PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 3 (PFIC3)
ABCB4/MDR3 Sequencing
MITOCHONDRIAL DNA ANALYSIS
Also known as: MDR3 Disease

Description:

The ABCB4 gene product (MDR3) resides in the hepatocyte canalicular membrane and functions as a phospholipid (PL) flippase. Patients with impaired function of ABCB4 have markedly low levels of PL in bile, leading to bile acid-induced bile duct damage as the main pathophysiological process of this disease. Progressive familial intrahepatic cholestasis 3 (PFIC3, OMIM #602347) is a chronic autosomal recessive disorder due to impaired function, or mutations of the ABCB4 gene, causing hepatomegaly, cholestasis, pruritus, hepatic fibrosis, and in some patients, end-stage liver disease. Many patients have severe cholestasis in the first year of life, which may progress to cirrhosis or liver failure. However, there are probably less severe forms of disease that resembles primary sclerosing cholangitis or recurrent cholelithiasis, especially intrahepatic gallstones, and can lead to intrahepatic cholestasis of pregnancy (ICP). Typical clinical confounders in infancy include biliary atresia (BA), PFIC1, PFIC2, as well as biliary tract diseases like congenital hepatic fibrosis, TPN-associated cholestasis, etc. In addition to finding no evidence of biliary tract obstruction, patients with PFIC3 have high serum GGT levels, while those with PFIC1 and PFIC2 have low/normal GGT levels. Liver biopsy findings are notable for biliary tract damage and proliferation, biliary fibrosis, cholestasis, and an absence of biliary tract plugs (as seen in BA). The child and his family may first become aware that there is something wrong during school age or adolescence, or even into adulthood (e.g., intrahepatic gallstones, or ICP).

Reasons for Referral:

Confirmation of a clinical diagnosis
Carrier testing

Testing Methodology:

The exons and flanking intron regions of ABCB4 ( MDR3) gene are PCR amplified and sequenced.

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adult: 14 cc; Child: 6 cc; Infant: 2-3 cc

Turnaround Time:

5 weeks

CPT Codes and Prices:

Index: 83891, 83898x27, 83904x54, 83912, 83894x2
Known Familial Mutation: 83904x4, 83898x2, 83912, 83891, 83894x2

Shipping Information

Forms:

>> Gene Sequencing Requisition or Mitochondrial Requisition - Mitochondrial Diagnostic Checklist is included

References:

1. Deleuze JF, Jacquemin E, Dubuisson C, Cresteil D, Dumont M, Erlinger S, Bernard O, Hadchouel M (1996). Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 23: 904-908.
2. Jacquemin E et al (2001). The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120: 1448-1458.
3. Oude Elferink RP, Paulusma CC, Groen AK (2006). Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 130: 908-925.

Test Codes:

Index: 3315
Known Familial Mutation: 3316