title: Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.
abstract: Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.
authors.affiliation: Department of Genetics, Faculty of Medicine, Porto, Portugal.|Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Nabais Sá
authors.affiliation: Molecular Genetics Laboratory, Viapath, UK.
authors.forename: H
authors.initials: H
authors.lastname: Storey
authors.affiliation: Genetics Centre, Guy's and St. Thomas' Hospital National Health Service Foundation Trust, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Flinter
authors.affiliation: Center for Nephrology and Metabolic Diseases, Weisswasser, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nagel
authors.affiliation: Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Nephrology, Hospital de São João, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Sampaio
authors.affiliation: Department of Nephrology, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Castro
authors.affiliation: Department of Nephrology, Hospital dos Marmeleiros, Funchal, Portugal.
authors.forename: J A
authors.initials: JA
authors.lastname: Araújo
authors.affiliation: Dialysis Clinic, NephroCare Restelo, Fresenius Medical Care, Lisboa, Portugal.
authors.forename: M A
authors.initials: MA
authors.lastname: Gaspar
authors.affiliation: Department of Nephrology, Hospital de Braga, Braga, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Soares
authors.affiliation: Dialysis Clinic Paredes, Diaverum, Paredes, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Dialysis Clinic, NephroCare Braga, Fresenius Medical Care, Braga, Portugal.
authors.forename: A C
authors.initials: AC
authors.lastname: Henriques
authors.affiliation: Department of Nephrology, Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: A G
authors.initials: AG
authors.lastname: da Costa
authors.affiliation: Dialysis Clinic Lumiar, Diaverum, Lisboa, Portugal.
authors.forename: C P
authors.initials: CP
authors.lastname: Abreu
authors.affiliation: Dialysis Clinic, NephroCare Lumiar, Fresenius Medical Care, Lisboa, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Ponce
authors.affiliation: Dialysis Clinic, NephroCare Viseu, Fresenius Medical Care, Viseu, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Alves
authors.affiliation: Dialysis Clinic Paredes, Diaverum, Paredes, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Pinho
authors.affiliation: Department of Ophthalmology, Porto, Portugal.
authors.forename: S E
authors.initials: SE
authors.lastname: Silva
authors.affiliation: Department of Otolaryngology, Porto, Portugal.|Medical Genetics Outpatient Clinic, Hospital de São João, Porto, Portugal.
authors.forename: C P
authors.initials: CP
authors.lastname: de Moura
authors.affiliation: Department of Ophthalmology, Hospital de Braga, Braga, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Mendonça
authors.affiliation: Unit of Renal Morphology, Department of Nephrology, Hospital Curry Cabral, Lisboa, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Nephrology, Hospital de São João, Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Pestana
authors.affiliation: Department of Genetics, Faculty of Medicine, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Alves
authors.affiliation: Department of Genetics, Faculty of Medicine, Porto, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: Department of Genetics, Faculty of Medicine, Porto, Portugal.|Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.|Medical Genetics Outpatient Clinic, Hospital de São João, Porto, Portugal.
authors.forename: J P
authors.initials: JP
authors.lastname: Oliveira
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006417:Hematuria / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011174:Portugal; D055815:Young Adult
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain
keywords: Alport syndrome; COL4A3; COL4A4; COL4A5; thin basement membrane nephropathy