Familial cryptic translocation resulting in Angelman syndrome:implications for imprinting or location of the Angelman gene? (original) (raw)

. 1996 Apr;58(4):777–784.

Abstract

Angelman syndrome (AS) is associated with a loss of maternal genetic information, which typically occurs as a result of a deletion at 15q11-q13 or paternal uniparental disomy of chromosome 15. We report a patient with AS as a result of an unbalanced cryptic translocation whose breakpoint, at 15q11.2, falls within this region. The proband was diagnosed clinically as having Angelman syndrome, but without a detectable cytogenetic deletion, by using high-resolution G-banding. FISH detected a deletion of D15S11 (IR4-3R), with an intact GABRB3 locus. Subsequent studies of the proband's mother and sister detected a cryptic reciprocal translocation between chromosomes 14 and 15 with the breakpoint being between SNRPN and D15S10 (3- 21). The proband was found to have inherited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter to 14q11.2. DNA methylation studies showed that the proband had a paternal-only DNA methylation pattern at SNRPN, D15S63 (PW71), and ZNF127. The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patterns at all three loci. These data suggest that the gene for AS most likely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally inherited imprinting center acts in trans in the unaffected balanced translocation carrier sister.

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Selected References

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  1. Boyd S. G., Harden A., Patton M. A. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur J Pediatr. 1988 Jun;147(5):508–513. doi: 10.1007/BF00441976. [DOI] [PubMed] [Google Scholar]
  2. Buiting K., Saitoh S., Gross S., Dittrich B., Schwartz S., Nicholls R. D., Horsthemke B. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet. 1995 Apr;9(4):395–400. doi: 10.1038/ng0495-395. [DOI] [PubMed] [Google Scholar]
  3. Butler M. G., Palmer C. G. Parental origin of chromosome 15 deletion in Prader-Willi syndrome. Lancet. 1983 Jun 4;1(8336):1285–1286. doi: 10.1016/s0140-6736(83)92745-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buxton J. L., Chan C. T., Gilbert H., Clayton-Smith J., Burn J., Pembrey M., Malcolm S. Angelman syndrome associated with a maternal 15q11-13 deletion of less than 200 kb. Hum Mol Genet. 1994 Aug;3(8):1409–1413. doi: 10.1093/hmg/3.8.1409. [DOI] [PubMed] [Google Scholar]
  5. Clayton-Smith J. Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individuals. Am J Med Genet. 1993 Apr 1;46(1):12–15. doi: 10.1002/ajmg.1320460105. [DOI] [PubMed] [Google Scholar]
  6. Clayton-Smith J., Webb T., Robb S. A., Dijkstra I., Willems P., Lam S., Cheng X. J., Pembrey M. E., Malcolm S. Further evidence for dominant inheritance at the chromosome 15q11-13 locus in familial Angelman syndrome. Am J Med Genet. 1992 Sep 15;44(2):256–260. doi: 10.1002/ajmg.1320440236. [DOI] [PubMed] [Google Scholar]
  7. Dittrich B., Robinson W. P., Knoblauch H., Buiting K., Schmidt K., Gillessen-Kaesbach G., Horsthemke B. Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13. Hum Genet. 1992 Nov;90(3):313–315. doi: 10.1007/BF00220089. [DOI] [PubMed] [Google Scholar]
  8. Driscoll D. J., Waters M. F., Williams C. A., Zori R. T., Glenn C. C., Avidano K. M., Nicholls R. D. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics. 1992 Aug;13(4):917–924. doi: 10.1016/0888-7543(92)90001-9. [DOI] [PubMed] [Google Scholar]
  9. Gartler S. M., Dyer K. A., Goldman M. A. Mammalian X chromosome inactivation. Mol Genet Med. 1992;2:121–160. doi: 10.1016/b978-0-12-462002-5.50010-8. [DOI] [PubMed] [Google Scholar]
  10. Glenn C. C., Nicholls R. D., Robinson W. P., Saitoh S., Niikawa N., Schinzel A., Horsthemke B., Driscoll D. J. Modification of 15q11-q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet. 1993 Sep;2(9):1377–1382. doi: 10.1093/hmg/2.9.1377. [DOI] [PubMed] [Google Scholar]
  11. Glenn C. C., Porter K. A., Jong M. T., Nicholls R. D., Driscoll D. J. Functional imprinting and epigenetic modification of the human SNRPN gene. Hum Mol Genet. 1993 Dec;2(12):2001–2005. doi: 10.1093/hmg/2.12.2001. [DOI] [PubMed] [Google Scholar]
  12. Glenn C. C., Saitoh S., Jong M. T., Filbrandt M. M., Surti U., Driscoll D. J., Nicholls R. D. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996 Feb;58(2):335–346. [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Mutirangura A., Greenberg F., Butler M. G., Malcolm S., Nicholls R. D., Chakravarti A., Ledbetter D. H. Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. Hum Mol Genet. 1993 Feb;2(2):143–151. doi: 10.1093/hmg/2.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mutirangura A., Jayakumar A., Sutcliffe J. S., Nakao M., McKinney M. J., Buiting K., Horsthemke B., Beaudet A. L., Chinault A. C., Ledbetter D. H. A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13) and refined localization of the SNRPN gene. Genomics. 1993 Dec;18(3):546–552. doi: 10.1016/s0888-7543(11)80011-x. [DOI] [PubMed] [Google Scholar]
  16. Nakao M., Sutcliffe J. S., Durtschi B., Mutirangura A., Ledbetter D. H., Beaudet A. L. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet. 1994 Feb;3(2):309–315. doi: 10.1093/hmg/3.2.309. [DOI] [PubMed] [Google Scholar]
  17. Razin A., Cedar H. DNA methylation and genomic imprinting. Cell. 1994 May 20;77(4):473–476. doi: 10.1016/0092-8674(94)90208-9. [DOI] [PubMed] [Google Scholar]
  18. Reed M. L., Leff S. E. Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nat Genet. 1994 Feb;6(2):163–167. doi: 10.1038/ng0294-163. [DOI] [PubMed] [Google Scholar]
  19. Reis A., Dittrich B., Greger V., Buiting K., Lalande M., Gillessen-Kaesbach G., Anvret M., Horsthemke B. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet. 1994 May;54(5):741–747. [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Sutcliffe J. S., Nakao M., Christian S., Orstavik K. H., Tommerup N., Ledbetter D. H., Beaudet A. L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994 Sep;8(1):52–58. doi: 10.1038/ng0994-52. [DOI] [PubMed] [Google Scholar]
  22. Wevrick R., Kerns J. A., Francke U. Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum Mol Genet. 1994 Oct;3(10):1877–1882. doi: 10.1093/hmg/3.10.1877. [DOI] [PubMed] [Google Scholar]