Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Abstract

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.

Novel association of familial testicular germ cell tumor and autosomal dominant polycystic kidney disease with PKD1 mutation

“…9 Frameshift, missense, nonsense, splicing, insertion, and rearrangement mutations have all been identified. 10 Specifically, a variant in the same splice acceptor we identified, c.1723-2A>C, has been previously reported as a cause of ADPKD, supporting this newly identified variant is also pathogenic.…”

Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases

“…However, the consequences of employing such a patient as a kidney donor in terms of their long-term renal function is unknown; these patients can have clinically significant extrarenal complications themselves or in offspring, such as PLD in GANAB, 15,20 and evidence that biallelic disease, the coincidence of a ULP PKD1 allele in trans with a fully inactivating PKD1 allele, can result in early onset PKD (see later section), suggests that obtaining a firm diagnosis is important. 4,[41][42][43][44][45]…”

“…62 Conversely, early diagnosis can be secondary to early symptoms, with "symptomatic" children diagnosed in utero or during childhood at risk of early hypertension, urologic events, reduced eGFR, and ESRD. [4][5][6]63,64 We propose to use the term ADPKD VEO when the diagnosis is made in utero or before 18 months, and ADPKD EO when the diagnosis is made before 15 years, in both cases excluding asymptomatic individuals diagnosed by systematic familial screening or incidentally (see Table 3 for proposed diagnosis criteria).…”

“…1 Whereas half of affected individuals reach ESRD by approximately 60 years, 2,3 ,1% of patients exhibit very early onset (VEO) disease, with a diagnosis made in utero or during infancy. [4][5][6] At the other end of the spectrum, patients can live a normal lifespan without requiring RRT. Most patients with ADPKD develop liver cysts as they age, with severe Polycystic liver disease (PLD) requiring surgical intervention occurring in a small minority of patients.…”

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease

“…Studies of atypical ADPKD patients homozygous (or compound heterozygous) for PKD1 missense mutations or patients with early-onset ADPKD with a truncating and likely hypomorphic allele (or two hypomorphic alleles) in trans also indicate the presence of hypomorphic PKD1 alleles. [12][13][14][15] Large ADPKD populations with mainly typical renal phenotypes and a wealth of clinical, imaging, and genetic data are now available from observational and clinical trials that can facilitate genotype-phenotype studies. Here, we describe genotype-phenotype and sex studies of patients without ESRD from the HALT PKD Clinical Trial and the Consortium of Radiologic Imaging Study of Polycystic Kidney Disease (CRISP) Observational Study, with a focus on the significance of PKD1 allelic effects.…”