title: Collagen type IV-related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families.
abstract: Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related 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: Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Nephrology, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Sampaio
authors.affiliation: Department of Nephrology, Porto, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Department of Genetics, Faculty of Medicine, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Alves
authors.affiliation: Department of Otolaryngology, Porto, Portugal.|Medical Genetics Outpatient Clinic, Porto, Portugal.
authors.forename: C P
authors.initials: CP
authors.lastname: Moura
authors.affiliation: Department of Ophthalmology, Hospital de São João, Porto, Portugal.
authors.forename: S E
authors.initials: SE
authors.lastname: Silva
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: Department of Medical Genetics, Hospital Dona Estefânia, Lisboa, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Dialysis Clinic of Santarém, NephroCare-Portugal, Santarém, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Neves
authors.affiliation: Department of Nephrology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Seabra
authors.affiliation: Department of Nephrology, Hospital de Braga, Braga, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Soares
authors.affiliation: Dialysis Clinic of Restelo, NephroCare-Portugal, Lisboa, Portugal.
authors.forename: M A
authors.initials: MA
authors.lastname: Gaspar
authors.affiliation: Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.|Dialysis Clinic of Santo Tirso, Uninefro, Santo Tirso, Portugal.
authors.forename: I
authors.initials: I
authors.lastname: Tavares
authors.affiliation: Department of Nephrology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Freitas
authors.affiliation: Department of Nephrology, Hospital de São Teotónio, Viseu, Portugal.|Dialysis Clinic of Guarda, NephroCare-Portugal, Guarda, Portugal.
authors.forename: T C
authors.initials: TC
authors.lastname: Sousa
authors.affiliation: Dialysis Clinic of Braga, NephroCare-Portugal, Braga, Portugal.
authors.forename: A C
authors.initials: AC
authors.lastname: Henriques
authors.affiliation: Department of Nephrology, Hospital Garcia de Orta, Almada, Portugal.
authors.forename: F T
authors.initials: FT
authors.lastname: Costa
authors.affiliation: Department of Nephrology, Hospital de Faro, Faro, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Morgado
authors.affiliation: Dialysis Clinic of Montijo, NephroCare-Portugal, Montijo, Portugal.
authors.forename: F T
authors.initials: FT
authors.lastname: Sousa
authors.affiliation: Department of Nephrology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.|Dialysis Clinic of Coimbra, NephroCare-Portugal, Coimbra, Portugal.
authors.forename: J P
authors.initials: JP
authors.lastname: Sousa
authors.affiliation: Department of Nephrology, Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: A G
authors.initials: AG
authors.lastname: da Costa
authors.affiliation: Department of Nephrology, Hospital Amato Lusitano, Castelo Branco, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Filipe
authors.affiliation: Department of Nephrology, Hospital de São Teotónio, Viseu, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Garrido
authors.affiliation: Dialysis Clinic of Covilhã, NephroCare-Portugal, Covilhã, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Montalban
authors.affiliation: Dialysis Clinic of Lumiar, NephroCare-Portugal, Lisboa, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Ponce
authors.affiliation: Dialysis Clinic of Viseu, NephroCare-Portugal, Viseu, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Alves
authors.affiliation: Dialysis Clinic of Guarda, NephroCare-Portugal, Guarda, Portugal.
authors.forename: B
authors.initials: B
authors.lastname: Faria
authors.affiliation: Unit of Renal Morphology, Department of Nephrology, Hospital Curry Cabral, Lisboa, Portugal.
authors.forename: M F
authors.initials: MF
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, Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Pestana
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, Porto, Portugal.
authors.forename: J P
authors.initials: JP
authors.lastname: Oliveira
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D011174:Portugal; D055815:Young Adult
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV
keywords: COL4A5 mutations; Portuguese population; X-linked Alport syndrome; genotype-phenotype correlation