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Evidence of digenic inheritance in Alport syndrome
  1. Maria Antonietta Mencarelli1,2,
  2. Laurence Heidet3,
  3. Helen Storey4,
  4. Michel van Geel5,
  5. Bertrand Knebelmann3,
  6. Chiara Fallerini1,
  7. Nunzia Miglietti6,
  8. Maria Fatima Antonucci1,
  9. Francesco Cetta7,
  10. John A Sayer8,
  11. Arthur van den Wijngaard5,
  12. Shu Yau4,
  13. Francesca Mari1,2,
  14. Mirella Bruttini1,2,
  15. Francesca Ariani1,2,
  16. Karin Dahan9,
  17. Bert Smeets5,
  18. Corinne Antignac10,11,12,
  19. Frances Flinter13,
  20. Alessandra Renieri1,2
  1. 1Medical Genetics, University of Siena, Siena, Italy
  2. 2Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
  3. 3APHP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Service de Néphrologie Pédiatrique, Hôpital Necker—Enfants Malades, Paris, France
  4. 4Molecular Genetics Laboratory, Guy's Hospital, London, UK
  5. 5Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands
  6. 6Clinica Pediatrica, Azienda Ospedaliera Spedali Civili, Brescia, Italy
  7. 7IRCCS MultiMedica, Milan, Italy
  8. 8Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
  9. 9Université Catholique de Louvain, Louvain, Belgium
  10. 10Inserm UMR 1163, Laboratory of Inherited Kidney Diseases, Paris, France
  11. 11Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, Paris, France
  12. 12APHP, Department of Genetics, Hôpital Necker—Enfants Malades, Paris, France
  13. 13Department of Clinical Genetics, Guy's & St Thomas’ NHS Foundation Trust, Guy's Hospital, London, UK
  1. Correspondence to Professor Alessandra Renieri, Medical Genetics, University of Siena, Policlinico Le Scotte, Siena 53100, Italy; alessandra.renieri{at}


Background Alport syndrome is a clinically heterogeneous, progressive nephropathy caused by mutations in collagen IV genes, namely COL4A3 and COL4A4 on chromosome 2 and COL4A5 on chromosome X. The wide phenotypic variability and the presence of incomplete penetrance suggest that a simple Mendelian model cannot completely explain the genetic control of this disease. Therefore, we explored the possibility that Alport syndrome is under digenic control.

Methods Using massively parallel sequencing, we identified 11 patients who had pathogenic mutations in two collagen IV genes. For each proband, we ascertained the presence of the same mutations in up to 12 members of the extended family for a total of 56 persons studied.

Results Overall, 23 mutations were found. Individuals with two pathogenic mutations in different genes had a mean age of renal function deterioration intermediate with respect to the autosomal-dominant form and the autosomal-recessive one, in line with molecule stoichiometry of the disruption of the type IV collagen triple helix.

Conclusions Segregation analysis indicated three possible digenic segregation models: (i) autosomal inheritance with mutations on different chromosomes, resembling recessive inheritance (five families); (ii) autosomal inheritance with mutations on the same chromosome resembling dominant inheritance (two families) and (iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (four families). This pedigree analysis provides evidence for digenic inheritance of Alport syndrome. Clinical geneticists and nephrologists should be aware of this possibility in order to more accurately assess inheritance probabilities, predict prognosis and identify other family members at risk.

  • Complex traits
  • Diagnostics tests
  • Genetic screening/counselling
  • Getting Research into Practice
  • Molecular genetics

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