Cholestasis Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: GA0501

The Blueprint Genetics Cholestasis Panel is a 31 gene test for genetic diagnostics of patients with clinical suspicion of Alagille syndrome, citrullinemia type 2, Crigler-Najjar syndrome types 1 and 2, dubin-Johnson syndrome, Gilbert syndrome, intrahepatic cholestasis of pregnancy type 3 or progressive familial intrahepatic cholestasis types 1-4.

Large majority of the disease targeted by this panel are inherited in autosomal recessive manner but Alagille syndrome is inherited by autosomal dominant mutations (JAG1) and cholestasis is associated to both recessive and dominant ABCB4 mutations. The panel cover also relatively benign disorders causing laboratory findings mimicking cholestasis such as hyperbilirubinemia (Gilbert syndrome, UGT1A1) and benign cholestasis (Dubin-Johnson syndrome; ABCC2).

About Cholestasis

Cholestasis is characterized by jaundice and pruritus. It can present as the hallmark feature in progressive familial intrahepatic cholestasis (PFIC) or as a feature in other inherited disorders such as Alagille syndrome where cholestasis occur in 95% of cases in neonatal period. PFIC is a group of autosomal recessive liver disorders due to defects in bile secretion and is characterized by intrahepatic cholestasis with disease onset usually in infancy and childhood (PFIC types 1-4, caused ATP8B1, ABCB11, ABCB4 and TJP2). PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Defects in PFIC-associated genes ATP8B1 and ABCB11 may also cause a milder disease called benign recurrent intrahepatic cholestasis. There are several other inherited disorders where cholestasis is frequent such as Alagille syndrome (JAG1 and NOTCH2), arthrogryposis, renal dysfunction, and cholestasis syndrome (ARC syndrome; VPS33B and VIPAS39), alpha-1-antitrypsin deficiency (SERPINA1), citrullinemia (SLC25A13), congenital defects of bile acid synthesis (HSD3B7 and AKR1D1), familial hypercholanemia (TJP2 and BAAT) and neonatal ichthyosis-sclerosing cholangitis syndrome (CLDN1). Prevalence of PFIC is unknown, Dubin-Johnson 1:1,300 in Iranian or Moroccan Jews, Alagille syndrome 1:30,000, Crigler-Najjar syndrome 1:1,000,000, whereas the Gilbert syndrome prevalence is 3-7% in population but it does not cause clinical symptoms.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Cholestasis Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCB4 Gallbladder disease, Low phospholipid-associated cholelithiasis, Cholestasis AD/AR 16 202
ABCB11 Cholestasis AD/AR 20 281
ABCC2 Dubin-Johnson syndrome AD/AR 16 51
ATP8B1 Intrahepatic cholestasis of pregnancy, Familial intrahepatic cholestasis, recurrent, Cholestasis, progressive familial intrahepatic AD/AR 17 120
CFTR Cystic fibrosis AR 366 1767
CYP7B1 Bile acid synthesis defect AR 13 41
DGUOK Mitochondrial DNA depletion syndrome AR 19 60
EPCAM Diarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, hereditary nonpolyposis AD/AR 15 63
FAH Tyrosinemia AR 21 98
JAG1 Alagille syndrome AD 102 557
LCT Lactase deficiency AR 10 24
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 39 47
MYO5B* Diarrhea, with microvillus atrophy AR 9 55
NEUROG3 Diarrhea, malabsorptive, congenital AR 2 9
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 21 56
NPC1 Niemann-Pick disease AR 73 441
NPC2 Niemann-pick disease AR 16 27
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 12 64
NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 20 71
NPHP4 Nephronophthisis, Senior-Loken syndrome AR 10 104
SERPINA1 Alpha-1-antitrypsin deficiency AR 29 82
SLC25A13 Citrin deficiency AR 20 106
SLC26A3 Diarrhea, secretory chloride, congenital AR 55 71
SMPD1 Niemann-Pick disease AR 52 230
SPINT2 Diarrhea, secretory sodium, congenital AD 6 10
TJP2 Cholestasis, progressive familial intrahepatic, Hypercholanemia, familial AR 15 15
TMEM216 Joubert syndrome, Meckel syndrome AR 8 8
TRMU Liver failure, infantile, Reversible infantile respiratory chain deficiency AR 12 16
TTC37 Trichohepatoenteric syndrome AR 10 36
UGT1A1 Crigler-Najjar syndrome, Gilbert syndrome AD/AR 25 140
VPS33B Arthrogryposis - renal dysfunction - cholestasis AD/AR 9 53

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
CFTR Chr7:117229530 c.1680-877G>T NM_000492.3 rs397508261
CFTR Chr7:117251609 c.3140-26A>G NM_000492.3 rs76151804
CFTR Chr7:117280015 c.3718-2477C>T NM_000492.3 rs75039782

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Cholestasis Panel that covers classical genes associated with Alagille syndrome, arthrogryposis, renal dysfunction, and cholestasis 1, citrullinemia type 2, congenital bile acid synthesis defect type 3, Crigler-Najjar syndrome types 1 and 2, dubin-Johnson syndrome, emphysema, related to alpha-1-antitrypsin deficiency, Gilbert syndrome, intrahepatic cholestasis of pregnancy type 3, progressive familial intrahepatic cholestasis types 1-4, transient infantile liver failure and tyrosinemia type 1. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Cholestasis Panel

ICD-10 Disease
K83.1 Progressive familial intrahepatic cholestasis types 1-4
E80.6 Dubin-Johnson syndrome
E80.5 Crigler-Najjar syndrome types 1 and 2
E80.4 Gilbert syndrome
Q44.7 Alagille syndrome
K83.1 Intrahepatic cholestasis of pregnancy type 3
E72.20 Citrullinemia type 2

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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