title: Alport syndrome: impact of digenic inheritance in patients management.
abstract: Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Fallerini
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Baldassarri
authors.affiliation: Department of Woman and Child Health, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatria, IRP, Città della Speranza, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Trevisson
authors.affiliation: Department of Woman and Child Health, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatria, IRP, Città della Speranza, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Morbidoni
authors.affiliation: Department of Pediatrics, Second University of Napoli, Napoli, Italy.
authors.forename: A
authors.initials: A
authors.lastname: La Manna
authors.affiliation: Nephrology and Dialysis, Ospedale San Giacomo Apostolo, Castelfranco Veneto, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lazzarin
authors.affiliation: Nephrology and Pediatric Dialysis, Ospedale S. Orsola Malpighi, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pasini
authors.affiliation: Renal immunopathology, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barbano
authors.affiliation: Nephrology and Dialysis, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy.
authors.forename: A R
authors.initials: AR
authors.lastname: Pinciaroli
authors.affiliation: Nephrology, Dialysis and Transplantation, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Garosi
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Frullanti
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Pinto
authors.affiliation: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Mencarelli
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: F
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: A
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ariani
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked; D005817:Genetic Counseling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D018570:Risk Assessment
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; C478159:COL4A5 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain
keywords: Alport syndrome; digenic inheritance; hypomorphic allele; massive parallel sequencing