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Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either  PKD1  or  PKD2 . Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of  PKD1 , genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting.   Materials and Methods:  Our protocol is based on high-throughput simultaneous sequencing of  PKD1  and  PKD2  after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD.   Results and Discussion:  We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in  PKD1 , 12% in  PKD2 . Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one,  de novo  variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing.  Among patients without  PKD1 / PKD2  variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in  PKHD1 , confirming the overlap between recessive and dominant PKD, and two patients with variants in  ALG8  and  PRKCSH , respectively.  Genotype-phenotype correlations showed that patients with  PKD1  variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with  PKD1  non-truncating (NT) mutations and >13 years earlier than patients with  PKD2  mutations. ADPKD- PKD1  T  cases showed a disease onset significantly earlier than ADPKD- PKD1  NT  and ADPK- PKD2 , as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions.

frontiers in genetics

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families