Polycystic Kidney Disease without an Apparent Family History

Abstract

The absence of a positive family history (PFH) in 10%-25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive <i>PKD1</i> and <i>PKD2</i> mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status. Subsequent reclassification of 209 analyzed patients revealed 72.2% (151 of 209) with a PFH, 15.3% (32 of 209) with <i>de novo</i> disease, 10.5% (22 of 209) with an indeterminate family history, and 1.9% (four of 209) with PFH in retrospect. Among the patients with <i>de novo</i> cases, we found two families with germline mosaicism and one family with somatic mosaicism. Additionally, analysis of renal imaging revealed that 16.3% (34 of 209) of patients displayed atypical PKD, most of which followed one of three patterns: asymmetric or focal PKD with PFH and an identified <i>PKD1</i> or <i>PKD2</i> mutation (15 of 34), asymmetric and <i>de novo</i> PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable <i>PKD1</i> or <i>PKD2</i> mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to <i>de novo</i> disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic <i>PKD1</i> and <i>PKD2</i> mutations. Furthermore, mutations of a newly identified gene for ADPKD, <i>GANAB</i>, and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.