Test Catalog

Test ID: ARPKZ    
Autosomal Recessive Polycystic Kidney Disease (ARPKD), Full Gene Analysis, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosis of individuals suspected of having autosomal recessive polycystic kidney disease (ARPKD)

 

Prenatal diagnosis if there is a high suspicion of ARPKD based on ultrasound findings

 

Carrier testing of individuals with a family history of ARPKD but an affected individual is not available for testing or disease-causing mutations have not been identified

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing to evaluate for mutations in the PKHD1 gene. Sanger sequencing may be performed to confirm detected variants.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added and charged separately. If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture for genetic test will be added and charged separately. For any prenatal specimen that is received, maternal cell contamination studies will be added.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Autosomal recessive polycystic kidney disease (ARPKD) is a disorder caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene. The incidence of ARPKD is approximately 1:20,000 and the estimated carrier frequency in the general population is 1:70. ARPKD is characterized by enlarged echogenic kidneys, congenital hepatic fibrosis, and pulmonary hypoplasia (secondary to oligohydramnios [insufficient volume of amniotic fluid] in utero). Most individuals with ARPKD present during the neonatal period and, of those, nearly one-third die of respiratory insufficiency. Early diagnosis, in addition to initiation of renal replacement therapy (dialysis or transplantation) and respiratory support, increases the 10-year survival rate significantly. Presenting symptoms include bilateral palpable flank masses in infants and subsequent observation of typical findings on renal ultrasound, often within the clinical context of hypertension and prenatal oligohydramnios. In rarer cases, individuals may present during childhood or adulthood with hepatosplenomegaly. Of those who survive the neonatal period, one-third progress to end-stage renal disease and up to one-half develop chronic renal insufficiency.

 

The PKHD1 gene maps to 6p12 and includes 67 exons. The PKHD1 gene encodes a protein called fibrocystin, which is localized to the primary cilia and basal body of renal tubular and biliary epithelial cells. Because ARPKD is an autosomal recessive disease, affected individuals must carry 2 deleterious mutations within the PKHD1 gene. Although disease penetrance is 100%, intrafamilial variation in disease severity has been observed. Mutation detection is often difficult due to the large gene size and the prevalence of private mutations that span the entire length of the gene.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of autosomal recessive polycystic kidney disease (ARPKD) may have a mutation that is not identified by this method (eg, large genomic deletions/duplications, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of ARPKD. For carrier testing, it is important to first document the presence of a polycystic kidney and hepatic disease 1 (PKHD1) gene mutation in an affected family member.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

 

Technical limitations:

In some cases, DNA variants of undetermined significance may be identified.

 

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

Evaluation tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.

 

Unless reported or predicted to cause disease, alterations in protein coding genes that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely pathogenic alterations or variants of uncertain significance that have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. Guay-Woodford LM, Desmond RA: Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 2003;111:1072-1080

3. Guay-Woodford LM, Bissler JJ, Braun MC, et al: Consensus Expert Recommendations for the Diagnosis and Management of Autosomal Recessive Polycystic Kidney Disease: Report of an International Conference. J. Pediatr. 2014 Sep;165(3):611-617

4. Gunay-Aygun M, Avner E, Bacallao RL, et al: Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr 2006;149:159-164

5. Harris PC, Rossetti S: Molecular genetics of autosomal recessive polycystic kidney disease. Mol Genet Metab 2004;81:75-85

Special Instructions Library of PDFs including pertinent information and forms related to the test