Autosomal Recessive Polycystic Kidney Disease: PKHD1 Gene Sequencing

Condition Description

The majority of individuals with autosomal recessive polycystic kidney disease (ARPKD) present in the neonatal period with enlarged echogenic kidneys. Clinical diagnostic criteria of autosomal recessive polycystic kidney disease (ARPKD) are:

Typical findings on renal imaging


One or more of the following:

  • Clinical/laboratory signs of hepatic fibrosis that leads to portal hypertension and may be manifested by hepato-splenomegaly and/or esophageal varices
  • Hepatic pathology demonstrating a developmental ductal plate abnormality
  • Absence of renal cysts in both parents, as demonstrated by ultrasound examination
  • Pathoanatomical proof of ARPKD in an affected sib
  • Parental consanguinity suggesting autosomal recessive inheritance

At initial presentation, approximately 45% of infants have liver abnormalities, including hepatomegaly, dilated intrahepatic biliary ducts, and increased echogenicity. Pulmonary hypoplasia resulting from oligohydramnios occurs in a number of affected infants. Approximately 30% of affected neonates die, primarily of respiratory insufficiency. More than 50% of affected children progress to end-stage renal disease (ESRD), usually in the first decade of life. With neonatal respiratory support and renal replacement therapies, the ten-year survival of those who live beyond the first year of life has improved to 82%. Fifteen-year survival is estimated to be 67%-79%. A minority of individuals present as older children, usually with hepatosplenomegaly as the presenting feature.

PKHD1 (6p21.1-p12) is the only gene known to be associated with ARPKD. Mutation detection rates for sequence analysis of the coding region and flanking intronic regions have not been reported; they are expected to be as high or higher than those reported for mutation scanning analyses. Mutation scanning by denaturing high-performance liquid chromatography (DHPLC) has demonstrated an overall mutation detection rate of 82%-85% when diagnostic criteria of ARPKD are met either prenatally or postnatally.

The incidence of ARPKD is estimated at 1:10,000 to 1:40,000. The true incidence may be underestimated because children may die in the neonatal period without a definitive diagnosis, and previously undetected young adults are being diagnosed by molecular genetic testing. The carrier frequency for a PKHD1 mutation in the general population is estimated to be 1:70.

For patients with suspected ARPKD, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

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Genes (1)

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This test is indicated for:

  • Confirmation of a clinical diagnosis of ARPKD
  • Carrier testing in adults with a family history of ARPKD


Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.


Clinical Sensitivity: Approximately 85% or higher when diagnostic criteria of ARPKD are met either prenatally or postnatally. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the PKHD1 gene by CGH array is available for those individuals in whom sequence analysis is negative (WG).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

How to Order

Requisition Forms