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Hereditary Cystic Kidney Diseases Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
ALG5 81479,81479
ALG8 81479,81479
ALG9 81479,81479
ANKS6 81479,81479
BICC1 81479,81479
CEP164 81479,81479
CEP290 81408,81479
CEP83 81479,81479
COL4A1 81408,81479
CRB2 81479,81479
CYS1 81479,81479
DCDC2 81479,81479
DICER1 81479,81479
DNAJB11 81479,81479
DZIP1L 81479,81479
GANAB 81479,81479
GLIS2 81479,81479
HNF1B 81405,81404
IFT140 81479,81479
IFT172 81479,81479
INVS 81479,81479
IQCB1 81479,81479
JAG1 81407,81406
LRP5 81406,81479
MAPKBP1 81479,81479
MUC1 81479,81479
NEK8 81479,81479
NOTCH2 81479,81479
NPHP1 81406,81405
NPHP3 81479,81479
NPHP4 81479,81479
OFD1 81479,81479
PAX2 81406,81479
PKD1 81407,81479
PKD2 81406,81479
PKHD1 81408,81479
PMM2 81479,81479
REN 81479,81479
RPGRIP1L 81479,81479
SDCCAG8 81479,81479
SEC61A1 81479,81479
TMEM67 81407,81479
TSC1 81406,81405
TSC2 81407,81406
TTC21B 81479,81479
UMOD 81406,81479
VHL 81479,81479
WDR19 81479,81479
ZNF423 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10619Genes x (49)81479 81404(x1), 81405(x3), 81406(x8), 81407(x4), 81408(x3), 81479(x79) $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Wuyan Chen, PhD

Clinical Features and Genetics

Clinical Features

Hereditary cystic kidney diseases manifest in children and adults with variable expression of renal cysts as well as unique extra-renal manifestations in each disease. These diseases can be recognized in terms of underlying etiology (ciliopathies or phakomatoses) or morphologic appearance (size, location, and complexity) (Dillman et al. 2017. PubMed ID: 28493804; Bergmann. 2017. PubMed ID: 29479522). In addition to radiological imaging, genetic testing of a panel of relevant genes simultaneously is able to help ensure a conclusive diagnosis.

The kidney ciliopathic disorders primarily include autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), nephronophthi­sis and medullary cystic kidney disease (MCKD). Manifestations in skeletal (Jeune syndrome), central nervous system (CNS) (Meckel-Gruber syndrome and Joubert syndrome) and other internal organs (ADPKD and ARPKD) are well documented. The cysts in renal ciliopathies can be macroscopic (ADPKD) or microscopic (ARPKD, nephronophthi­sis and MCKD).

The phakomatoses comprise a heterogeneous group of hereditary neurocutaneous multi­system disorders. Tissues of ectodermal origin such as CNS, eyes, and skin are commonly affected. Abdominal manifestations are also common in this group of disorders such as renal cystic lesions in patients with tuberous sclerosis complex (TSC) and von Hippel–Lindau syndrome. The cysts in the phakomatoses are generally macroscopic and scattered throughout the kidney(s).

In addition, HNF1B-nephropathy represents a common phenocopy of ARPKD and ADPKD (Bergmann. 2017. PubMed ID: 29479522). Beyond renal cysts, its wide clinical spectrum encompasses diabetes, genital tract malformations, elevated liver enzymes, hyperuricemia and electrolyte disturbances.

Genetics

Hereditary cystic kidney diseases can be categorized into two primary groups in regards of underlying etiology: ciliopathies and the phakomatoses (Dillman et al. 2017. PubMed ID: 28493804).

Ciliopathies represent a group of disorders caused by genetic defects in genes encoding proteins that are involved in formation or function of the primary cilia. The primary cilia are sensory organelles with critical roles in cellular signaling pathways including proliferation and differentiation, cellular motility, and cellular polarity. The kidneys are one of the major affected organs in ciliopathies. Hereditary cystic kidney diseases within this category primarily include ADPKD, ARPKD, nephronophthi­sis and medullary cystic kidney disease (MCKD).

