Patient From Family 2A 4-year-old boy who showed echogenic kidneys and enlarged kidneys at 35 weeks prenatally and who presented with renal cysts soon after birth (Table 1) was referred to the McMaster Children’s Hospital (Hamilton, ON, Canada). His renal function was normal, with an eGFR of 132 (based on the Schwartz formulaS13). On ultrasound, multiple small cortical cysts were seen in both kidneys. The largest cyst measured 13 × 9 × 9 mm in the upper pole of the right kidney and 14 × 13 × 10 mm in the lower pole of the left kidney. The right kidney measured 7.2 × 4.4 cm and the left kidney 7.7 × 3.5 cm, which is within the normal range at this age. There was a mild increase in size compared to 6 months earlier (right kidney: 6.5 × 3.3 cm; left kidney: 7.0 × 3.0 cm), but no hydronephrosis or hydroureter. Corticomedullary differentiation was preserved, and there were no signs of hydronephrosis or hydroureter. In the last 2 years, his ultrasound findings were stable, with mild interval enlargement of the renal cysts and mild interval growth of both kidneys. He continued to grow well. No albuminuria or high blood pressure were reported.The families of both of his parents had been diagnosed with ADPKD (Figure 1). Sanger sequencing of both PKD1 and PKD2 showed that his mother is a carrier of a pathogenic truncating PKD2 mutation in exon 1 c.124_125ins52bp p.(Ala42fs∗66) and his father has a truncating PKD1 mutation in exon 18 c.7288C>T p.(Arg2430∗). The young boy was affected with bilineal inherited disease, that is, carrying the paternal PKD1 truncating mutation and the maternal PKD2 truncating mutation.The father was tested presymptomatically at age 18 years because of a positive family history for ADPKD and turned out to carry the familial PKD1 mutation. At age 31, he showed moderate disease progression, with eGFR 56 ml/min per 1.73 m2 and Ht-TKV of 1246 ml/m (Mayo class 1D). Other affected older relatives of the father reached renal failure between 46 and 50 years of age.His mother was also tested presymptomatically at age 19 years because of a positive family history. She carries the PKD2 mutation. At age 28, ultrasound imaging showed mildly enlarged kidneys with small cysts bilaterally. At age 30, her eGFR was 56 ml/min per 1.73 m2. Both parents showed mild liver cysts. There are multiple older affected relatives of the mother, all having the typical mild disease.Go to:DiscussionHere we describe, for the first time, 2 patients carrying a truncating mutation both in PKD1 and in PKD2. The patient described in case 1 developed ESRD at a young age, and the patient described in case 2 was diagnosed postnatally with cysts in both kidneys. Both patients had rapidly progressive disease that was more severe than that of their family members, who had only 1 mutation. The patient described in case 1 required kidney transplantation at the age of 38 years, which was much earlier compared to his father, who received a kidney transplant at the age of 60 years, as well as when compared to the median age for ESRD in patients with truncating PKD1 mutations of 58 years.2 Of interest, the patient described in case 1 also showed an extreme liver phenotype, suggesting that the combination of mutations also affects the growth of liver cysts.The patient described in case 2 showed early presentation of a few renal cysts, detected postnatally by ultrasound, and at age 4 years, multiple cortical cysts could be seen. It is likely that this patient has a more progressive disease than the parents but data at young age from the parents or other affected relatives are not available. An alternative explanation could be the involvement of yet another gene. Therefore, a gene panel−based Next Generation Sequencing approach was used. Both index cases were analyzed for the presence of variants in a gene panel of 76 genes, postulated to be involved in cystic kidney disease (Supplementary Methods). In case 1, no additional variants were identified; however, in case 2, a heterozygous variant in the VHL gene ({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3 (c.556G>A p.[Glu186Lys]) was identified. There are conflicting interpretations of this variant, either as class 3 or class 4 (Supplementary Methods), and it is unlikely that this variant will have an effect on the phenotype of the patient. The parents have not been screened for this variant.