Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12 (original) (raw)

. 1995 Nov;57(5):1068–1073.

Abstract

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome.

1068

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alagille D., Estrada A., Hadchouel M., Gautier M., Odièvre M., Dommergues J. P. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987 Feb;110(2):195–200. doi: 10.1016/s0022-3476(87)80153-1. [DOI] [PubMed] [Google Scholar]
  2. Alagille D., Odièvre M., Gautier M., Dommergues J. P. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975 Jan;86(1):63–71. doi: 10.1016/s0022-3476(75)80706-2. [DOI] [PubMed] [Google Scholar]
  3. Anad F., Burn J., Matthews D., Cross I., Davison B. C., Mueller R., Sands M., Lillington D. M., Eastham E. Alagille syndrome and deletion of 20p. J Med Genet. 1990 Dec;27(12):729–737. doi: 10.1136/jmg.27.12.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Byrne J. L., Harrod M. J., Friedman J. M., Howard-Peebles P. N. del(20p) with manifestations of arteriohepatic dysplasia. Am J Med Genet. 1986 Aug;24(4):673–678. doi: 10.1002/ajmg.1320240411. [DOI] [PubMed] [Google Scholar]
  5. Cohen D., Chumakov I., Weissenbach J. A first-generation physical map of the human genome. Nature. 1993 Dec 16;366(6456):698–701. doi: 10.1038/366698a0. [DOI] [PubMed] [Google Scholar]
  6. Deprettere A., Portmann B., Mowat A. P. Syndromic paucity of the intrahepatic bile ducts: diagnostic difficulty; severe morbidity throughout early childhood. J Pediatr Gastroenterol Nutr. 1987 Nov-Dec;6(6):865–871. doi: 10.1097/00005176-198711000-00008. [DOI] [PubMed] [Google Scholar]
  7. Desmaze C., Scambler P., Prieur M., Halford S., Sidi D., Le Deist F., Aurias A. Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization. Hum Genet. 1993 Feb;90(6):663–665. doi: 10.1007/BF00202489. [DOI] [PubMed] [Google Scholar]
  8. Dhorne-Pollet S., Deleuze J. F., Hadchouel M., Bonaïti-Pellié C. Segregation analysis of Alagille syndrome. J Med Genet. 1994 Jun;31(6):453–457. doi: 10.1136/jmg.31.6.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Driscoll D. A., Budarf M. L., Emanuel B. S. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet. 1992 May;50(5):924–933. [PMC free article] [PubMed] [Google Scholar]
  10. Emanuel B. S. Molecular cytogenetics: toward dissection of the contiguous gene syndromes. Am J Hum Genet. 1988 Nov;43(5):575–578. [PMC free article] [PubMed] [Google Scholar]
  11. Green E. D., Olson M. V. Systematic screening of yeast artificial-chromosome libraries by use of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1213–1217. doi: 10.1073/pnas.87.3.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hamabe J., Fukushima Y., Harada N., Abe K., Matsuo N., Nagai T., Yoshioka A., Tonoki H., Tsukino R., Niikawa N. Molecular study of the Prader-Willi syndrome: deletion, RFLP, and phenotype analyses of 50 patients. Am J Med Genet. 1991 Oct 1;41(1):54–63. doi: 10.1002/ajmg.1320410116. [DOI] [PubMed] [Google Scholar]
  13. Hol F. A., Hamel B. C., Geurds M. P., Hansmann I., Nabben F. A., Daniëls O., Mariman E. C. Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family. Hum Genet. 1995 Jun;95(6):687–690. doi: 10.1007/BF00209488. [DOI] [PubMed] [Google Scholar]
  14. Legius E., Fryns J. P., Eyskens B., Eggermont E., Desmet V., de Bethune G., Van den Berghe H. Alagille syndrome (arteriohepatic dysplasia) and del(20)(p11.2) Am J Med Genet. 1990 Apr;35(4):532–535. doi: 10.1002/ajmg.1320350419. [DOI] [PubMed] [Google Scholar]