PKD1 and PKD2 are the two major causative genes for ADPKD (Rossetti et al. 2007. PubMed ID: 17582161; Audrézet et al. 2012. PubMed ID: 22508176). Accounting for a small fraction of ADPKD-spectrum cases, defects in the GANAB, DNAJB11, and IFT140 genes result in an atypical (mild) form of ADPKD (Porath et al. 2016. PubMed ID: 27259053; Cornec-Le Gall et al. 2018. PubMed ID: 29706351; Senum et al. 2022. PubMed ID: 34890546).

PKHD1 is the primary causative gene for ARPKD (Bergmann. 2017. PubMed ID: 29479522; Ward et al. 2002. PubMed ID: 11919560). Accounting for a small fraction of genetically positive cases, DZIP1L was newly identified as the second causative gene for ARPKD (Lu et al. 2017. PubMed ID: 28530676; Hartung and Guay-Woodford. 2017. PubMed ID: 28736432).

Nephronophthi­sis is a group of genetically heterogeneous disorders inherited in an autosomal recessive manner (Hildebrandt et al. 2009. PubMed ID: 19118152). To date, defects in at least 20 genes have been reported to cause nephronophthisis (Srivastava et al. 2017. PubMed ID: 29379777).

The causative genes for autosomal dominant medullary cystic kidney disease (MCKD), also known as autosomal dominant tubulointerstitial kidney disease (ADTKD), include HNF1BUMOD, MUC1, REN and SEC61A1 (Cornec-Le Gall et al. 2019. PubMed ID: 30819518; Hart et al. 2002. PubMed ID: 12471200; Kirby et al. 2013. PubMed ID: 23396133). Of note, the HNF1B-related renal disorders, termed HNF1B-nephropathy, have a wide clinical phenotypic spectrum and variable age of onset from in utero to adulthood, including congenital anomalies of the kidney and urinary tract (CAKUT), tubular transport abnormalities, chronic tubulointerstitial and cystic renal disease (Izzi et al. 2020. PubMed ID: 33305128). Around 30–50% of pathogenic HNF1B variants arise de novo. A large deletion (~1.4Mb) including the entire HNF1B gene can be found in ~50% of patients with HNF1B-nephropathy. HNF1B encodes hepatocyte nuclear factor-1-beta, which is the master regulator of a number of polycystic kidney disease genes.

The phakomatoses in this panel include two autosomal dominant disorders: tuberous sclerosis complex (TSC) (with the contiguous gene syndrome caused by a contiguous deletion at PKD1 and TSC2) and von Hippel–Lindau syndrome. TSC is caused by defects in the TSC1 and TSC2 genes while Von Hippel-Lindau disease is due to defects in the VHL gene (Northrup et al. 2018. PubMed ID: 20301399; Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405). These genes encode tumor suppressors.

This panel also includes some other genes that have been associated with renal cystic lesions including COL4A1, CRB2, LRP5, JAG1, NOTCH2, OFD1, PAX2, SEC61A1 and DICER1.

Clinical Sensitivity - Sequencing with CNV PGxome

To our knowledge, genetic testing sensitivity of each gene included in this panel in a large clinically heterogeneous cohort of patients with hereditary cystic kidney diseases has not been reported in the literature. The clinical sensitivities listed as below are based on individual well-defined disease entities.

In two large cohort studies of autosomal dominant polycystic kidney disease (ADPKD), the overall pathogenic variants detection rate of PKD1 and PKD2 is about 89%, in which defects in PKD1 and PKD2 explain approximately 85% and 15% of genetically positive ADPKD cases, respectively (Rossetti et al. 2007. PubMed ID: 17582161; Audrézet et al. 2012. PubMed ID: 22508176). Large deletions and duplications in PKD1 and PKD2 are relatively rare (<4%) in ADPKD patients (Bataille et al. 2011. PubMed ID: 22008521; Audrézet et al. 2012. PubMed ID: 22508176). After PKD1 and PKD2, IFT140 LoF variants likely represent the third most common cause of cystic kidney disease, accounting for >1% of ADPKD-spectrum-affected individuals (Senum et al. 2022. PubMed ID: 34890546). Defects in GANAB and DNAJB11 account for another ~0.3% and ~ 1% of total ADPKD (Porath et al. 2016. PubMed ID: 27259053; Cornec-Le Gall et al. 2018. PubMed ID: 29706351).

