Expert consensus guidelines for the genetic diagnosis of Alport syndrome
Por:
Savige, J, Ariani, F, Mari, F, Bruttini, M, Renieri, A, Gross, O, Deltas, C, Flinter, F, Ding, J, Gale, DP, Nagel, M, Yau, M, Shagam, L, Torra, R, Ars, E, Hoefele, J, Garosi, G, Storey, H
Publicada:
1 jul 2019
Resumen:
Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
Filiaciones:
Savige, J:
Univ Melbourne, Melbourne & Northern Hlth, Dept Med, Parkville, Vic 3050, Australia
Ariani, F:
Univ Siena, Med Genet, Siena, Italy
Mari, F:
Univ Siena, Med Genet, Siena, Italy
Bruttini, M:
Univ Siena, Med Genet, Siena, Italy
Renieri, A:
Univ Siena, Med Genet, Siena, Italy
Gross, O:
Univ Gottingen, Clin Nephrol & Rheumatol, Gottingen, Germany
Deltas, C:
Univ Cyprus, Mol Med Res Ctr, Nicosia, Cyprus
Flinter, F:
Guys & St Thomas NHS Fdn Trust, Dept Clin Genet, London, England
Ding, J:
Peking Univ, Hosp 1, Beijing, Peoples R China
Gale, DP:
UCL, Royal Free Hosp, Ctr Nephrol, London, England
Nagel, M:
Ctr Nephrol & Metab Disorders, Weisswasser, Germany
Yau, M:
Viapath, Guys Hosp, Genet, London, England
Shagam, L:
Pirogov Russian Med Univ, Inst Pediat, Moscow, Russia
Torra, R:
Univ Autonoma Barcelona, Inst Invest Carlos III, Fundacio Puigvert, Inherited Kidney Disorders,Nephrol Dept, Barcelona, Spain
Ars, E:
Univ Autonoma Barcelona, Inst Invest Carlos III, Fundacio Puigvert, Mol Biol Lab, Barcelona, Spain
Hoefele, J:
Tech Univ Munich, Inst Human Genet, Munich, Germany
Garosi, G:
Azienda Osped Univ Senese, Nephrol Dialysis & Transplantat, Siena, Italy
Storey, H:
Viapath, Guys Hosp, Genet, London, England
Green Published
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