  15. Melis R., Bradley P., Elsner T., Robertson M., Lawrence E., Gerken S., Albertsen H., White R. Polymorphic SSR (simple-sequence-repeat) markers for chromosome 20. Genomics. 1993 Apr;16(1):56–62. doi: 10.1006/geno.1993.1140. [DOI] [PubMed] [Google Scholar]
  16. Mueller R. F. The Alagille syndrome (arteriohepatic dysplasia). J Med Genet. 1987 Oct;24(10):621–626. doi: 10.1136/jmg.24.10.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nicholls R. D., Knoll J. H., Glatt K., Hersh J. H., Brewster T. D., Graham J. M., Jr, Wurster-Hill D., Wharton R., Latt S. A. Restriction fragment length polymorphisms within proximal 15q and their use in molecular cytogenetics and the Prader-Willi syndrome. Am J Med Genet. 1989 May;33(1):66–77. doi: 10.1002/ajmg.1320330109. [DOI] [PubMed] [Google Scholar]
  18. Ohagi S., LaMendola J., LeBeau M. M., Espinosa R., 3rd, Takeda J., Smeekens S. P., Chan S. J., Steiner D. F. Identification and analysis of the gene encoding human PC2, a prohormone convertase expressed in neuroendocrine tissues. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4977–4981. doi: 10.1073/pnas.89.11.4977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pollet N., Dhorne-Pollet S., Deleuze J. F., Boccaccio C., Driancourt C., Raynaud N., Le Paslier D., Hadchouel M., Meunier-Rotival M. Construction of a 3.7-Mb physical map within human chromosome 20p12 ordering 18 markers in the Alagille syndrome locus. Genomics. 1995 Jun 10;27(3):467–474. doi: 10.1006/geno.1995.1078. [DOI] [PubMed] [Google Scholar]
  20. Schnittger S., Höfers C., Heidemann P., Beermann F., Hansmann I. Molecular and cytogenetic analysis of an interstitial 20p deletion associated with syndromic intrahepatic ductular hypoplasia (Alagille syndrome). Hum Genet. 1989 Oct;83(3):239–244. doi: 10.1007/BF00285164. [DOI] [PubMed] [Google Scholar]
  21. Shulman S. A., Hyams J. S., Gunta R., Greenstein R. M., Cassidy S. B. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. 1984 Oct;19(2):325–332. doi: 10.1002/ajmg.1320190215. [DOI] [PubMed] [Google Scholar]
  22. Spinner N. B., Rand E. B., Fortina P., Genin A., Taub R., Semeraro A., Piccoli D. A. Cytologically balanced t(2;20) in a two-generation family with alagille syndrome: cytogenetic and molecular studies. Am J Hum Genet. 1994 Aug;55(2):238–243. [PMC free article] [PubMed] [Google Scholar]
  23. Teebi A. S., Murthy D. S., Ismail E. A., Redha A. A. Alagille syndrome with de novo del(20) (p11.2). Am J Med Genet. 1992 Jan 1;42(1):35–38. doi: 10.1002/ajmg.1320420109. [DOI] [PubMed] [Google Scholar]
  24. Weber J. L. Informativeness of human (dC-dA)n.(dG-dT)n polymorphisms. Genomics. 1990 Aug;7(4):524–530. doi: 10.1016/0888-7543(90)90195-z. [DOI] [PubMed] [Google Scholar]
  25. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]
  26. Whitington P. F., Whitington G. L. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988 Jul;95(1):130–136. doi: 10.1016/0016-5085(88)90301-0. [DOI] [PubMed] [Google Scholar]
  27. Zhang F., Deleuze J. F., Aurias A., Dutrillaux A. M., Hugon R. N., Alagille D., Thomas G., Hadchouel M. Interstitial deletion of the short arm of chromosome 20 in arteriohepatic dysplasia (Alagille syndrome). J Pediatr. 1990 Jan;116(1):73–77. doi: 10.1016/s0022-3476(05)81648-8. [DOI] [PubMed] [Google Scholar]