Recent studies indicate that living donors biologically related to their transplant recipient may be at higher risk of ESRD compared to unrelated donors, possibly secondary to shared genetics.

To facilitate screening of living donors for known or suspected genetic disease, we developed a platform that couples targeted genomic enrichment and massively parallel sequencing (TGE+MPS) of 120 renal disease genes. In a pilot study to validate this Genetic Renal Diseases Panel (GRDP) we studied 7 negative controls and 4 transplant candidates with known or presumed genetic renal disease who had biologically related donors. Samples were bar-coded and sequenced on the Illumina MiSeq®. On average, we identified 500 variants per sample at an average depth-of-coverage of 390x. After filtering to remove low quality and common variants, rare/novel variants were annotated based on Human Gene Mutation Database (HGMD®). Pathogenicity of novel variants was predicted in silico using algorithms to score variants based on conservation and function. To optimize clinical relevance of generated data, variants were discussed in the context of patient phenotype, clinical data and observed genetic results. We identified causal variants in 2 of 4 transplant candidates with presumed genetic renal disease. One patient with a family history of autosomal dominant polycystic kidney disease segregated a novel truncating variant in PKD1 Y2622X and this information was used to exclude genetic risk in a young relative who has been accepted as a kidney donor. No pathogenic mutations were identified in a second patient with a family history of renal disease where phenotypic differences between affected individuals made the clinical diagnosis of a genetic renal disease uncertain and the negative genetic screen facilitated the acceptance and subsequent donation by a biologically related donor.

By identifying specific mutations, we were able to offer asymptomatic family members genetic counseling and exclude disease in others at risk and improve the long term safely of living donation. We anticipate that the GRDP will provide a cost-effective test to assist clinicians in the evaluation of living donors with a family history of known and unknown kidney diseases.

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