POS-419 GENOTYPE-PHENOTYPE CORRELATIONS OF PREDICTED LOSS OF FUNCTION MUTATIONS IN ATYPICAL ADPKD GENES

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) are mostly caused by mutations in PKD1 and PKD2, but could also be a result of mutations in ALG8, ALG9, GANAB, LRP5, PKHD1, PRKCSH, and SEC63. However, the penetrance and expressivity of mutations in these atypical ADPKD genes has been largely unexplored. To better understand their impact, we used whole exome sequencing (WES) data in an electronic health record (EHR)-based research cohort to evaluate the phenotypic spectrum of rare predicted loss of function (pLOF) mutations in atypical ADPKD genes. We used data from 135,947 adults in the Geisinger MyCode™ Community Health Initiative study with WES data available. Participants with rare (minor allele frequency <0.0001) pLOF variants (start-loss, frameshift or early termination/stop-gain) of the atypical ADPKD genes were included in this study. ADPKD-associated International Classification Diseases (ICD) codes were examined for polycystic kidney disease (Q61.2, Q61.3, 753.13, 753.12), any kidney cyst-related ICD code (Q61.2, Q61.3, 753.13, 753.12, N28.1, 593.2, Q61.9, 753.10), liver cystic disease (Q44.6, 573.8, 751.61), and end-stage kidney disease (ESKD) (585.6, V45.11, V56.0, V56.8, V45.12, V56.31, V56.32, N18.6, Z99.2, Z94.0, T86.19, T85.71XA, Z49.31, T86.11, Z91.15, E13.22, Z49.32). To ascertain potential under-classification using ICD codes, chart reviews were performed by at least 1 nephrologist on all DNAJB11, ALG9, and GANAB carriers with available EHR data. Corresponding data for PKD2 carriers were examined for comparison. Out of 135,947 adults, there were a total of 585 carriers of atypical ADPKD pLOF mutations (77 ALG8, 20 ALG9, 13 DNAJB11, 14 GANAB, 98 LRP5, 279 PKHD1, 44 PRKSCH, 40 SEC63). Prevalence of ADPKD by ICD code for carriers of atypical ADPKD pLOF mutations was 7-8% for DNAJB11 and GANAB, and 0-1% for ALG8, ALG9, LRP5, PKHD1, PRKSCH, and SEC63. Prevalence of any kidney cyst-related ICD code was 31% for DNAJB11; 11-15% for ALG8, ALG9, GANAB, and PRKCSH; 6-8% for LRP5, PKHD1, and SEC63. Prevalence of liver cyst ICD code was 10-13% for SEC63 and ALG9; 7-8% for GANAB and DNAJB11; 1-4% for ALG8, LRP5, PKHD1, and PRKCSH. Prevalence of ESKD ICD code was 5-10% for ALG9, DNAJB11, and SEC63; 0-4% for ALG8, GANAB, LRP5, PKHD1, and PRKCSH. In chart reviews of patients with sufficient imaging data, prevalence of bilateral kidney cysts was: 64% for ALG9, 56% for DNAJB11, and 20% for GANAB whereas prevalence of bilateral kidney cysts or hypodense lesions too small to characterize was 73% for ALG9, 78% for DNAJB11, and 40% for GANAB. By comparison, among PKD2 pLOF carriers, 93% had bilateral kidney cysts, 78% had ADPKD ICD code, 81% had any kidney cyst-related ICD code, 19% had liver cystic ICD code, and 26% had ESKD ICD code. Carriers of rare pLOF mutations in atypical ADPKD genes commonly cause kidney cysts and nephrolithiasis. The penetrance of ADPKD-related diagnoses was highest for PKD2, intermediate for ALG9 and DNAJB11, and lower for GANAB, LRP5, PKHD1, PRKSCH, and SEC63. These findings demonstrate the value of genetic testing in improving our understanding of prognosis of polycystic kidney and liver diseases with potential screening and management implications.