Classification and diagnosis of the molecular basis of cholestasis

Abstract

The methods and compositions of the invention find use in the clinical diagnosis of cholestasis related syndromes, particularly PFIC types 1, 2, and 3; BRIC types 1 and 2; Alagille syndrome, and alpha 1-antitrypsin deficiency. The compositions of the invention include isolated nucleic acid molecules and oligonucleotide pairs suitable for use in amplifying regions of cholestasis related genes. Compositions of the invention include a cholestasis related gene resequencing microarray suitable for determining the nucleotide sequence of a region of a cholestasis related gene. Knowledge of the nucleotide sequence of one or more regions of a patient's cholestasis related gene allows diagnosis of the patient's syndrome.

1 . An isolated nucleic acid molecule consisting of a nucleotide sequence selected from the group consisting of:
 (a) the nucleotide sequence set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and   (b) a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70   
     
     
         2 . A library of isolated nucleic acid molecules comprising a first isolated nucleic acid molecule and at least a second isolated nucleic acid molecule wherein the nucleotide sequences of said nucleic acid molecules are selected from the group consisting of:
 (a) the nucleotide sequence set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and   (b) a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70   
     
     
         3 . The library of  claim 2 , consisting of 3-10, 11-20, 21-30, 31-40, 41-50, 51-60, or 61-70 isolated nucleic acid molecules having a nucleotide sequence selected from the group consisting of:
 (a) the nucleotide sequence set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and   (b) a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NOS:1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70   
     
     
         4 - 9 . (canceled) 
     
     
         10 . A resequencing microarray comprising of nucleic acid probes having a nucleotide sequence derived from the nucleotide sequences set forth in SEQ ID NOS:71-75. 
     
