Human Genetics

, Volume 126, Issue 4, pp 589–602 | Cite as

Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping

  • Ayman W. El-Hattab
  • Teresa A. Smolarek
  • Martha E. Walker
  • Elizabeth K. Schorry
  • LaDonna L. Immken
  • Gayle Patel
  • Mary-Alice Abbott
  • Brendan C. Lanpher
  • Zhishuo Ou
  • Sung-Hae L. Kang
  • Ankita Patel
  • Fernando Scaglia
  • James R. Lupski
  • Sau Wai Cheung
  • Pawel Stankiewicz
Original Investigation

Abstract

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.

References

  1. Armstrong E, Cannizzaro L, Bergman M, Huebner K, Alitalo K (1993) The c-src tyrosine kinase (CSK) gene, a potential antioncogene, localizes to human chromosome region 15q23–q25. Cytogenet Cell Genet 60:119–120CrossRefGoogle Scholar
  2. Ben-Shachar S, Lanpher B, German JR, Potocki L, Sreenath Nagamani SC, Franco LM, Malphrus A, Bottenfield GW, Spence JE, Amato S, Rousseau JA, Moghaddam B, Skinner C, Skinner SA, Bernes S, Armstrong N, Shinawi M, Stankiewicz P, Patel A, Cheung S-W, Lupski JR, Beaudet AL, Sahoo T (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 46:382–388Google Scholar
  3. Bettelheim D, Hengstaschlager M, Drhonsky R, Eppel W, Bernaschek G (1998) Two cases of prenatally diagnosed diaphragmatic hernia accompanied by the same undescribed chromosomal deletion (15q24 de novo). Clin Genet 53:319–320PubMedCrossRefGoogle Scholar
  4. Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, Lupski JR (2003) Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am J Hum Genet 73:1302–1315CrossRefPubMedGoogle Scholar
  5. Bi W, Sapir T, Shchelochkov OA, Zhang F, Withers MA, Hunter JV, Levy T, Shinder V, Peiffer DA, Gunderson KL, Nezarati MM, Shotts VA, Amato SS, Savage SK, Harris DJ, Day-Salvatore DL, Horner M, Lu XY, Sahoo T, Yanagawa Y, Beaudet AL, Cheung SW, Martinez S, Lupski JR, Reiner O (2009) Increased LIS1 expression affects human and mouse brain development. Nat Genet 41:168–177CrossRefPubMedGoogle Scholar
  6. Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D (1999) A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality—and tolerance of segmental aneuploidy—in humans. Am J Hum Genet 64:1702–1708CrossRefPubMedGoogle Scholar
  7. Browne CE, Hatchwell E, Protopapas A, Ramos J (2000) Duplication of medial 15q confirmed by FISH. J Med Genet 37:E10CrossRefPubMedGoogle Scholar
  8. Carvalho CM, Zhang F, Liu P, Patel A, Sahoo T, Bacino CA, Shaw C, Peacock S, Pursley A, Tavyev YJ, Ramocki MB, Nawara M, Obersztyn E, Vianna-Morgante AM, Stankiewicz P, Zoghbi HY, Cheung SW, Lupski JR (2009) Complex rearrangements in patients with duplications of MECP2 can occur by Fork stalling and template switching. Hum Mol Genet 18:2188–2203CrossRefPubMedGoogle Scholar
  9. Cheung SW, Shaw CA, Yu W, Li J, Ou Z, Patel A, Yatsenko SA, Cooper ML, Furman P, Stankiewicz P, Lupski JR, Chinault AC, Beaudet AL (2005) Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med 7:422–432PubMedCrossRefGoogle Scholar
  10. Clark RD (1984) Letter to the editor: del(15)(q22q24) syndrome with Potter sequence. Am J Med Genet 19:703–705CrossRefPubMedGoogle Scholar
  11. Cushman LJ, Torres-Martinez W, Cherry AM, Manning MA, Abdul-Rahman O, Anderson CE, Punnett HH, Thurston VC, Sweeney D, Vance GH (2005) A report of three patients with an interstitial deletion of chromosome 15q24. Am J Med Genet 137:65–71CrossRefPubMedGoogle Scholar
  12. Dhaliwal MK, Menos D, Checkley P, Lieber E (1990) A case of an unbalanced interstitial translocation involving chromosome 4p and 15q in a newborn with multiple congenital anomalies. Am J Hum Genet 47(Suppl):A28Google Scholar
  13. Fleischer TC, Yun UJ, Ayer DE (2003) Identification and characterization of three new components of the mSin3A corepressor complex. Mol Cell Biol 23:3456–3467CrossRefPubMedGoogle Scholar
  14. Formiga LF, Poenaru L, Couronne F, Flori E, Eibel JL, Deminatti MM, Savary JB, Lai JL, Gilgenkrantz S, Pierson M (1988) Interstitial deletion of chromosome15: two cases. Hum Genet 80:401–404CrossRefPubMedGoogle Scholar
  15. Gu W, Zhang F, Lupski JR (2008) Mechanisms for human genomic rearrangements. Pathogenetics 1:4CrossRefPubMedGoogle Scholar
  16. Han JY, Kim KH, Lee HD, Moon SY, Shaffer LG (1999) De novo direct duplication of 15q15 → q24 in a newborn boy with mild manifestations. Am J Med Genet 87:395–398CrossRefPubMedGoogle Scholar
  17. Kiholm Lund AB, Hove HD, Kirchhoff M (2008) A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients. Eur J Med Genet 51:520–526CrossRefPubMedGoogle Scholar
  18. Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M (2007) A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet 50:256–263CrossRefPubMedGoogle Scholar
  19. Klopocki E, Graul-Neumann LM, Grieben U, Tönnies H, Ropers HH, Horn D, Mundlos S, Ullmann R (2008) A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH. Eur J Pediatr 167:903–908CrossRefPubMedGoogle Scholar
  20. Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, de Vries BB (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 38:999–1001CrossRefPubMedGoogle Scholar
  21. Lee JA, Carvalho CM, Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 28:1235–1247CrossRefGoogle Scholar
