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 PKD1 and PKD2 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 de novo 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 de novo 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 PKD1 or PKD2 mutation (15 of 34), asymmetric and de novo PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable PKD1 or PKD2 mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to de novo disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic PKD1 and PKD2 mutations. Furthermore, mutations of a newly identified gene for ADPKD, GANAB, and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.

Keywords: family history; human genetics; polycystic kidney disease.

Figure 1.

The distribution of mutation classes in study patients differs according to their family history classification. DND, de novo disease; IFH, indeterminate family history; NMD, no mutations detected; non-PT PKD1, nontruncating PKD1 mutations; PFH, positive family history; PFHR, positive family history in retrospect; PKD2, PKD2 mutations; PT PKD1, protein-truncating PKD1 mutations.

Figure 2.

Flowchart of systematic imaging review of the TGESP cohort. The study subjects were classified into subgroups with a positive or apparently negative family history and typical or atypical PKD.

Figure 3.

Representative images of three patients with asymmetric PKD. (A and B) Coronal and axial enhanced CT images depicting almost complete replacement of an enlarged right kidney by numerous cysts. (C and D) Coronal and axial T2-weighted MRI images show normal-sized kidneys. Cystic disease is predominantly within the right kidney and liver. (E and F) Coronal and axial T2-weighted MRI images reveal an enlarged left kidney with numerous cysts. In each patient, the contralateral kidney contained significantly fewer cysts and was of normal size.

Figure 4.

Examples of atypical PKD identified by renal imaging. Coronal MR images of three patients with (A and B) focal and (C) asymmetric PKD. (A) A 58-year-old man with a positive family history of kidney cysts in two brothers. He had multiple cysts (more than ten per kidney) bilaterally and enlarged kidneys from several large to very large cysts. His total kidney volume measured 3.63 L. He was screened negative for PKD1 and PKD2 mutations. (B) A 57-year-old man with negative family history of PKD presented with incidental findings of focal bilateral renal cysts (>20 cysts in each kidney) and normal kidney function. He was screened negative for PKD1 and PKD2 mutations. (C and D) Coronal and axial MR images of a 55 year old man with incidental findings of unilateral PKD (>50 cysts in his left kidney). He was mutation negative with an unconfirmed possible family history of renal cysts in his 83-year-old father.

Figure 5.

Examples of germline mosaicism. (A) TOR186 is a pedigree with proven germline mosaicism. Two members (II:3 and II:4) inherited the same pathogenic PKD1 mutation (c.7666C>T; p.Q2556X) from their apparently unaffected parents. (B) TOR109 is a pedigree with suspected germline mosaicism with no detectable PKD1 or PKD2 mutation. U/S, ultrasound scan.

Figure 6.

An example of PKD1 somatic mosaicism. (A) A pedigree (TOR135) with somatic mosaicism and germline disease transmission. (B) MRI shows asymmetric PKD in the affected mother with somatic mosaicism. (C) Sanger sequencing showing a 1-bp PKD1 frameshift deletion (c.2605delC; p.R869FS28X) unequivocally in the daughter (D) but not in the mother (M). (D) Quantitative analysis by capillary electrophoresis of the PCR product encompassing the PKD1 mutation site shows that the ratio of mutant to normal alleles is approximately 1:1 in the daughter (D) but only approximately 1:10 the mother (M).