     
         11 . The resequencing microarray of  claim 10  comprising nucleic acid probes having a nucleotide sequence selected from the group consisting of:
 (a) a segment of a nucleotide sequence set forth in nucleotides 1 to 483 of SEQ ID NO:71; nucleotides 25,479 to 25,620 of SEQ ID NO:71; nucleotides 27,398 to 27,555 of SEQ ID NO:71; nucleotides 30,753 to 30,895 of SEQ ID NO:71; nucleotides 30,966 to 31,071 of SEQ ID NO:71; nucleotides 34,199 to 34,315 of SEQ ID NO:71; nucleotides 34,378 to 34,492 of SEQ ID NO:71; nucleotides 36,534 to 36,660 of SEQ ID NO:71; nucleotides 36,737 to 36,939 of SEQ ID NO:71; nucleotides 37,396 to 37,528 of SEQ ID NO:71; nucleotides 40,069 to 40,303 of SEQ ID NO:71; nucleotides 43,559 to 43,811 of SEQ ID NO:71; nucleotides 46,951 to 47,038 of SEQ ID NO:71; nucleotides 47,874 to 48,074 of SEQ ID NO:71; nucleotides 57,044 to 57,276 of SEQ ID NO:71; nucleotides 60,486 to 60,642 of SEQ ID NO:71; nucleotides 62,584 to 62,792 of SEQ ID NO:71; nucleotides 63,526 to 63,681 of SEQ ID NO:71; nucleotides 64,899 to 65,018 of SEQ ID NO:71; nucleotides 69,451 to 69,627 of SEQ ID NO:71; nucleotides 70,604 to 70,936 of SEQ ID NO:71; nucleotides 76,649 to 76,916 of SEQ ID NO:71; nucleotides 77,991 to 78,118 of SEQ ID NO:71; nucleotides 79,337 to 79,626 of SEQ ID NO:71; nucleotides 79,894 to 80,076 of SEQ ID NO:71; nucleotides 81,569 to 81,743 of SEQ ID NO:71; nucleotides 83,354 to 83,756 of SEQ ID NO:71; nucleotides 1 to 401 of SEQ ID NO:72; nucleotides 13,430 to 13,576 of SEQ ID NO:72; nucleotides 14,783 to 14,848 of SEQ ID NO:72; nucleotides 17,228 to 17,323 of SEQ ID NO:72; nucleotides 18,072 to 18,354 of SEQ ID NO:72; nucleotides 34,860 to 34,991 of SEQ ID NO:72; nucleotides 36,100 to 36,277 of SEQ ID NO:72; nucleotides 37,700 to 37,915 of SEQ ID NO:72; nucleotides 40,657 to 40,825 of SEQ ID NO:72; nucleotides 45,298 to 45,516 of SEQ ID NO:72; nucleotides 51,603 to 51,760 of SEQ ID NO:72; nucleotides 54,895 to 55,049 of SEQ ID NO:72; nucleotides 57,742 to 57,911 of SEQ ID NO:72; nucleotides 59,532 to 59,779 of SEQ ID NO:72; nucleotides 61,367 to 61,581 of SEQ ID NO:72; nucleotides 62,031 to 62,276 of SEQ ID NO:72; nucleotides 63,092 to 63,199 of SEQ ID NO:72; nucleotides 67,274 to 67,420 of SEQ ID NO:72; nucleotides 73,454 to 73,662 of SEQ ID NO:72; nucleotides 86,621 to 86,769 of SEQ ID NO:72; nucleotides 86,816 to 87,021 of SEQ ID NO:72; nucleotides 95,149 to 95,396 of SEQ ID NO:72; nucleotides 96,157 to 96,442 of SEQ ID NO:72; nucleotides 99,049 to 99,249 of SEQ ID NO:72; nucleotides 100,720 to 100,961 of SEQ ID NO:72; nucleotides 104,220 to 104,470 of SEQ ID NO:72; nucleotides 106,779 to 106,969 of SEQ ID NO:72; nucleotides 107,760 to 108,687 of SEQ ID NO:72; nucleotides 1 to 1,802 of SEQ ID NO:73; nucleotides 1,803 to 2,186 of SEQ ID NO:73; nucleotides 2,299 to 2,400 of SEQ ID NO:73; nucleotides 3,075 to 3,254 of SEQ ID NO:73; nucleotides 3,611 to 3,760 of SEQ ID NO:73; nucleotides 3,879 to 4,008 of SEQ ID NO:73; nucleotides 6,675 to 6,773 of SEQ ID NO:73; nucleotides 16,442 to 16,636 of SEQ ID NO:73; nucleotides 24,758 to 24,859 of SEQ ID NO:73; nucleotides 26,215 to 26,450 of SEQ ID NO:73; nucleotides 27,556 to 27,771 of SEQ ID NO:73; nucleotides 29,258 to 29,426 of SEQ ID NO:73; nucleotides 32,145 to 32,360 of SEQ ID NO:73; nucleotides 34,375 to 34,532 of SEQ ID NO:73; nucleotides 35,577 to 35,731 of SEQ ID NO:73; nucleotides 35,906 to 36,075 of SEQ ID NO:73; nucleotides 38,948 to 39,195 of SEQ ID NO:73; nucleotides 39,513 to 39,727 of SEQ ID NO:73; nucleotides 47,785 to 47,990 of SEQ ID NO:73; nucleotides 52,430 to 52,644 of SEQ ID NO:73; nucleotides 55,298 to 55,488 of SEQ ID NO:73; nucleotides 57,125 to 57,273 of SEQ ID NO:73; nucleotides 59,275 to 59,396 of SEQ ID NO:73;.nucleotides 60,730 to 60,857 of SEQ ID NO:73; nucleotides 61,835 to 62,082 of SEQ ID NO:73; nucleotides 65,633 to 65,777 of SEQ ID NO:73; nucleotides 67,317 to 67,501 of SEQ ID NO:73; nucleotides 69,958 to 70,158 of SEQ ID NO:73; nucleotides 71,116 to 71,357 of SEQ ID NO:73; nucleotides 72,835 to 73,106 of SEQ ID NO:73; nucleotides 76,069 to 76,259 of SEQ ID NO:73;,nucleotides 77,048 to 77,349 of SEQ ID NO:73; nucleotides 1 to 1,015 of SEQ ID NO:74; nucleotides 1,415 to 1,764 of SEQ ID NO:74; nucleotides 6,490 to 6,689 of SEQ ID NO:74; nucleotides 8,080 to 8,239 of SEQ ID NO:74; nucleotides 10,407 to 10,502 of SEQ ID NO:74; nucleotides 15,699 to 15,997 of SEQ ID NO:74; nucleotides 17,963 to 18,067 of SEQ ID NO:74; nucleotides 21,823 to 21,997 of SEQ ID NO:74; nucleotides 22,171 to 22,334 of SEQ ID NO:74; nucleotides 22,727 to 22,884 of SEQ ID NO:74; nucleotides 24,061 to 24,218 of SEQ ID NO:74; nucleotides 24,786 to 24,943 of SEQ ID NO:74; nucleotides 25,314 to 25,404 of SEQ ID NO:74; nucleotides 25,699 to 25,916 of SEQ ID NO:74; nucleotides 26,311 to 26,505 of SEQ ID NO:74; nucleotides 27,318 to 27,526 of SEQ ID NO:74; nucleotides 28,337 to 28,494 of SEQ ID NO:74; nucleotides 28,952 to 29,109 of SEQ ID NO:74; nucleotides 29,165 to 29,322 of SEQ ID NO:74; nucleotides 29,442 to 29,602 of SEQ ID NO:74; nucleotides 30,037 to 30,108 of SEQ ID NO:74; nucleotides 30,558 to 30,687 of SEQ ID NO:74; nucleotides 31,820 to 31,977 of SEQ ID NO:74; nucleotides 32,529 to 32,682 of SEQ ID NO:74; nucleotides 32,728 to 33,005 of SEQ ID NO:74; nucleotides 33,177 to 33,352 of SEQ ID NO:74; nucleotides 33,488 to 33,682 of SEQ ID NO:74; nucleotides 34,466 to 36,779 of SEQ ID NO:74; nucleotides 1 to 538 of SEQ ID NO:75; nucleotides 539 to 792 of SEQ ID NO:75; nucleotides 886 to 1,033 of SEQ ID NO:75; nucleotides 6,308 to 7,001 of SEQ ID NO:75; nucleotides 8,408 to 8,722 of SEQ ID NO:75; nucleotides 9,938 to 10,129 of SEQ ID NO:75; or nucleotides 10,909 to 11,232 of SEQ ID NO:75; and 
 (b) a segment that differs by one nucleotide alteration from a segment of (a). 
 
