Comprehensive Test (PKD1/PKDS)                                                                      


Mendelian Inheritance in Man number: *606702

Click here for Gene Reviews Clinical Summary.

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is characterized by enlarged cystic kidneys and hepatic fibrosis. The diagnosis is often made pre- or neonatally, but some patients are still diagnosed later in life. The severity varies widely, with a high mortality rate in the first months of life. ARPKD is one of the more common hereditary childhood nephropathies with an estimated incidence of 1:20,000-1:40,000. The carrier frequency in the general population is estimated to be 1 in 70 to 1 in 100. Mutations in PKHD1 are scattered throughout the gene. Most families carry their own “private” mutations. For more information on the condition please refer to the review on the GeneTests website and Online Mendelian Inheritance in Man.

Genetics of ARPKD

The gene for ARPKD, PKHD1 (Polycystic Kidney and Hepatic Disease 1), resides on chromosome 6p21-p12, spans 470 kb of genomic DNA and is the only gene known to be associated with the wide clinical spectrum of autosomal recessive polycystic kidney disease. 86 exons have been identified and multiple alternative transcripts are known. Over 300 mutations have been reported. Missense, nonsense, frameshift, splicing and multi-exon deletions can occur and the mutations are located throughout the length of the gene, with no major mutational hotspots known, as shown in the PKHD1 mutation database


  • Diagnostic testing: confirmation of diagnosis by direct sequence analysis of longest open reading frame in patients with symptoms indicative/suspicious of a diagnosis of ARPKD;
  • Carrier testing by direct sequence analysis of longest open reading frame in partners of known PKHD1 carriers.


By amplification and bidirectional sequencing of all exons constituting the longest open reading frame of the PKHD1 gene and copy number analysis, our group has identified mutations in >82% of alleles of patients with confirmed clinical diagnosis of ARPKD. [Sharp et al 2005 J Med Genet, Zvereff et al 2010 Genet Test Mol Biomarkers] Hence, in ~96% of families, at least one mutation is identified after bidirectional sequencing of all exons constituting the longest open reading frame.

We offer a three tiered approach to testing. First (Tiers 1 & 2), comprehensive bidirectional sequencing is performed for the 67 exons within the longest open reading frame of the PKHD1 gene. Approximately 80% of the 82% (or ~65% total) of identifiable pathogenic mutations detectable by Sanger sequencing can be found in 23 common exons. These 23 exons are exons are 3, 5, 9, 14, 16, 20, 21, 22, 30, 32-34, 36, 37, 39, 43, 50, 54, 55, 57-59 and 61. If 2 clear-cut pathogenic mutations are found in these exons, testing will be charged at a reduced rate for tier 1 only; please see the billing section for additional information. As Tier 1 identifies ~65% of all pathogenic sequencing mutations on each allele of the PKHD1 gene, the likelihood of finding two mutations in a proband in Tier 1 is only ~42% (or 65 x 65%). Therefore we automatically reflex to Tier 2 for all patients where tier 1 is not fully informative.


. Complete sequence analysis (Tiers 1 and 2) provides a detection rate of ~82% for mutations in each allele of the PKHD1 gene, making the likelihood of finding at least one mutation in the proband ~96%, and the likelihood of finding two mutations in the proband >67% (82 x 82%).

In 2009, a publication by Michel-Calemard et. al described a deep intronic splicing mutation that was determined to be a French found mutation: IVS46+653 A>G. This mutation has been added to the complete sequence analysis option (Tiers 1 & 2), and would be missed by gDNA based sequencing of all exons and splice donor/acceptor sequences only.    

If less than two clearly pathogenic mutations are identified after complete sequencing analysis, copy number analysis of the PKHD1 gene by MLPA is recommended as the next step (Tier 3).  Copy number analysis by MLPA will detect deletions/duplications of one or multiple exons [Zvereff et al 2010 Genet Test Mol Biomarkers].  Multiexon deletions/duplications have been identified in approximately 2% in the cohorts studied thus far. Inclusion of MLPA analysis will increase the overall detection rate for PKHD1 mutations to >84%.

