Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases

Abstract

Data indicate significant phenotypic and genotypic overlap, plus a common pathogenesis, between two groups of inherited disorders, autosomal dominant polycystic kidney diseases (ADPKD), a significant cause of ESRD, and autosomal dominant polycystic liver diseases (ADPLD), which result in significant PLD with minimal PKD. Eight genes have been associated with ADPKD (PKD1 and PKD2), ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B), or both (GANAB). Although genetics is only infrequently used for diagnosing these diseases and prognosing the associated outcomes, its value is beginning to be appreciated, and the genomics revolution promises more reliable and less expensive molecular diagnostic tools for these diseases. We therefore propose categorization of patients with a phenotypic and genotypic descriptor that will clarify etiology, provide prognostic information, and better describe atypical cases. In genetically defined cases, the designation would include the disease and gene names, with allelic (truncating/nontruncating) information included for PKD1 Recent data have shown that biallelic disease including at least one weak ADPKD allele is a significant cause of symptomatic, very early onset ADPKD. Including a genic (and allelic) descriptor with the disease name will provide outcome clues, guide treatment, and aid prevalence estimates.

Keywords: ADPKD; cystic kidney; liver cysts; polycystic kidney disease.

Figure 1.

These eight kidney and liver images illustrate the different genic and allelic forms of ADPKD and ADPLD, and the most frequent differential diagnosis. (A) ADPKD-PKD1^T: MRI of a 45-year-old male patient with a truncating PKD1 mutation (c.4880_4883delATGT; p.Tyr1627fs), who has an eGFR_CKDEPI=15.1 ml/min per 1.73 m² and HtTKV=3853 ml/m. (B) ADPKD-PKD1^NT: MRI of a 55-year-old woman with a PKD1 nontruncating mutation (c.2180T>C, p.Leu727Pro) with well preserved kidney function (eGFR=63.4 ml/min per 1.73 m²) and HtTKV=439 ml/m. Significant PLD is present. (C) ADPKD-PKD2: MRI of a 53-year-old man, with a PKD2 mutation (c.1057G>A, p.Glu353Lys), who has well preserved kidney function (eGFR=68.6 ml/min per 1.73 m²) and HtTKV=1245 ml/m. Note that a few large cysts in the right kidney largely explain the enlarged HtTKV. (D) ADPKD-PKD1 ULP: Contrast-enhanced CT-scan of a 48-year-old woman, with a ULP PKD1 nontruncating mutation (c.9829C>T, p.Arg3277Cys), who has a total of five cysts in the right kidney and one cyst in the left kidney, a normal eGFR, and nonenlarged kidneys. (E) ADPKD-GANAB: CT-scan of 45-year-old woman with a GANAB mutation (c.1914_1915delAG; p.Asp640fs) who has bilateral kidney cysts, a normal eGFR (104 ml/min) and HtTKV (318 ml/m), and without significant PLD. (F) A common differential diagnosis: ADTKD:HNF1B. MRI of 30-year-old woman with a large deletion of the entire HNF1B gene, who has preserved kidney function (75.5 ml/min per 1.73 m²) and approximately ten cysts per kidney (HtTKV=196.9 ml/m). (G) ADPKD-PKD1^NT MRI of 54-year-old woman with severe PLD (HtTLV=4695 ml/min; liver resection performed after this MRI) and normal-sized kidneys, with a total of 12 bilateral small cysts. A PKD1^NT allele was identified (c.3284A>G, p.Tyr1095Cys), with no mutation identified in other ADPLD genes. (H) ADPLD-PRKCSH MRI of a 49-year-old man with predominant PLD (HtTLV=7271 ml/min; liver resection was performed after this MRI) and mild PKD (eight cysts in the left kidney). A right nephrectomy was performed at 42 years (atrophic cystic kidney with suspected malignancy). The PRKCSH (c.1386T>G, p.Tyr462*) mutation was identified. MRI, magnetic resonance imaging; CT, computed tomography.