Expert consensus guidelines for the genetic diagnosis of Alport syndrome
Ημερομηνία
2019Συγγραφέας
Savige, JudyAriani, Francesca
Mari, Francesca
Bruttini, Mirella
Renieri, Alessandra
Gross, Oliver
![ORCID logo](https://orcid.org/sites/default/files/images/orcid_16x16.png)
Flinter, Frances
Ding, Jie
Gale, Daniel P.
Nagel, Mato
Yau, Michael
Shagam, Lev
Torra, Roser
Ars, Elisabet
Hoefele, Julia
Garosi, Guido
Storey, Helen
ISSN
1432-198XSource
Pediatric NephrologyVolume
34Issue
7Pages
1175-1189Google Scholar check
Metadata
Εμφάνιση πλήρους εγγραφήςΕπιτομή
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.