If 2 pathogenic mutations are identified in the proband, parental testing is mandatory to determine that the mutations reside on two different alleles.  Parental testing is performed free of charge, if parental samples are submitted the same week as the sample of the proband. 

If only 1 clearly pathogenic mutation is identified in a proband with clinically evident ARPKD (as per pathology report and completed phenotypic checklist), additional haplotype testing can be performed, which will allow prenatal testing in the future, if desired.


We require either a minimum of 5 milliliters of whole EDTA blood (diagnostic or carrier testing) or a biopsy fragment from skin/liver/spleen (fresh or frozen) or cultured cells (diagnostic testing).

For those families with no family history of ARPKD that have a fetus suspected to have ARPKD based on ultrasound results, we can perform comprehensive analysis starting from T25 flasks of either cultured CVS or cultured amniocytes (>70% confluent), sent at ambient temperature.  Please also send 1-5 ml of blood or buccal swab sample from the mother for maternal contamination studies.

Please contact the lab prior to amniocentesis or chorion villi sampling if you wish to pursue comprehensive analysis starting from a fetal sample.


If the specimen is from clinics within UAB or Kirklin Clinic, please call 934-5562 for pickup.  If specimens are being sent from some other location, please ship via UPS or Federal Express.

1. Be sure that the shipping air bill is marked “Priority”, either Domestic or International.
2. Specimens must be packaged to prevent breakage and absorbent material must be included in the package to absorb liquids in the event that breakage occurs.  Also, the package must be shipped in double watertight containers (e.g. a specimen pouch + the shipping companies Diagnostic Envelope). You can use our collection kits, which we will send to physicians directly upon request.
3.   Please contact us (Email –, Phone – 205-934-5562) prior to sample shipment and provide us with the date of shipment and the tracking number of the package, so that we can better ensure receipt of the samples


Normal service: 20 working days

RUSH testing: 8 working days.  No RUSH testing is currently available for copy number analysis (Tier 3).



Please find the most up to date prices and CPT codes for our testing services under the "Prices" tab of this website.


ARPKD Test Requisition including the phenotypic data form.

Note: Detailed and accurate completion of this document is necessary for reporting purposes. The Medical Genomics Laboratory issues its clinical reports based on the demographic data provided by the referring institution on the lab requisition form. It is the responsibility of the referring institution to provide accurate information. If an amended report is necessary due to inaccurate or illegible documentation, additional reports will be drafted with charge.  

Requests for Molecular Genetic testing for ARPKD will not be accepted for the following reasons:

  • No label (patients full name and date of collection) on the specimens
  • No referring physician’s or genetic counselor’s names and addresses
  • No billing information
  • No informed consent
  • No phenotypic checklist

For more information, test requisition forms, or sample collection and mailing kits, please call: 205-934-5562.


Bergmann C, Senderek J, Kupper F, Schneider F, Dornia C, Windelen E, Eggermann T, Rudnik-Schoneborn S, Kirfel J, Furu L, Onuchic LF, Rossetti S, Harris PC, Somlo S, Guay-Woodford L, Germino GG, Moser M, Buttner R, Zerres K. (2004) PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD).  Hum Mutat. 2004 May;23(5):453-63 (pubmed)

Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, Somlo S, Germino GG, Guay-Woodford LM. (2005). Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J. Med. Genet. Apr; 42(4): 336-49. (pubmed)

Zerres K, Rudnik-Schoneborn S, Senderek J, Eggermann T, Bergmann C. (2003) Autosomal recessive polycystic kidney disease (ARPKD). J Nephrol. 2003 May-Jun;16(3):453-8. (pubmed)

Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Kunze J, Mononen T, Kaariainen H, Kirfel J, Moser M, Buettner R, Bergmann C. (2004) New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene. Clin Genet. 2004 Jul;66(1):53-7. (pubmed)

Zvereff V, Yao S, Ramsey J, Mikhail FM, Vijzelaar R, Messiaen L (2010) Identification of PKHD1 multiexon deletions using multiplex ligation-dependent probe amplification and quantitative polymerase chain reaction.  Genet Test Mol Biomarkers.  2010 Aug;14(4):505-10.  (pubmed)