Cystic Kidney Disease Panel
Updated

Last modified: Mar 21, 2018

Summary

  • Is a 40 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with multicystic dysplastic kidneys with or without additional congenital anomalies.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

40

Test code

KI0901

CPT codes

SEQ 81405
SEQ 81406
SEQ 81407
DEL/DUP 81479

Summary

The Blueprint Genetics Cystic Kidney Disease Panel (test code KI0901):

  • Is a 40 gene panel that includes assessment of selected non-coding disease-causing variants
  • Exons 1-33 of the *PKD1* have multiple segmentally duplicated pseudogenes that reduce sensitivity of NGS diagnostics in general. However, Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >40) for 99.5% of the target regions in *PKD1* gene. Our validation showed high mean coverage of 199X for the *PKD1* gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in *PKD1* gene although clinical validation has not been performed at large scale.

  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

Test Specific Strength

Exons 1-33 of the *PKD1* have multiple segmentally duplicated pseudogenes that reduce sensitivity of NGS diagnostics in general. However, Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >40) for 99.5% of the target regions in *PKD1* gene. Our validation showed high mean coverage of 199X for the *PKD1* gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in *PKD1* gene although clinical validation has not been performed at large scale.

ICD codes

Commonly used ICD-10 code(s) when ordering the Cystic Kidney Disease Panel

ICD-10 Disease
Q61.19 Autosomal recessive polycystic kidney disease
Q61.9 Cystic kidney disease
Q61.2 Autosomal dominant polycystic kidney disease

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

In addition to polycystic kidney disease (PKD), the Cystic Kidney Disease Panel offers diagnostics for other multicystic dysplastic kidney disorders (MCDK), such as congenital anomalies with unilateral or bilateral kidney enlargement, distended by multiple cysts, and non-functional and medullary cystic kidney disease. MCDK frequently presents antenatally at routine ultrasound scans, with the majority detected around the 20th week of gestation. Most patients with unilateral MCDK are asymptomatic if the other kidney is fully functional but may occasionally present with abdominal obstructive signs when the cysts become too large. They may also develop hypertension, proteinuria, and renal failure in the long run. Hypertrophy of the contralateral kidney may occur in 24-46% cases before birth, and in up to 80% of cases in the years after birth. Bilateral MCDK is considered a lethal entity. At birth, affected infants have features of the Potter sequence (constellation of signs resulting from prolonged in utero oligohydramnios) with severe pulmonary hypoplasia and severe renal failure, and they often die shortly after birth. The global prevalence of MCDK is not known, but the birth prevalence of the unilateral MCDK is estimated at 1:4,300 live births.

Genes in the Cystic Kidney Disease Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ANKS6 Nephronophthisis AR 5 12
CEP83 Nephronophthisis AR 9 10
CEP164 Nephronophthisis AR 8 8
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 96 266
COL4A1 Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease AD 46 97
CRB2 Focal segmental glomerulosclerosis, Ventriculomegaly with cystic kidney disease AR 11 21
DCDC2 Deafness AR 9 9
DZIP1L Polycyctic kidney disease 5 4
EYA1 Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome AD 39 197
GANAB Polycystic kidney and/or polycystic liver disease 3 6 11
GLIS2 Nephronophthisis AR 3 3
HNF1B Renal cell carcinoma, nonpapillary chromophobe, Renal cysts and diabetes syndrome AD 32 225
IFT172 Retinitis pigmentosa, Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 20 23
INVS Nephronophthisis AR 12 33
IQCB1 Senior-Loken syndrome AR 19 37
JAG1 Alagille syndrome AD 100 568
LRP5* Van Buchem disease, Osteoporosis-pseudoglioma syndrome, Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis AD/AR/Digenic 44 170
MAPKBP1 Nephronophthisis 20 6 6
NEK8 Nephronophthisis AR 4 16
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 25 61
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 14 73
NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 24 72
NPHP4 Nephronophthisis, Senior-Loken syndrome AR 12 108
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 133 156
PAX2 Isolated renal hypoplasia, Papillorenal syndrome AD 23 88
PKD1* Polycystic kidney disease AD 104 1655
PKD2 Polycystic kidney disease AD 28 287
PKHD1 Polycystic kidney disease AR 154 520
RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 35 45
SDCCAG8 Bardet-Biedl syndrome, Senior-Loken syndrome AR 12 18
SEC61A1 Hyperuricemic nephropathy, familial juvenile 4 2 2
SIX5 Branchiootorenal syndrome AD 3 9
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 82 153
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 106 336
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 260 1093
TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic dysplasia (ATD; Jeune) AR 8 53
UMOD Familial juvenile hyperuricemic nephropathy, Glomerulocystic kidney disease with hyperuricemia and isosthenuria AD 22 98
VHL Erythrocytosis, familial, Pheochromocytoma AD/AR 170 594
WDR19 Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune) AD/AR 20 28
ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
COL4A1 Chr13:110802678 c.*32G>T NM_001845.4
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
EYA1 Chr8:72156939 c.1051-12T>G NM_000503.4
EYA1 Chr8:72211483 c.640-15G>A NM_000503.4
JAG1 Chr20:10629767 c.1349-12T>G NM_000214.2
PKD1 Chr16:2140209 c.12445-14T>C NM_001009944.2
PKHD1 Chr6:51747238 c.7350+653A>G NM_138694.3
TSC2 Chr16:2127477 c.2838-122G>A NM_000548.3
TSC2 Chr16:2138031 c.5069-18A>G NM_000548.3 rs45484794
TSC2 Chr16:2110656 c.976-15G>A NM_000548.3 rs45517150

Added and removed genes from the panel

Genes added Genes removed
ANKS6
CEP164
CEP290
CEP83
COL4A1
CRB2
DCDC2
DZIP1L
GANAB
GLIS2
IFT172
INVS
IQCB1
JAG1
LRP5
MAPKBP1
NEK8
NOTCH2
NPHP1
NPHP3
NPHP4
OFD1
RPGRIP1L
SDCCAG8
SEC61A1
TMEM67
TSC1
TSC2
TTC21B
VHL
WDR19
ZNF423
BICC1

Test strength

Exons 1-33 of the *PKD1* have multiple segmentally duplicated pseudogenes that reduce sensitivity of NGS diagnostics in general. However, Blueprint Genetics custom assay has good coverage (>20x) with high mapping rates (mapping quality >40) for 99.5% of the target regions in *PKD1* gene. Our validation showed high mean coverage of 199X for the *PKD1* gene. Thus, our NGS Panel is not expected to have major limitations in detecting variants in *PKD1* gene although clinical validation has not been performed at large scale.

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics cystic kidney disease panel covers classical genes associated with autosomal recessive polycystic kidney disease, cystic kidney disease and autosomal dominant polycystic kidney disease. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.