Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease

Abstract

Importance: Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression.

Objective: To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort.

Design, setting, and participants: This retrospective observational study used an unselected health system-based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review.

Exposures: Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2.

Main outcomes and measures: Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease.

Results: Of 174 172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P < .001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign.

Conclusions and relevance: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.

Figure 1.. Study Flow and Penetrance of PKD1 and PKD2 Variants

Evaluation of 174 172 patients with exome sequencing revealed loss-of-function variants in PKD1 and PKD2 or in-frame deletions and missense variants in PKD1 and PKD2 classified as likely pathogenic in the Mayo PKD database. ADPKD indicates autosomal dominant polycystic kidney disease; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. ^aThere is overlap of 131 individuals in both the genotype-first and the phenotype-first analyses. ^bADPKD diagnosis defined as having 1 or more of the following ICD-9 or ICD-10 codes in electronic health record: Q61.2, Q61.3, 753.12, or 753.13. ^cSee Figure 2 and Figure 3 for details. ^dClassified as likely pathogenic in the Mayo PKD database. ^eChart review by radiologist and nephrologist.

Figure 2.. Prevalence, Phenotypic Spectrum, and Genetic Determinants of Autosomal Dominant Polycystic Kidney Disease

This sunburst plot illustrates genotypic and phenotypic details of 303 patients with autosomal dominant polycystic kidney disease (ADPKD) based on International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes from an overall population of 174 172 individuals with exome sequencing. CNV indicates copy number variation; VUS, variants of uncertain significance. ^aOf the 26 participants with other kidney diseases, 6 had autosomal recessive polycystic kidney disease, 2 had tuberous sclerosis, 2 had congenital abnormalities of kidney and urinary tract, 2 had 17q12 syndrome, 4 had a family history of ADPKD but no clear evidence of disease, and 10 had a few kidney cysts not meeting criteria for ADPKD. ^bTypical imaging phenotype was defined as bilateral and diffuse distribution of cysts with moderate or severe replacement of kidney tissue by cysts. Mild imaging phenotype was defined as bilateral and diffuse but with mild replacement of kidney tissue by cysts. Atypical imaging phenotype included cystic involvement that was not symmetric, nondiffuse, or accompanied by kidney atrophy (see Methods section of text). ^cIndividuals with atypical or mild ADPKD are much less likely to have a potential variant identified as a contributor to ADPKD, with 11 of 23 atypical cases and 11 of 17 mild cases having a potential genetic cause. Among these, few had PKD1 or PKD2 protein-truncating or likely pathogenic variants. The majority had novel variants in PKD1, PKD2, or other genes associated with cystic kidney or liver disease. ^dAmong 195 individuals with typical ADPKD, 120 had a PKD1 variant, 30 had a PKD2 variant, and 8 had a variant in another cystic gene. No genetic variant was found in the remaining 37 patients.

Figure 3.. Genetic and Phenotypic Heterogeneity in Confirmed ADPKD Cases

A, Examples: left, a patient with a PKD1 truncating variant (Glu1061Ter) with coronal image in a noncontrast computed tomographic (CT) scan, demonstrating innumerable cortical kidney cysts bilaterally, which enlarge the kidneys and replace the normal kidney parenchyma, consistent with typical ADPKD. Family pedigree shows segregation of ADPKD among members with available genetic and clinical data. Middle, likely pathogenic PKD1 missense variant (Arg3719Gln) carrier in which coronal image from a contrast-enhanced CT scan shows innumerable cortical kidney cysts bilaterally, which enlarge the kidneys and replace the normal kidney parenchyma, consistent with typical ADPKD. Family pedigree shows ADPKD among variant carriers. Right, a carrier of PKD1 (Ala2511Pro), which was been previously classified as likely benign by the Mayo PKD database and variants of uncertain significance by VarSome, in which coronal image from a noncontrast CT scan shows innumerable cortical kidney cysts bilaterally, which enlarge the kidneys and replace the normal kidney parenchyma, consistent with typical ADPKD. In PKD1 or PKD2 variants that were previously unreported or had been classified as benign or variants of uncertain significance, family pedigrees were examined when possible. PKD1 (Ala2511Pro) clearly segregates with ADPKD in pedigree analysis. B, Individuals with atypical or mild ADPKD are much less likely to have a potential variant identified as a contributor to their ADPKD, with only over half of each group being genetically resolved. Among these, few had PKD1 or PKD2 loss of function or likely pathogenic variants, while the majority had novel variants in PKD1, PKD2, or other genes related to cystic kidney disease, including a previously unreported GANAB Asp647Val variant that co-segregates with ADPKD in pedigree analyses. C, Pedigree analysis of 1 family of GANAB (Asp647Val) carriers. The image on the left is a coronal image from a contrast-enhanced CT scan demonstrating relatively mild replacement of kidney parenchyma with a minority of cysts accounting for more than half of the enlarged total kidney volume, consistent with the lopsided subtype of atypical ADPKD. The image on the right is a coronal image from a noncontrast CT scan demonstrating relatively few cortical kidney cysts bilaterally with minimal replacement of the normal kidney parenchyma, consistent with mild ADPKD.