  22. Nagamani SC, Zhang F, Shchelochkov OA, Bi W, Ou Z, Scaglia F, Probst FJ, Shinawi M, Eng C, Hunter JV, Sparagana S, Lagoe E, Fong CT, Pearson M, Doco-Fenzy M, Landais E, Mozelle M, Chinault AC, Patel A, Bacino CA, Sahoo T, Kang SH, Cheung SW, Lupski JR, Stankiewicz P (2009) Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J Med Genet (in press)Google Scholar
  23. Niehues R, Hasilik M, Alton G, Körner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T (1998) Carbohydrate-deficient glycoprotein syndrome type Ib: phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 101:1414–1420CrossRefPubMedGoogle Scholar
  24. Ou Z, Kang SH, Shaw CA, Carmack CE, White LD, Patel A, Beaudet AL, Cheung SW, Chinault AC (2008) Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses. Genet Med 10:278–289PubMedGoogle Scholar
  25. Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL (2007) Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424:398–405CrossRefGoogle Scholar
  26. Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, Nürnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fernández-Martínez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, Nürnberg P, Reis A, Rauch A (2007) Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet 80:550–560CrossRefPubMedGoogle Scholar
  27. Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR (2007) Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80:633–649CrossRefPubMedGoogle Scholar
  28. Probst FJ, Roeder ER, Enciso VB, Ou Z, Cooper ML, Eng P, Li J, Gu Y, Stratton RF, Chinault AC, Shaw CA, Sutton VR, Cheung SW, Nelson DL (2007) Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation. Am J Med Genet 143A:1358–1365CrossRefPubMedGoogle Scholar
  29. Reim K, Wegmeyer H, Brandstatter JH, Xue M, Rosenmund C, Drebach T, Hofmann K, Brose N (2005) Structurally and functionally unique complexins at retinal ribbon synapses. J Cell Biol 69:669–680CrossRefGoogle Scholar
  30. Roggenbuck JA, Mendelsohn NJ, Tenenholz B, Ladda RL, Fink JM (2004) Duplication of the distal long arm of chromosome 15: report of three new patients and review of the literature. Am J Med Genet 126A:398–402CrossRefPubMedGoogle Scholar
  31. Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJ, Eichler EE (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38:1038–1042CrossRefPubMedGoogle Scholar
  32. Sharp AJ, Selzer RR, Veltman JA, Gimelli S, Gimelli G, Striano P, Coppola A, Regan R, Price SM, Knoers NV, Eis PS, Brunner HG, Hennekam RC, Knight SJ, de Vries BB, Zuffardi O, Eichler EE (2007) Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 16:567–572CrossRefPubMedGoogle Scholar
  33. Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJ, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322–328CrossRefPubMedGoogle Scholar
  34. Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 38:1032–1037CrossRefPubMedGoogle Scholar
  35. Shchelochkov OA, Cooper ML, Ou Z, Peacock S, Yatsenko SA, Brown CW, Fang P, Stankiewicz P, Cheung SW (2008) Mosaicism for r(X) and der(X)del(X)(p11.23)dup(X)(p11.21p11.22) provides insight into the possible mechanism of rearrangement. Mol Cytogenet 1:16CrossRefPubMedGoogle Scholar
  36. Slavotinek AM (2008) Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 124:1–17CrossRefPubMedGoogle Scholar
  37. Spruijt L, Engelen JJM, Bruinen-Smeijsters LP, Albrechts JCM, Schrander J, Schrander-Stumpel CTRM (2004) A patient with a de novo 15q24q26.1 interstitial deletion, developmental delay, mild dysmorphism and very blue irises. Am J Med Genet 129A:312–315CrossRefPubMedGoogle Scholar
  38. Stankiewicz P, Beaudet AL (2007) Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 17:182–192CrossRefPubMedGoogle Scholar
  39. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18:74–82CrossRefPubMedGoogle Scholar
  40. Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL (2001) Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46, XY sex reversal and adrenal insufficiency. J Clin Endocr Metab 86:3820–3825CrossRefPubMedGoogle Scholar
  41. Van Esch H, Backx L, Pijkels E, Fryns JP (2009) Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome. Eur J Med Genet 52:153–156CrossRefPubMedGoogle Scholar
  42. Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR (2009) The DNA replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exonic complex rearrangements. Nat Genet (in press)Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ayman W. El-Hattab
    • 1
  • Teresa A. Smolarek
    • 2
  • Martha E. Walker
    • 2
  • Elizabeth K. Schorry
    • 2
  • LaDonna L. Immken
    • 3
  • Gayle Patel
    • 3
  • Mary-Alice Abbott
    • 4
  • Brendan C. Lanpher
    • 5
  • Zhishuo Ou
    • 1
  • Sung-Hae L. Kang
    • 1
  • Ankita Patel
    • 1
  • Fernando Scaglia
    • 1
  • James R. Lupski
    • 1
  • Sau Wai Cheung
    • 1
  • Pawel Stankiewicz
    • 1
    • 6
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Division of Human GeneticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.Clinical Genetics, Specially for ChildrenAustinUSA
  4. 4.Clinical GeneticsBaystate Medical CenterSpringfieldUSA
  5. 5.Division of Genetics and Genomic MedicineVanderbilt UniversityNashvilleUSA
  6. 6.Department of Medical GeneticsInstitute of Mother and ChildWarsawPoland

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