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

J. Savige*, H. Storey, E. Watson, J.M. Hertz, C. Deltas, A. Renieri, F. Mari, P. Hilbert, P. Plevova, P. Byers, A. Cerkauskaite, M. Gregory, R. Cerkauskiene, D.G. Ljubanovic, F. Becherucci, C. Errichiello, L. Massella, V. Aiello, R. Lennon, L. HopkinsonA. Koziell, A. Lungu, H.M. Rothe, J. Hoefele, M. Zacchia, T.N. Martic, A. Gupta, A. van Eerde, S. Gear, S. Landini, V. Palazzo, L. Al-Rabadi, K. Claes, A. Corveleyn, E. Van Hoof, M. van Geel, M. Williams, E. Ashton, H. Belge, E. Ars, A. Bierzynska, C. Gangemi, B.S. Lipska-Zietkiewicz

*Corresponding author for this work

Research output: Contribution to journalEditorialAcademicpeer-review

27 Citations (Web of Science)

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 alpha 5, alpha 3 and alpha 4 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.
Original languageEnglish
Pages (from-to)1186-1197
Number of pages12
JournalEuropean Journal of Human Genetics
Volume29
Issue number8
DOIs
Publication statusPublished - 1 Aug 2021

Keywords

  • AMINO-ACID-SEQUENCE
  • IV COLLAGEN
  • BASEMENT-MEMBRANE
  • OSTEOGENESIS IMPERFECTA
  • GLYCINE SUBSTITUTIONS
  • MEDICAL GENETICS
  • AMERICAN-COLLEGE
  • MUTATIONS
  • CHAIN
  • DISEASE

Cite this