteine residues in the carboxy non-collagenous domain.
- Defining a Minor Allele Frequency (MAF) threshold for benign variants was challenging due to inheritance patterns, hypomorphic variants, and founder effects. Heterozygous COL4A3/COL4A4 variants were found as incidental findings in databases.
Conclusions:
- The expanded screening criteria aim to improve early detection of Alport syndrome and related conditions.
- Refined variant assessment criteria and identification of mutational hotspots aid in interpreting genetic findings.
- Interpreting hypomorphic variants in COL4A3-COL4A5 genes remains a significant challenge requiring further research.
Abstract:
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.
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