Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups
Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.
Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-A woman whose father is heterozygous for an ADPKD-causing mutation in PKD1 and whose mother is unaffected has a child with a man with no family history of ADPKD. What is the percent chance that their first child will have ADPKD? (Note: Assume the woman's ADPKD status is unknown.)

Question

Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups

Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.

Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-A woman whose father is heterozygous for an ADPKD-causing mutation in PKD1 and whose mother is unaffected has a child with a man with no family history of ADPKD. What is the percent chance that their first child will have ADPKD? (Note: Assume the woman's ADPKD status is unknown.)

Quizplus · Accepted Answer

11ecba2d_0f91_c9e3_a3bf_e5b7891ba3e4_MD0008_00 Based on the passage, ADPKD is an autosomal dominant disease, signifying that only one copy of a dominant allele is necessary to produce the phenotype. The disease-causing genes, PDK1 and PDK2, are located on autosomal (nonsex) chromosomes and, as a result, each parent transmits one of two gene copies to their child. In the given scenario, let the following be true: For PKD1: A is the dominant mutated allele and a is the recessive wild-type allele For PKD2: _EMEM_ is the dominant mutated allele and b is the recessive wild-type allele The woman's mother is unaffected, and therefore has the genotype aabb. However, the woman's father has ADPKD as he is heterozygous for a dominant PKD1 mutation, so he has the genotype Aabb. For PDK2, each parent contributes a wild-type b allele to the woman, giving her the genotype bb. A heterozygous parent has a 50% chance of transmitting the mutation to his or her offspring. Therefore, for PDK1 the father (Aa) will either transmit the mutant A allele with a 0.5 probability or the wild-type a allele with a 0.5 probability. In contrast, the mother (aa) can only pass on the wild-type a allele to the woman. This woman's genotype will either be aabb (normal) or Aabb (ADPKD). The percent chance that this woman could have an ADPKD-affected child with a man who has no family history of ADPKD (ie, aabb genotype) is given by the probability rule for independent events: P(child with ADPKD) = P(mother inherited A allele from her father) × P(mother passes this A allele to the child) P(child with ADPKD) = (0.5)(0.5) = 0.25, or 25% Educational objective: In autosomal dominant inheritance, transmission of only one copy of a dominant allele is necessary to produce the phenotype. A heterozygous parent has a 50% chance of transmitting the mutation to their offspring.

Passage Autosomal Dominant Polycystic Kidney Disease (ADPKD) Is One of the the Most