Genotype–Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease

Abstract

The phenotypes that are associated with the common forms of polycystic kidney disease (PKD)-autosomal dominant (ADPKD) and autosomal recessive (ARPKD)-are highly variable in penetrance. This is in terms of severity of renal disease, which can range from neonatal death to adequate function into old age, characteristics of the liver disease, and other extrarenal manifestations in ADPKD. Influences of the germline mutation are at the genic and allelic levels, but intrafamilial variability indicates that genetic background and environmental factors are also key. In ADPKD, the gene involved, PKD1 or PKD2, is a major factor, with ESRD occurring 20 yr later in PKD2. Mutation position may also be significant, especially in terms of the likelihood of vascular events, with 5 mutations most detrimental. Variance component analysis in ADPKD populations indicates that genetic modifiers are important, but few such factors (beyond co-inheritance of a TSC2 mutation) have been identified. Hormonal influences, especially associated with more severe liver disease in female individuals, indicate a role for nongenetic factors. In ARPKD, the combination of mutations is critical to the phenotypic outcome. Patients with two truncating mutations have a lethal phenotype, whereas the presence of at least one missense change can be compatible with life, indicating that many missense changes are hypomorphic alleles that generate partially functional protein. Clues from animal models and other forms of PKD highlight potential modifiers. The information that is now available on both genes is of considerable prognostic value with the prospects from the ongoing genetic revolution that additional risk factors will be revealed.

LRP5 variants may contribute to ADPKD

“…5,6 The genotype-phenotype correlation is not completely understood in ADPKD. 7 Linkage studies identified two disease-causing genes, Polycystic Kidney Disease 1 protein (PKD1; Chr.16p13.3; NG_ 008617.1) and Polycystic Kidney Disease 2 protein (PKD2; Chr.4q22.1; NG_008604.1). 8,9 Molecular screening may confirm the clinical diagnosis with a mutation frequency of 76% PKD1 and 13% PKD2.…”

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

“…In addition, several other extrarenal manifestations occur less frequently but can be observed at any age and disease stage [2,4,5]. The variability of organ involvement in ARPKD is not completely understood [6,7]; however, different combinations of mutations in the fibrocystin gene PKHD1 and its resulting changes in the fibrocystin/polyductin protein structure may at least partially explain the phenotypic variance [7,8]. It is widely recognized and corroborated by intrafamilial clinical variability among affected siblings that resulting ARPKD phenotypes frequently cannot be simply explained on the basis of the PKHD1 genotype.…”

“…It is widely recognized and corroborated by intrafamilial clinical variability among affected siblings that resulting ARPKD phenotypes frequently cannot be simply explained on the basis of the PKHD1 genotype. Phenotypes may also depend on the background of other genes, combinations of mutations or diseasemodifying genes, epigenetic factors, hormonal effects, and environmental influences [6,7,9]. However, severe phenotypes, such as neonatal demise, are more often associated with chain-terminating, truncating PKHD1 mutations than with moderate phenotypes, and the presence of two chainterminating mutations invariably results in perinatal lethality [8,10].…”

Clinical Study on Autosomal Dominant Polycystic Kidney Disease among South Indians

“…Polycystic kidney disease is broadly divided into 2 forms, autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) [4][5][6][7][8]. The diseases are caused by mutation either in PKD1 (85%) or PKD2 (15%) and PKD3 (rare) genes [7][8][9][10][11][12].…”