Digenic inheritance in Alport syndrome. M. Mencarelli1,2, L. Heidet3, H. Storey4, M. van Geel5, B. Knebelmann3, C. Fallerini1, L. Dosa1,2, N. Miglietti6, M. F. Antonucci1,2, F. Cetta7, A. van den Wijngaard5, S. Yau4, F. Mari1,2, M. Bruttini1,2, F. Ariani1,2, K. Dahan8, B. Smeets5, C. Antignac3,9,10, F. Flinter11, A. Renieri1,2 1) Medical Genetics, University of Siena, Siena, Italy; 2) Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; 3) 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) Molecular Genetics Laboratory, Viapath, 5th Floor Tower Wing, Guys Hospital, London SE1 9RT, England; 5) Clinical Genetics, Maastricht University Medical Centre, The Netherlands; 6) Clinica Pediatrica, Azienda Ospedaliera Spedali Civili, Brescia, Italy; 7) IRCCS MultiMedica, Milan, Italy; 8) Université Catholique de Louvain, Belgium; 9) Inserm UMR 1163, Laboratory of Inherited Kidney Diseases, Paris, France; 10) Paris Descartes-Sorbonne Paris Cité Université, Imagine Institute, Paris, France; 11) Department of Clinical Genetics, Guy's & St Thomas' NHS Foundation Trust, Guys Hospital, London SE1 9RT, England.

   Alport syndrome (AS) is a clinically and genetically heterogeneous inherited progressive nephropathy associated with deafness and characteristic ocular lesions. Monogenic inheritance models are well known, with semidominant X-linked inheritance, linked to COL4A5 gene, or autosomal dominant or recessive inheritance, linked to COL4A3 or COL4A4 gene. The increased availability of massive parallel sequencing permits identification of families with pathogenic mutations in more than one disease-gene, suggesting digenic inheritance models. We present a series of 11 families, in which individuals with 2 pathogenic mutations in different Alport associated genes are more severely affected than heterozygotes. The double heterozygotes mean age of renal function deterioration is intermediate with respect to the autosomal dominant form and the autosomal recessive one, in line with molecule stoichiometry of the disruption of the triple helix of the type IV collagen alpha chains building the basement membrane of the glomeruli. Furthermore, segregation analysis indicates three possible segregation models: i) digenic autosomal inheritance with linked mutations in trans mimicking a recessive disease (5 families); ii) autosomal inheritance with linked mutations in cis mimicking a dominant disease (2 families); iii) unlinked autosomal and X-linked inheritance having its own peculiar segregation (4 families including one with triallelic inheritance). In summary, in this work we provide evidence for the first time of the digenic inheritance of Alport syndrome. Our results are of interest scientifically and have implications for genetic counselling. Clinical geneticists should be made aware of the digenic model of inheritance in Alport syndrome in order to assess the exact recurrence risk and give the correct prognosis.

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