     
     
         12 . A method of determining the nucleotide sequence of a region of a cholestasis related gene of a human subject comprising the steps of:
 (a) obtaining a biological sample from said human subject;   (b) providing an oligonucleotide pair of the invention;   (c) performing enzymatic amplification of a region of a cholestasis related gene;   (d) providing amplified DNA having the nucleotide sequence of a region a cholestasis related gene; and   (e) determining the nucleotide sequence of a region of the amplified DNA.   
     
     
         13 . The method of  claim 12 , wherein the oligonucleotide pair of the invention is selected from the group consisting of:
 (a) the oligonucleotide pair consisting of a first nucleic acid molecule having the. nucleotide sequence set forth in SEQ ID NO:1 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:2;   (b) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:3 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:4;   (c) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:5 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:6;   (d) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:7 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:8;   (e) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:9 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:10;   (f) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:11 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:12;   (g) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:13 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:14;   (h) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:15 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:16;   (i) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:17 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:18;   (j) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:19 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:20;   (k) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:21 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:22;   (l) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:23 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:24;   (m) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:25 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:26;   (n) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:27 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:28;   (o) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:29 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:30;   (p) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:31 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:32;   (q) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:33 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:34;   (r) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:35 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:36;   (s) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:37 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:38;   (t) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO/39 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:40;   (u) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:41 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:42;   (v) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:43 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:44;   (w) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:45 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:46;   (x) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:47 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:48;   (y) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:49 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:50;   (z) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:51 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:52;   (aa) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:53 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:54;   (ab) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:55 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:56;   (ac) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:57 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:58;   (ad) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:59 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:60;   (ac) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:61 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:62;   (af) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:63 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:64;   (ag) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:65 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:66;   (ah) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:67 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:68;   (ai) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:69 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:70;   (aj) an oligonucleotide pair comprising a first nucleic acid molecule having a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, or SEQ ID NO:69; and   (ak) an oligonucleotide pair comprising a second nucleic acid molecule having a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, or SEQ ID NO:70   
     
     
         14 . The method of  claim 12 , comprising the step of providing a cholestasis related gene resequencing microarray. 
     
     
         15 . The method of  claim 12 , wherein the nucleotide sequence of multiple amplified regions is determined, 
     
     
         16 . The method of  claim 12 , wherein the nucleotide sequence of a region of at least one, two, three, four or five cholestasis related genes is compared with a standard sequence profile. 
     
     
         17 . The method of  claim 12 , wherein the cholestasis related gene is selected from the group consisting of ATP8B1 (SEQ ID NO:71); ABCB4 (SEQ ID NO:73); ABCB11 (SEQ ID NO:72); JAG1 (SEQ ID NO:74); and SERPINA-1 (SEQ ID NO:75). 
     
