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 and 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 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 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 or mutation (15 of 34), asymmetric and PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable or mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic and mutations. Furthermore, mutations of a newly identified gene for ADPKD, , and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.

ADPKD Progression in Patients With No Apparent Family History and No Mutation Detected by Sanger Sequencing

“…Unlike Reed et al 1 and Iliuta et al, 3 we were unable to examine the parents of our trial participants. In a recent study, after extensive investigation of the parents of 209 patients with PKD, there were 58 FH − patients: 32 (15.3%) had a de novo mutation, 22 (10.5%) still had indeterminate family history, and 4 (1.9%) had an FH + in retrospect.…”

“…Among patients with a clinical and imaging-based diagnosis of autosomal dominant polycystic kidney disease (ADPKD), a negative family history for ADPKD (FH − ) has been reported in 10% 1 and 14.2% 2 (this proportion is 27.8% in a broader PKD population 3 ). Clinical reasons for an FH − are unavailable information about the biological parents and undiagnosed mild or variable ADPKD associated with de novo mutations.…”

“…Clinical reasons for an FH − are unavailable information about the biological parents and undiagnosed mild or variable ADPKD associated with de novo mutations. 1–3 The genetic causes for clinically variable ADPKD include locus heterogeneity ( PKD1, PKD2 , and GANAB ), allelic heterogeneity (truncating and non-truncating mutations), hypomorphic alleles, mosaicism, modifier genes, and rare combinations of these. 4–7 In 5% to 10% of patients with apparent ADPKD, no mutation is detected (NMD).…”

Genotype-Clinical Correlations in Polycystic Kidney Disease with No Apparent Family History

“…It was reported that PKD1 or PKD2 mutation is found in 95.3% of ADPKD patients with a positive family history versus 55.5% of PKD patients without an apparent family history [3]. We previously identified PKD1 or PKD2 mutation in 60.4% of PKD patients without an apparent family history [5].…”

“…Two genes causing ADPKD have been identified, and it has been reported that 85% of patients have a mutation of polycystic kidney disease 1 (PKD1) gene (ch 16p13.3, 46 exons), while 15% have a mutation of PKD2 gene (ch 4q21, 15 exons) [2]. When making a diagnosis of ADP-KD, a family history of PKD and the number of renal cysts on imaging are important factors, but it was reported that about 25% of PKD patients do not have an apparent family history [3]. Apart from ADPKD, there are many other diseases that cause the development of numerous cysts in the kidneys, including autosomal recessive PKD (ARP-KD), nephronophthisis (NPHP), oral-facial-digital syndrome.…”