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Evidence of digenic inheritance in Alport syndrome

Maria Antonietta Mencarelli, Laurence Heidet, Helen Storey, Michel van Geel, Bertrand Knebelmann, Chiara Fallerini, Nunzia Miglietti, Maria Fatima Antonucci, Francesco Cetta, John A Sayer, Arthur van den Wijngaard, Shu Yau (+8 others)
2015 Journal of Medical Genetics  

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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. Using massively parallel sequencing, we identified 11
more » ... ients 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. 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. Segregation analysis indicated three possible digenic segregation models: i) autosomal inheritance with linked mutations in trans mimicking recessive inheritance (5 families); ii) autosomal inheritance with linked mutations in cis mimicking dominant inheritance (2 families); and iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (4 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 recurrence risk, predict prognosis and identify other family members at risk.
doi:10.1136/jmedgenet-2014-102822 pmid:25575550 fatcat:b7zjarukhbgptn3gpp34gek2fa
Citation

Maria Antonietta Mencarelli, Laurence Heidet, Helen Storey, Michel van Geel, Bertrand Knebelmann, Chiara Fallerini, Nunzia Miglietti, Maria Fatima Antonucci, Francesco Cetta, John A Sayer, Arthur van den Wijngaard, Shu Yau, Francesca Mari, Mirella Bruttini, Francesca Ariani, Karin Dahan, Bert Smeets, Corinne Antignac, Frances Flinter, Alessandra Renieri. "Evidence of digenic inheritance in Alport syndrome." Journal of Medical Genetics 52.3 (2015) 163-174