Since we primarily use Next Generation Sequencing (NGS) to test the PKD1 gene (see Testing Strategy section), gene conversions can be missed. However, our internal data suggested gene conversions are rare (<0.5%) in PKD1. These events have been found by long-range PCR based Sanger sequencing, but not by NGS only. Therefore, to increase detection rate (but by a very limited amount) of PKD1 pathogenic variants, Sanger sequencing for exons 1 to 33 (homologous regions) of PKD1 may be ordered.

Homozygous or compound heterozygous pathogenic variants in PKHD1 can be found in ~80% of ARPKD patients regardless of disease severity. Approximately 95% of affected individuals were found to have at least one pathogenic variant in PKHD1 (Bergmann. 2017. PubMed ID: 29479522). Defects in the DZIP1L gene were found in only two of 743 (~0.3%) unrelated individuals with suspected ARPKD or sporadic PKD (Lu et al. 2017. PubMed ID: 28530676).

HNF1B pathogenic variants were found via Sanger sequencing in up to 7% of patients/fetuses with renal hypodysplasia in three large cohort studies (Weber et al. 2006. PubMed ID: 16971658; Thomas et al. 2011. PubMed ID: 21380624; Madariaga et al. 2013. PubMed ID: 23539225). A large deletion (~1.4Mb) including the entire HNF1B gene can be found in ~50% of patients with HNF1B-nephropathy (Bergmann. 2017. PubMed ID: 29479522). The current NGS panel test can detect this large deletion.

Sensitivity of genetic testing for nephronophthisis is approximately 30% overall (Hildebrandt et al. 2009. PubMed ID: 19118152). Approximately 20% of individuals with nephronophthisis have a homozygous deletion encompassing the NPHP1 gene. The current NGS panel test can detect the ~279kb deletion in the NPHP1 gene in both heterozygous and homozygous states.

Pathogenic variants can be identified in approximately 85% of individuals with tuberous sclerosis complex (TSC); 15% of individuals with TSC will not have a pathogenic variant identified (Northrup et al. 2018. PubMed ID: 20301399).

Genetic testing for VHL achieves a molecular diagnosis in 90-100% of patients with VHL disease (Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

DNA analysis of the PKD1 gene is complicated and challenging due to the presence of several PKD1 pseudogenes. There is high sequence similarity of exons 1 to 33 between PKD1 and its pseudogenes (Audrézet et al. 2012. PubMed ID: 22508176). We have validated Next Generation Sequencing (NGS) to reliably sequence these exons.

For the PKD1 gene, including exons 1 to 33 (homologous regions), we primarily use Next Generation Sequencing (NGS) (~96%) complimented with Sanger sequencing for low-coverage regions (~4%). For any pathogenic, likely pathogenic, and uncertain variants found in exons 1 to 33 (homologous regions) via NGS, we use long-range PCR based Sanger sequencing to confirm them. Therefore, this test provides full coverage of all coding exons of the PKD1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Due to homologous sequence, gene conversion events in the PKD1 gene have been reported in the literature and found at PreventionGenetics. Our internal data suggested gene conversions are rare (<0.5%) in PKD1. These events have been found by long-range PCR based Sanger sequencing, but not by NGS only. Therefore, Sanger sequencing for exons 1 to 33 (homologous regions) of PKD1 may also be ordered.

To date, the only documented pathogenic variant in MUC1 causing medullary cystic kidney disease is the insertion of a single cytosine in one copy of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence (Kirby et al. 2013. PubMed ID: 23396133). Our current sequencing methodology has not been validated to detect this variant.

Regarding copy number variants (CNVs) analysis, because of the paucity of CNVs and the complicated nature of sequence in PKD1, CNV analysis for this gene can be performed via the multiplex ligation-dependent amplification (MLPA) assay with limited increased sensitivity (compared to Next-Gen sequencing CNV analysis), and can be ordered separately (Test #2058).

This panel typically provides 98.8% coverage of all coding exons of the genes, PKD1 and PKD2 are covered 100%, plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients with hereditary cystic kidney diseases.

