Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.
| Title: | Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. |
|---|---|
| Authors: | Savige J; Department of Medicine (MH and NH), The University of Melbourne, Parkville, VIC, Australia. jasavige@unimelb.edu.au.; Storey H; Molecular Genetics, Viapath Laboratories, Guy's Hospital, London, UK.; Watson E; Elizabeth Watson, South West Genomic Laboratory Hub, North Bristol Trust, Bristol, UK.; Hertz JM; Jens Michael Hertz, Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Deltas C; Center of Excellence in Biobanking and Biomedical Research and Molecule Medicine Center, University of Cyprus, Nicosia, Cyprus.; Renieri A; Medical Genetics, University of Siena, Siena, Italy.; Mari F; Institute de Pathologie et de Genetique ASBL, Departement de Biologie Moleculaire, Gosselies, Belgium.; Hilbert P; Institute de Pathologie et de Genetique ASBL, Departement de Biologie Moleculaire, Gosselies, Belgium.; Plevova P; Department of Medical Genetics, and Department of Biomedical Sciences, University Hospital of Ostrava, Ostrava, Czech Republic.; Byers P; Departments of Pathology and Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.; Cerkauskaite A; Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.; Gregory M; Division of Nephrology, Department of Medicine, University of Utah Health, Salt Lake City, UT, USA.; Cerkauskiene R; Clinic of Pediatrics, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.; Ljubanovic DG; Department of Pathology, University of Zagreb, School of Medicine, Dubrava University Hospital, Zagreb, Croatia.; Becherucci F; Nephrology Unit and Meyer Children's University Hospital, Firenze, Italy.; Errichiello C; Nephrology Unit and Meyer Children's University Hospital, Firenze, Italy.; Massella L; Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Aiello V; Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola Hospital, University of Bologna, Bologna, Italy.; Lennon R; Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.; Hopkinson L; Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.; Koziell A; School of Immunology and Microbial Sciences, Faculty of Life Sciences, King's College London, London, UK.; Lungu A; Fundeni Clinical Institute, Pediatric Nephrology Department, Bucharest, Romania.; Rothe HM; Centre for Nephrology and Metabolic Disorders, Weisswasser, Germany.; Hoefele J; Institute of Human Genetics, Technical University of Munich, München, Germany.; Zacchia M; Nephrology Unit, University of Campania, Naples, Italy.; Martic TN; Department of Biology, School of Medicine University of Zagreb, Zagreb, Croatia.; Gupta A; Birmingham Children's Hospital, Birmingham, UK.; van Eerde A; Departments of Genetics and Center for Molecular Medicine, University Medical Center, Utrecht University, Utrecht, The Netherlands.; Gear S; Alport UK, Gloucester, UK.; Landini S; Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.; Palazzo V; Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.; Al-Rabadi L; Health Sciences Centre, University of UTAH, Salt Lake City, UT, USA.; Claes K; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.; Corveleyn A; Center for Human Genetics, University Hospitals and KU Leuven, Leuven, Belgium.; Van Hoof E; Center for Human Genetics, University Hospitals and KU Leuven, Leuven, Belgium.; van Geel M; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.; Williams M; Bristol Genetics Laboratory Pathology Sciences, Southmead Hospital, Bristol, UK.; Ashton E; North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.; Belge H; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Ars E; Inherited Kidney Disorders, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.; Bierzynska A; Bristol Renal Unit, Bristol Medical School, University of Bristol, Bristol, UK.; Gangemi C; Division of Nephrology and Dialysis, University Hospital of Verona, Verona, Italy.; Lipska-Ziętkiewicz BS; Centre for Rare Diseases, and Clinical Genetics Unit, Medical University of Gdansk, Gdansk, Poland. |
| Source: | European journal of human genetics : EJHG [Eur J Hum Genet] 2021 Aug; Vol. 29 (8), pp. 1186-1197. Date of Electronic Publication: 2021 Apr 15. |
| Publication Type: | Journal Article; Consensus Statement |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9302235 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5438 (Electronic) Linking ISSN: 10184813 NLM ISO Abbreviation: Eur J Hum Genet Subsets: MEDLINE |
| Imprint Name(s): | Publication: : London : Nature Publishing Group; Original Publication: Basel ; New York : Karger, [1992- |
| MeSH Terms: | Consensus* ; Practice Guidelines as Topic*; Genetic Testing/*methods ; Nephritis, Hereditary/*genetics; Autoantigens/genetics ; Collagen Type IV/genetics ; Genetic Testing/standards ; Nephritis, Hereditary/diagnosis ; Humans ; Phenotype |
| 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.; (© 2021. The Author(s).) |
| Comments: | Erratum in: Eur J Hum Genet. 2024 Jan;32(1):132. doi: 10.1038/s41431-023-01288-x.. (PMID: 36721056) |
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| Grant Information: | UL1 TR002538 United States TR NCATS NIH HHS |
| Substance Nomenclature: | 0 (Autoantigens); 0 (COL4A4 protein, human); 0 (COL4A5 protein, human); 0 (Collagen Type IV); 0 (type IV collagen alpha3 chain) |
| Entry Date(s): | Date Created: 20210415 Date Completed: 20220316 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8384871 |
| DOI: | 10.1038/s41431-021-00858-1 |
| PMID: | 33854215 |
| Database: | MEDLINE |
Journal Article; Consensus Statement