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Collagen type IV ‐related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families

2014; Wiley; Volume: 88; Issue: 5 Linguagem: Inglês

10.1111/cge.12521

1399-0004

Maria João Nabais Sá, Helen Storey, Frances Flinter, Mato Nagel, Susana Sampaio, R. Castro, José Augusto Dias Araújo, Marian Gaşpar, Carlos Soares, Anne Andrade Matiazi de Oliveira, António Castro Henriques, Adília Costa, Camila Abreu, P Ponce, Rui Alves, L. Pinho, Sérgio Estrela‐Silva, Carla Pinto Moura, Luís Mendonça, Filipa Carvalho, Manuel Pestana, Susana P. Alves, Filipa Carvalho, João Paulo Oliveira,

Platelet Disorders and Treatments

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.