Maria Antonietta Mencarelli1, Laurence Heidet2, Helen Storey3, Michel van Geel4, Bertrand Knebelmann2, Chiara Fallerini5, Nunzia Miglietti6, Maria Fatima Antonucci5, Francesco Cetta7, John A Sayer8, Arthur van den Wijngaard4, Shu Yau3, Francesca Mari1, Mirella Bruttini1, Francesca Ariani1, Karin Dahan9, Bert Smeets4, Corinne Antignac10, Frances Flinter11, Alessandra Renieri1. 1. Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 2. 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. 3. Molecular Genetics Laboratory, Guy's Hospital, London, UK. 4. Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands. 5. Medical Genetics, University of Siena, Siena, Italy. 6. Clinica Pediatrica, Azienda Ospedaliera Spedali Civili, Brescia, Italy. 7. IRCCS MultiMedica, Milan, Italy. 8. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK. 9. Université Catholique de Louvain, Louvain, Belgium. 10. 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. 11. Department of Clinical Genetics, Guy's & St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Complex traits; Diagnostics tests; Genetic screening/counselling; Getting Research into Practice; Molecular genetics
Authors: Gaspard Kerner; Matthieu Bouaziz; Aurélie Cobat; Benedetta Bigio; Andrew T Timberlake; Jacinta Bustamante; Richard P Lifton; Jean-Laurent Casanova; Laurent Abel Journal: Proc Natl Acad Sci U S A Date: 2020-07-27 Impact factor: 11.205