Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome : refining the ACMG criteria
Savige, Judy (The University of Melbourne)
Storey, Helen (Guy's and St Thomas' NHS Foundation Trust (Regne Unit))
Watson, Elizabeth (South West Genomic Laboratory Hub, North Bristol Trust)
Hertz, Jens Michael (Odense University Hospital (Dinamarca))
Deltas, Constantinos (University of Cyprus. Center of Excellence in Biobanking and Biomedical Research and Molecule Medicine Center)
Renieri, Alessandra (University of Siena. Medical Genetics)
Mari, Francesca (Institute de Pathologie et de Genetique ASBL (Bèlgica). Departement de Biologie Moleculaire)
Hilbert, Pascale (Institute de Pathologie et de Genetique ASBL (Bèlgica). Departement de Biologie Moleculaire)
Plevova, Pavlina (University Hospital of Ostrava. Department of Medical Genetics, and Department of Biomedical Sciences)
Byers, Peter (University of Washington. Departments of Pathology and Medicine)
Cerkauskaite, Agne (Vilnius University. Institute of Biomedical Sciences)
Gregory, Martin (University of Utah Health. Division of Nephrology)
Cerkauskiene, Rimante (Vilnius University. Clinic of Pediatrics)
Ljubanović, Danica Galešić (University of Zagreb)
Becherucci, Francesca (Nephrology Unit and Meyer Children's University Hospital)
Errichiello, Carmela (Nephrology Unit and Meyer Children's University Hospital)
Massella, Laura (Bambino Gesù Children's Hospital)
Aiello, Valeria (University of Bologna)
Lennon, Rachel (The University of Manchester)
Hopkinson, Louise (The University of Manchester Sciences, Faculty of Biology Medicine and Health)
Koziell, Ania (King's College London)
Lungu, Adrian (Fundeni Clinical Institute)
Rothe, Hansjorg Martin (Centre for Nephrology and Metabolic Disorders, Weisswasser, Germany)
Hoefele, Julia (Technische Universität München. Institut für Humangenetik)
Zacchia, Miriam (Nephrology Unit, University of Campania)
Martic, Tamara Nikuseva (School of Medicine University of Zagreb)
Gupta, Asheeta (Birmingham Children's Hospital)
van Eerde, Albertien (Utrecht University. Departments of Genetics and Center for Molecular MedicinE)
Gear, Susie (Alport UK)
Landini, Samuela (University of Florence. Medical Genetics Unit)
Palazzo, Viviana (Meyer Children's University Hospital)
al-Rabadi, Laith (University of UTAH. Health Sciences Centre)
Claes, Kathleen (University Hospitals Leuven (Bèlgica))
Corveleyn, Anniek (University Hospitals Leuven (Bèlgica))
Van Hoof, Evelien (University Hospitals Leuven (Bèlgica))
van Geel, Micheel (Maastricht University Medical Center)
Williams, Maggie (Southmead Hospital)
Ashton, Emma (Great Ormond Street Hospital for Children (Londres))
Belge, Hendica (Radboud University Medical Center)
Ars, Elisabet (Institut d'Investigació Biomèdica Sant Pau)
Bierzynska, Agnieszka (University of Bristol. Bristol Renal Unit, Bristol Medical School)
Gangemi, Concetta (University Hospital of Verona (Itàlia))
Lipska-Ziętkiewicz, Beata S. (Medical University of Gdansk. Centre for Rare Diseases, and Clinical Genetics Unit)
Universitat Autònoma de Barcelona

Date:	2021
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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Informe ; recerca ; Versió publicada
Subject:	Diseases ; Alport syndrome
Published in:	European Journal of Human Genetics, Vol. 29 (april 2021) , p. 1186-1197, ISSN 1476-5438

DOI: 10.1038/s41431-021-00858-1
PMID: 33854215

12 p, 1.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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