Exome sequencing of Saudi Arabian patients with ADPKD

<b>Purpose:</b> Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and enlargement and dysfunction of the kidneys. The Consortium of Radiologic Imaging Studies of the Polycystic Kidney Disease (CRISP) cohort revealed that 89.1% had either a <i>PKD1</i> or <i>PKD2</i> mutation. Of the CRISP patients with a genetic cause detected, mutations in <i>PKD1</i> accounted for 85%, while mutations in the <i>PKD2</i> accounted for the remaining 15%. Here, we report exome sequencing of 16 Saudi patients diagnosed with ADPKD and 16 ethnically matched controls. <b>Methods:</b> Exome sequencing was performed using combinatorial probe-anchor synthesis and improved DNA Nanoballs technology on BGISEQ-500 sequencers (BGI, China) using the BGI Exome V4 (59 Mb) Kit. Identified variants were validated with Sanger sequencing. <b>Results:</b> With the exception of GC-rich exon 1, we obtained excellent coverage of <i>PKD1</i> (mean read depth = 88) including both duplicated and non-duplicated regions. Of nine patients with typical ADPKD presentations (bilateral symmetrical kidney involvement, positive family history, concordant imaging, and kidney function), four had protein truncating <i>PKD1</i> mutations, one had a <i>PKD1</i> missense mutation, and one had a <i>PKD2</i> mutation. These variants have not been previously observed in the Saudi population. In seven clinically diagnosed ADPKD cases but with atypical features, no <i>PKD1</i> or <i>PKD2</i> mutations were identified, but rare predicted pathogenic heterozygous variants were found in cystogenic candidate genes including <i>PKHD1, PKD1L3, EGF, CFTR</i>, and <i>TSC2</i>. <b>Conclusions:</b> Mutations in PKD1 and PKD2 are the most common cause of ADPKD in Saudi patients with typical ADPKD. <b>Abbreviations:</b> ADPKD: Autosomal dominant polycystic kidney disease; <i>CFTR</i>: Cystic fibrosis transmembrane conductance regulator; <i>EGF</i>: Epidermal growth factor; MCIC: Mayo Clinic Imaging Classification; PKD: Polycystic kidney disease; <i>TSC2</i>: Tuberous sclerosis complex 2