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

2021; Springer Nature; Volume: 29; Issue: 8 Linguagem: Inglês

10.1038/s41431-021-00858-1

1476-5438

Judy Savige, Helen Storey, E. Watson, Jens Michael Hertz, Constantinos Deltas, Alessandra Renieri, Francesca Mari, Pascale Hilbert, Pavlína Plevová, Peter H. Byers, Agnė Čerkauskaitė, Martin C. Gregory, Rimantė Čerkauskienė, Danica Galešić Ljubanović, Francesca Becherucci, Carmela Errichiello, Laura Massella, Valeria Aiello, Rachel Lennon, Louise Hopkinson, Ania Koziell, Adrian Lungu, H. Rothe, Julia Hoefele, Miriam Zacchia, Tamara Nikuševa Martić, Asheeta Gupta, Albertien M. van Eerde, Susie Gear, Samuela Landini, Viviana Palazzo, Laith Al‐Rabadi, Kathleen Claes, Anniek Corveleyn, Elke Van Hoof, Micheel van Geel, Maggie Williams, Emma Ashton, Hendica Belge, Elisabet Ars, Agnieszka Bierżyńska, Concetta Gangemi, Beata S. Lipska‐Ziętkiewicz,

Renal Diseases and Glomerulopathies

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.