title: Evidence of digenic inheritance in Alport syndrome.
abstract: 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.
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.affiliation: APHP, 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.affiliation: Molecular Genetics Laboratory, Guy's Hospital, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Storey
authors.affiliation: Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.affiliation: APHP, 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Knebelmann
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fallerini
authors.affiliation: Clinica Pediatrica, Azienda Ospedaliera Spedali Civili, Brescia, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Miglietti
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Maria Fatima
authors.initials: MF
authors.lastname: Antonucci
authors.affiliation: IRCCS MultiMedica, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cetta
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
authors.affiliation: Molecular Genetics Laboratory, Guy's Hospital, London, UK.
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Bruttini
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ariani
authors.affiliation: Université Catholique de Louvain, Louvain, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.affiliation: Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Smeets
authors.affiliation: Inserm UMR 1163, Laboratory of Inherited Kidney Diseases, Paris, France Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, Paris, France APHP, Department of Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: Department of Clinical Genetics, Guy's & St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; C478159:COL4A5 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain
keywords: Complex traits; Diagnostics tests; Genetic screening/counselling; Getting Research into Practice; Molecular genetics