UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

Savige, J; Ariani, F; Mari, F; Bruttini, M; Renieri, A; Gross, O; Deltas, C; ... Storey, H; + view all (2019) Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatric Nephrology , 34 (7) pp. 1175-1189. 10.1007/s00467-018-3985-4. Green open access

[thumbnail of Gale_Final Alport genetics guide- Revision 2.pdf]
Preview
Text
Gale_Final Alport genetics guide- Revision 2.pdf - Accepted Version

Download (627kB) | Preview

Abstract

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.

Type: Article
Title: Expert consensus guidelines for the genetic diagnosis of Alport syndrome
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00467-018-3985-4
Publisher version: https://doi.org/10.1007/s00467-018-3985-4
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Alport syndrome, Collagen IV genes, Next generation sequencing, Pathogenic variants
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10052872
Downloads since deposit
236Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item