     
         18 . (canceled) 
     
     
         19 . A method of diagnosing a cholestasis related syndrome comprising the steps of:
 (a) obtaining a biological sample from a human subject exhibiting cholestasis;   (b) performing enzymatic amplification of a region of a cholestasis related gene, wherein said cholestasis related gene is selected from the group consisting of: ATP8B1 (SEQ ID NO:71); ABCB4 (SEQ ID NO:73); ABCB11 (SEQ ID NO:72); JAG1 (SEQ ID NO:74); and SERPIN-1 (SEQ ID NO:75);   (c) providing amplified DNA having the nucleotide sequence of a region of a cholestasis related gene;   (d) determining the nucleotide sequence of a region of the amplified DNA, and   (e) comparing the nucleotide sequence of the amplified DNA with a standard sequence profile.   
     
     
         20 . The method of  claim 19  comprising the step of providing a cholestasis related gene resequencing microarray. 
     
     
         21 . The method of  claim 19 , wherein said cholestasis related syndrome is selected from the group consisting of cholestasis, neonatal cholestasis, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, alpha-1 anti-trypsin deficiency, Alagille syndrome, intrahepatic cholestasis of pregnancy, primary sclerosing cholangitis, biliary atresia, cholelithiasis, cirrhosis of the liver, and septicemia. 
     
     
         22 . The method of  claim 19 , comprising the step of providing at least one oligonucleotide pair selected from the group consisting of:
 (a) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:1 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:2;   (b) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:3 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:4;   (c) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:5 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:6;   (d) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:7 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:8;   (e) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:9 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:10;   (f) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:11 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:12;   (g) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:13 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:14;   (h) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:15 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:16;   (i) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:17 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:18;   (j) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:19 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:20;   (k) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:21 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:22;   (l) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:23 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:24;   (m) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:25 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:26;   (n) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:27 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:28;   (o) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:29 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:30;   (p) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:31 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:32;   (q) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:33 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:34;   (r) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:35 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:36;   (s) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:37 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:38;   (t) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:39 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:40;   (u) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:41 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:42;   (v) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:43 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:44;   (w) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:45 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:46;   (x) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:47 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:48;   (y) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:49 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:50;   (z) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:51 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:52;   (aa) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:53 and a second nucleic acid molecule haying the nucleotide sequence set forth in SEQ ID NO:54;   (ab) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:55 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:56;   (ac) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:57 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:58;   (ad) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:59 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:60;   (ae) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:61 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:62;   (af) the oligonucleotide pair, consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:63 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:64;   (ag) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:65 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:66;   (ah) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:67 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:68;   (ai) the oligonucleotide pair consisting of a first nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:69 and a second nucleic acid molecule having the nucleotide sequence set forth in SEQ ID NO:70;   (aj) an oligonucleotide pair comprising a first nucleic acid molecule having a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, or SEQ ID NO:69; and   (ak) an oligonucleotide pair comprising a second nucleic acid molecule having a nucleotide sequence that differs by one nucleotide alteration from that set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22. SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, or SEQ ID NO:70   
     
     
         23 . The method of  claim 19 , wherein enzymatic amplification of a region of multiple cholestasis related genes occurs. 
     
     
         24 . The method of  claim 19 , wherein the nucleotide sequences of multiple amplified DNA are determined. 
     
     
         25 . A method of determining cholestasis classification in a subject exhibiting cholestasis comprising:
 (a) obtaining a biological sample from said subject;   (b) performing enzymatic amplification of a region of a cholestasis related gene, wherein said cholestasis related gene is selected from the group consisting of: ATP8B1 (SEQ ID NO:71), ABCB4 (SEQ ID NO:73), ABCB11 (SEQ ID NO:72), JAG1 (SEQ ID NO:74), and SERPINA-1 (SEQ ID NO:75);   (c) providing amplified DNA having the nucleotide sequence of a region of a cholestasis related gene;   (d) determining the nucleotide sequence of a region of the amplified DNA; and   (e) comparing the nucleotide sequence of the region with a standard sequence profile.   
     
     
         26 . The method of  claim 25 , wherein the step of determining the nucleotide sequence of a region of a cholestasis related gene further comprises the step of providing a cholestasis related gene resequencing microarray. 
     
     
         27 . A method of predicting the prognosis for a subject exhibiting cholestasis comprising:
 (a) obtaining a biological sample from said subject;   (b) performing enzymatic amplification of a region of a cholestasis related gene;   (c) providing amplified DNA having the nucleotide sequence of a region a cholestasis related gene;   (d) determining the nucleotide sequence of a region of a cholestasis related gene of said human subject, and   (e) comparing the nucleotide sequence of the region with a standard sequence profile.   
     
     
         28 . The method of  claim 27 , wherein the step of determining the nucleotide sequence of a region of a cholestasis related gene further comprises the step of providing a cholestasis related gene resequencing microarray.