Expert consensus guidelines for the genetic diagnosis of Alport syndrome

  • Judy Savige
  • Francesca Ariani
  • Francesca Mari
  • Mirella Bruttini
  • Alessandra Renieri
  • Oliver Gross
  • Constantinos Deltas
  • Frances Flinter
  • Jie Ding
  • Daniel P. Gale
  • Mato Nagel
  • Michael Yau
  • Lev Shagam
  • Roser Torra
  • Elisabet Ars
  • Julia Hoefele
  • Guido Garosi
  • Helen Storey


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.


Alport syndrome Collagen IV genes Next generation sequencing Pathogenic variants 


Compliance with Ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© IPNA 2018

Authors and Affiliations

  • Judy Savige
    • 1
  • Francesca Ariani
    • 2
  • Francesca Mari
    • 2
  • Mirella Bruttini
    • 2
  • Alessandra Renieri
    • 2
  • Oliver Gross
    • 3
  • Constantinos Deltas
    • 4
  • Frances Flinter
    • 5
  • Jie Ding
    • 6
  • Daniel P. Gale
    • 7
  • Mato Nagel
    • 8
  • Michael Yau
    • 9
  • Lev Shagam
    • 10
  • Roser Torra
    • 11
  • Elisabet Ars
    • 12
  • Julia Hoefele
    • 13
  • Guido Garosi
    • 14
  • Helen Storey
    • 9
  1. 1.Department of Medicine, Melbourne and Northern HealthThe University of MelbourneParkvilleAustralia
  2. 2.Medical GeneticsUniversity of SienaSienaItaly
  3. 3.Clinic of Nephrology and RheumatologyUniversity of GottingenGottingenGermany
  4. 4.Molecular Medicine Research CentreUniversity of CyprusNicosiaCyprus
  5. 5.Department of Clinical GeneticsGuys’ and St Thomas’ NHS Foundation TrustLondonUK
  6. 6.Peking University First HospitalBeijingChina
  7. 7.Centre for Nephrology, Royal Free HospitalUniversity College LondonLondonUK
  8. 8.Centre for Nephrology and Metabolic DisordersWeisswasserGermany
  9. 9.Genetics, Guy’s HospitalViapathLondonUK
  10. 10.Institute of PediatricsPirogov Russian Medical UniversityMoscowRussia
  11. 11.Inherited Kidney Disorders, Nephrology Department, Fundacio Puigvert, Instituto de Investigacion Carlos IIIUniversitat Autonoma de BarcelonaBarcelonaSpain
  12. 12.Molecular Biology Laboratory, Fundacio Puigvert, Instituto de Investigacion Carlos IIIUniversitat Autonoma de BarcelonaBarcelonaSpain
  13. 13.Institute of Human GeneticsTechnical University MunichMunichGermany
  14. 14.Nephrology, Dialysis and TransplantationAzienda Ospedaliera Universitaria SeneseSienaItaly

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