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.

Possible Digenic Disease in a Caucasian Family with <b><i>COL4A3</i></b> and <b><i>COL4A5</i></b> Mutations

“…Our findings provide substantial evidence for possible digenic inheritance of Alport syndrome by concomitant mutations also in this combination of Alport genes, as to our knowledge only one single patient has been reported so far with concomitant COL4A3/COL4A5 mutations, that is, a de novo COL4A5 mutation combined with an inherited COL4A3 mutation, which were associated with a notably severe phenotype [15].…”

“…Together, the results indicate that Alport syndrome is under digenic control by COL4A3/COL4A4 and COL4A4/COL4A5. There is only one report on a patient with Alport syndrome with an inherited COL4A3 mutation combined with a de novo COL4A5 mutation [15]. Our study reports the findings of at least 6 more cases on a pedigree with 2 concomitant COL4A3/COL4A5 mutations.…”

The<b><i> COL4A3</i></b> and <b><i>COL4A4</i></b> Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family

“…Recently, Mencarelli et al [2015] suggested that a digenic inheritance pattern should be considered in AS. The clinical manifestations of digenic mutations in COL4A3 and COL4A4 varied obviously, and the correlation of genotype and phenotype is still not fully known [Schaffer, 2013;Mencarelli et al, 2015;Fallerini et al, 2017]. In our report, heterozygous COL4A3 and COL4A4 mutations in cis were detected in the patients II-2, III-4, III-9, and IV-2 who showed isolated hematuria and normal renal function without other extrarenal manifestations ( Table 1 ).…”

“…All these results showed that COL4A3 and COL4A4 digenic mutations in cis are responsible for BFH. However, Fallerini et al [2017] reported 2 families having COL4A3 and COL4A4 mutations in cis with a more severe phenotype. The phenotype of a gene dosage effect and synergism in COL4A3 / COL4A4 genes is not fully elucidated, and therefore expanding the BFH family sample sizes is essential.…”

“…Recently, Mencarelli et al [2015] demonstrated the existence of a digenic inheritance in AS. However, genotype-phenotype correlations and the spectrum of diseases caused by digenic mutations in COL4A3 and COL4A4 are still not fully known [Mencarelli et al, 2015;Fallerini et al, 2017]. Here, we report a family affected by BFH with COL4A3 / COL4A4 mutations in cis.…”