Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome (original) (raw)

Abstract

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.

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Selected References

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  1. Baraitser M., Patton M., Lam S. T., Brett E. M., Wilson J. The Angelman (Happy Puppet) syndrome: is it autosomal recessive? Clin Genet. 1987 May;31(5):323–330. doi: 10.1111/j.1399-0004.1987.tb02816.x. [DOI] [PubMed] [Google Scholar]
  2. Clayton-Smith J., Pembrey M. E. Angelman syndrome. J Med Genet. 1992 Jun;29(6):412–415. doi: 10.1136/jmg.29.6.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Donlon T. A. Similar molecular deletions on chromosome 15q11.2 are encountered in both the Prader-Willi and Angelman syndromes. Hum Genet. 1988 Dec;80(4):322–328. doi: 10.1007/BF00273644. [DOI] [PubMed] [Google Scholar]
  4. Fryburg J. S., Breg W. R., Lindgren V. Diagnosis of Angelman syndrome in infants. Am J Med Genet. 1991 Jan;38(1):58–64. doi: 10.1002/ajmg.1320380114. [DOI] [PubMed] [Google Scholar]
  5. Hall J. G. How imprinting is relevant to human disease. Dev Suppl. 1990:141–148. [PubMed] [Google Scholar]
  6. 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]
  7. Hamabe J., Kuroki Y., Imaizumi K., Sugimoto T., Fukushima Y., Yamaguchi A., Izumikawa Y., Niikawa N. DNA deletion and its parental origin in Angelman syndrome patients. Am J Med Genet. 1991 Oct 1;41(1):64–68. doi: 10.1002/ajmg.1320410117. [DOI] [PubMed] [Google Scholar]
  8. Heutink P., van der Mey A. G., Sandkuijl L. A., van Gils A. P., Bardoel A., Breedveld G. J., van Vliet M., van Ommen G. J., Cornelisse C. J., Oostra B. A. A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet. 1992 Apr;1(1):7–10. doi: 10.1093/hmg/1.1.7. [DOI] [PubMed] [Google Scholar]
  9. Hultén M., Armstrong S., Challinor P., Gould C., Hardy G., Leedham P., Lee T., McKeown C. Genomic imprinting in an Angelman and Prader-Willi translocation family. Lancet. 1991 Sep 7;338(8767):638–639. doi: 10.1016/0140-6736(91)90652-6. [DOI] [PubMed] [Google Scholar]
  10. Kaplan L. C., Wharton R., Elias E., Mandell F., Donlon T., Latt S. A. Clinical heterogeneity associated with deletions in the long arm of chromosome 15: report of 3 new cases and their possible genetic significance. Am J Med Genet. 1987 Sep;28(1):45–53. doi: 10.1002/ajmg.1320280107. [DOI] [PubMed] [Google Scholar]
  11. Knoll J. H., Glatt K. A., Nicholls R. D., Malcolm S., Lalande M. Chromosome 15 uniparental disomy is not frequent in Angelman syndrome. Am J Hum Genet. 1991 Jan;48(1):16–21. [PMC free article] [PubMed] [Google Scholar]
  12. Knoll J. H., Nicholls R. D., Magenis R. E., Graham J. M., Jr, Lalande M., Latt S. A. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet. 1989 Feb;32(2):285–290. doi: 10.1002/ajmg.1320320235. [DOI] [PubMed] [Google Scholar]
  13. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  14. Ledbetter D. H., Riccardi V. M., Airhart S. D., Strobel R. J., Keenan B. S., Crawford J. D. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. 1981 Feb 5;304(6):325–329. doi: 10.1056/NEJM198102053040604. [DOI] [PubMed] [Google Scholar]
  15. Lindeman R., Kouts S., Woodage T., Smith A., Trent R. J. Dinucleotide repeat polymorphism of D15S10 in the Prader-Willi chromosome region (PWCR). Nucleic Acids Res. 1991 Oct 11;19(19):5449–5449. doi: 10.1093/nar/19.19.5449-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Malcolm S., Clayton-Smith J., Nichols M., Robb S., Webb T., Armour J. A., Jeffreys A. J., Pembrey M. E. Uniparental paternal disomy in Angelman's syndrome. Lancet. 1991 Mar 23;337(8743):694–697. doi: 10.1016/0140-6736(91)90278-w. [DOI] [PubMed] [Google Scholar]
  17. Nicholls R. D., Knoll J. H., Butler M. G., Karam S., Lalande M. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature. 1989 Nov 16;342(6247):281–285. doi: 10.1038/342281a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Saitoh S., Kubota T., Ohta T., Jinno Y., Niikawa N., Sugimoto T., Wagstaff J., Lalande M. Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABAA receptor beta 3-subunit gene. Lancet. 1992 Feb 8;339(8789):366–367. doi: 10.1016/0140-6736(92)91686-3. [DOI] [PubMed] [Google Scholar]
  20. Smeets D. F., Hamel B. C., Nelen M. R., Smeets H. J., Bollen J. H., Smits A. P., Ropers H. H., van Oost B. A. Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med. 1992 Mar 19;326(12):807–811. doi: 10.1056/NEJM199203193261206. [DOI] [PubMed] [Google Scholar]
  21. Wagstaff J., Knoll J. H., Fleming J., Kirkness E. F., Martin-Gallardo A., Greenberg F., Graham J. M., Jr, Menninger J., Ward D., Venter J. C. Localization of the gene encoding the GABAA receptor beta 3 subunit to the Angelman/Prader-Willi region of human chromosome 15. Am J Hum Genet. 1991 Aug;49(2):330–337. [PMC free article] [PubMed] [Google Scholar]
  22. Wagstaff J., Knoll J. H., Glatt K. A., Shugart Y. Y., Sommer A., Lalande M. Maternal but not paternal transmission of 15q11-13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nat Genet. 1992 Jul;1(4):291–294. doi: 10.1038/ng0792-291. [DOI] [PubMed] [Google Scholar]
  23. Zavodny P. J., Petro M. E., Kumar C. C., Dailey S. H., Lonial H. K., Narula S. K., Leibowitz P. J. The nucleotide sequence of chicken smooth muscle myosin light chain two. Nucleic Acids Res. 1988 Feb 11;16(3):1214–1214. doi: 10.1093/nar/16.3.1214. [DOI] [PMC free article] [PubMed] [Google Scholar]