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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

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.

SUBMITTER: Savige J

PROVIDER: S-EPMC8384871 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

Savige Judy J Storey Helen H Watson Elizabeth E Hertz Jens Michael JM Deltas Constantinos C Renieri Alessandra A Mari Francesca F Hilbert Pascale P Plevova Pavlina P Byers Peter P Cerkauskaite Agne A Gregory Martin M Cerkauskiene Rimante R Ljubanovic Danica Galesic DG Becherucci Francesca F Errichiello Carmela C Massella Laura L Aiello Valeria V Lennon Rachel R Hopkinson Louise L Koziell Ania A Lungu Adrian A Rothe Hansjorg Martin HM Hoefele Julia J Zacchia Miriam M Martic Tamara Nikuseva TN Gupta Asheeta A van Eerde Albertien A Gear Susie S Landini Samuela S Palazzo Viviana V Al-Rabadi Laith L Claes Kathleen K Corveleyn Anniek A Van Hoof Evelien E van Geel Micheel M Williams Maggie M Ashton Emma E Belge Hendica H Ars Elisabeth E Bierzynska Agnieszka A Gangemi Concetta C Lipska-Ziętkiewicz Beata S BS

European journal of human genetics : EJHG 20210415 8

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 meeti ...[more]

PMID: 33854215

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Dataset Information

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

Publications

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

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