Neonatal and Adult Cholestasis: Sequencing Panel

Condition Description

Neonatal cholestasis is often clinically defined as the prolonged occurrence of conjugated hyperbilirubinemia in the newborn period, due to impairments in the flow of bile. It is caused by a diverse group of hepatobiliary diseases with overlapping clinical presentations, supporting a need for multi-gene diagnostic panel.

The incidence of neonatal cholestasis is estimated to be 1 in 2500 live births. Genetic and metabolic causes account for at least 25-30% of all cases of neonatal cholestasis, generally due to impairments of hepatobiliary transport, intermediary metabolism, storage disorders, or bile duct dysgenesis. Several of these disorders are life-threatening and benefit from early diagnosis and intervention, yet diagnosing the specific cause via routine serum chemistries or by evaluation of liver biopsies is not as definitive as direct genetic testing. Moreover, several cholestatic entities develop in adults that are caused by variants in these same genes. 

Highlights for pediatricians, internists, gastroenterologists, and hepatologists include:

  • PFICs, Alagille syndrome, A1AT, bile acid synthetic disorders, CF, etc., all on one platform
  • Extremely rare cholangiopathies, (nephronophthises, ARPKD) as well as causes of neonatal liver failure (DGUOK and others)
  • Opportunities to diagnose adult-onset cholestatic syndromes, including BRIC, LPAC, and ICP
  • Evaluation of hyperbilrubinemia: Crigler-Najjar and Dubin-Johnson syndromes


Reference:

  • Arya G, Balistreri WF. Pediatric liver disease in the United States: epidemiology and impact. J Gastroenterol Hepatol. 2002 May;17(5):521–5.

Genes (66)

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Indications

This test is indicated for:

  • Newborns and adults with chronic liver disease.

Methodology

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.

Detection

Next Generation Sequencing: Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions/duplications will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's clinical/biochemical phenotype.

Analytical Sensitivity: ~99%.

Specimen Requirements

When sample fails to meet the acceptable criteria, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
Saliva
SLV

Requirements
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.
DNA, Isolated
DNA

Requirements
Microtainer
8µg
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.
Whole Blood (EDTA)
WBP

Requirements
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 24 hours of collection. Do not refrigerate or freeze.
  • Neonatal and Adult Cholestasis: Deletion/Duplication Panel

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