Diseases

Name Inheritance OMIM ID
Adolescent Nephronophthisis AR 604387
Alagille Syndrome 1 AD 118450
Alagille Syndrome 2 AD 610205
Angiopathy, Hereditary, With Nephropathy, Aneurysms, And Muscle Cramps AD 611773
Congenital Disorder Of Glycosylation Type 1A AR 212065
Congenital Disorder Of Glycosylation Type 1L AR 608776
Diabetes Mellitus, Noninsulin-Dependent AD 125853
Gillessen-Kaesbach-Nishimura syndrome AR 263210
Hyperuricemic Nephropathy, Familial Juvenile, 2 AD 613092
Hyperuricemic Nephropathy, Familial Juvenile, 4 AD 617056
Infantile Nephronophthisis AR 602088
Joubert Syndrome 10 XL 300804
Joubert Syndrome 7 AR 611560
Maturity-Onset Diabetes Of The Young, Type 5 AD 137920
Medullary Cystic Kidney Disease 1 AD 174000
Medullary Cystic Kidney Disease 2 AD 603860
Nephronophthisis AR 256100
Nephronophthisis 11 AR 613550
Nephronophthisis 12 AR 613820
Nephronophthisis 13 AR 614377
Nephronophthisis 14 AR 614844
Nephronophthisis 15 AR 614845
Nephronophthisis 16 AR 615382
Nephronophthisis 18 AR 615862
Nephronophthisis 19 AR 616217
Nephronophthisis 20 AR 617271
Nephronophthisis 4 AR 606966
Nephronophthisis 7 AR 611498
Nephronophthisis 9 AR 613824
Papillorenal Syndrome AD 120330
Pleuropulmonary Blastoma AD 601200
Polycyctic Kidney Disease 3 AD 600666
Polycystic Kidney Disease 1 AD 173900
Polycystic Kidney Disease 2 AD 613095
Polycystic Kidney Disease 5 AR 617610
Polycystic Kidney Disease 6 with or without Polycystic Liver Disease AD 618061
Polycystic Kidney Disease, Infantile Type AR 263200
Polycystic liver disease 3 with or without kidney cysts AD 617874
Polycystic Liver Disease 4 with or without Kidney Cysts AD 617875
Renal Tubular Dysgenesis AR 267430
Senior-Loken Syndrome 5 AR 609254
Senior-Loken Syndrome 6 AR 610189
Senior-Loken Syndrome 7 AR 613615
Short-Rib Thoracic Dysplasia 10 with or without Polydactyly AR 615630
Short-Rib Thoracic Dysplasia 9 with or without Polydactyly AR 266920
Tuberous Sclerosis 1 AD 191100
Tuberous Sclerosis 2 AD 613254
Ventriculomegaly with Cystic Kidney Disease AR 219730
Von Hippel-Lindau Syndrome AD 193300
{Renal dysplasia, cystic, susceptibility to} AD 601331

Related Test

Name
PGxome®

Citations

  • Audrézet et al. 2012. PubMed ID: 22508176
  • Bataille et al. 2011. PubMed ID: 22008521
  • Bergmann. 2017. PubMed ID: 29479522
  • Cornec-Le Gall et al. 2018. PubMed ID: 29706351
  • Cornec-Le Gall et al. 2019. PubMed ID: 30819518
  • Dillman et al. 2017. PubMed ID: 28493804
  • Hart et al. 2002. PubMed ID: 12471200
  • Hartung and Guay-Woodford. 2017. PubMed ID: 28736432
  • Hildebrandt et al. 2009. PubMed ID: 19118152
  • Izzi et al. 2020. PubMed ID: 33305128
  • Kirby et al. 2013. PubMed ID: 23396133
  • Lu et al. 2017. PubMed ID: 28530676
  • Madariaga et al. 2013. PubMed ID: 23539225
  • Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405
  • Northrup et al. 2020. PubMed ID: 20301399
  • Porath et al. 2016. PubMed ID: 27259053
  • Rossetti et al. 2007. PubMed ID: 17582161
  • Senum et al. 2022. PubMed ID: 34890546
  • Srivastava et al. 2017. PubMed ID: 29379777
  • Thomas et al. 2011. PubMed ID: 21380624
  • Ward et al. 2002. PubMed ID: 11919560
  • Weber et al. 2006. PubMed ID: 16971658

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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