Constitutional Complex Chromosomal Rearrangements (CCRs) are very rare. While the vast majority of CCRs involve more than one chromosome, only seven cases describe CCRs with four or more breakpoints within a single chromosome. Here, we present a patient with multiple congenital anomalies and mental retardation. Array Comparative Genomic Hybridisation (array CGH), FISH and Multicolour Banding FISH revealed a de novo complex rearrangement with two deletions, a duplication and an inversion of 4q. This CCR involving at least seven breakpoints is one of the most complex rearrangements of a single chromosome reported thus far. Potential mechanisms generating such complex rearrangements are discussed.

1.
Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN: Translocation and gross deletion breakpoints in human inherited disease and cancer. I: Nucleotide composition and recombination-associated motifs. Hum Mutat 22:229–244 (2003).
2.
Aten JA, Stap J, Krawczyk PM, van Oven CH, Hoebe RA, Essers J, Kanaar R: Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303:92–95 (2004).
3.
Ballif BC, Yu W, Shaw CA, Kashork CD, Shaffer LG: Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum Mol Genet 12:2153–2165 (2003).
4.
Batanian JR, Eswara MS: De novo apparently balanced complex chromosome rearrangement (CCR) involving chromosomes 4, 18, and 21 in a girl with mental retardation: report and review. Am J Med Genet 78:44–51 (1998).
5.
Chudoba I, Hickmann G, Friedrich T, Jauch A, Kozlowski P, Senger G: mBAND: a high resolution multicolor banding technique for the detection of complex intrachromosomal aberrations. Cytogenet Genome Res 104:390–393 (2004).
6.
Chuzhanova N, Abeysinghe SS, Krawczak M, Cooper DN: Translocation and gross deletion breakpoints in human inherited disease and cancer. II: Potential involvement of repetitive sequence elements in secondary structure formation between DNA ends. Hum Mutat 22:245–251 (2003).
7.
de Vries BB, Pfundt R, Leisink M, Koolen DA, Vissers LE, Janssen IM, Reijmersdal S, Nillesen WM, Huys EH, Leeuw N, Smeets D, Sistermans EA, Feuth T, Ravenswaaij-Arts CM, van Kessel AG, Schoenmakers EF, Brunner HG, Veltman JA: Diagnostic genome profiling in mental retardation. Am J Hum Genet 77:606–616 (2005).
8.
Gribble SM, Prigmore E, Burford DC, Porter KM, Ng BL, Douglas EJ, Fiegler H, Carr P, Kalaitzopoulos D, Clegg S, Sandstrom R, Temple IK, Youings SA, Thomas NS, Dennis NR, Jacobs PA, Crolla JA, Carter NP: The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes. J Med Genet 42:8–16 (2005).
9.
Houge G, Liehr T, Schoumans J, Ness GO, Solland K, Starke H, Claussen U, Stromme P, Akre B, Vermeulen S: Ten years follow up of a boy with a complex chromosomal rearrangement: going from a >5 to 15-breakpoint CCR. Am J Med Genet A 118:235–240 (2003).
10.
Kuechler A, Ziegler M, Blank C, Rommel B, Bullerdiek J, Ahrens J, Claussen U, Liehr T: A highly complex chromosomal rearrangement between five chromosomes in a healthy female diagnosed in preparation for intracytoplasmatic sperm injection. J Histochem Cytochem 53:355–357 (2005).
11.
Kurahashi H, Shaikh T, Takata M, Toda T, Emanuel BS: The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats. Am J Hum Genet 72:733–738 (2003).
12.
Patsalis PC, Evangelidou P, Charalambous S, Sismani C: Fluorescence in situ hybridization characterization of apparently balanced translocation reveals cryptic complex chromosomal rearrangements with unexpected level of complexity. Eur J Hum Genet 12:647–653 (2004).
13.
Romain DR, Columbano-Green LM, Parfitt RG, Chapman CJ, Smythe RH, Gebbie OB: A complex structural rearrangement of chromosome 4 in a woman without phenotypic features of Wolf-Hirschhorn syndrome. Clin Genet 28:166–172 (1985).
14.
Rosenberg C, Knijnenburg J, Chauffaille ML, Brunoni D, Catelani AL, Sloos W, Szuhai K, Tanke HJ: Array CGH detection of a cryptic deletion in a complex chromosome rearrangement. Hum Genet 116:390–394 (2005).
15.
Roth DB, Wilson JH: Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol Cell Biol 6:4295–4304 (1986).
16.
Shaw CJ, Lupski JR: Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 13 Spec No 1:R57–64 (2004).
17.
Shim SH, Wyandt HE, McDonald-McGinn DM, Zackai EZ, Milunsky A: Molecular cytogenetic characterization of multiple intrachromosomal rearrangements of chromosome 2q in a patient with Waardenburg’s syndrome and other congenital defects. Clin Genet 66:46–52 (2004).
18.
Speicher MR, Carter NP: The new cytogenetics: blurring the boundaries with molecular biology. Nat Rev Genet 6:782–792 (2005).
19.
Tonk VS, Wilson GN, Yatsenko SA, Stankiewicz P, Lupski, JR Schutt RC, Northup JK, Velagaleti GV: Molecular cytogenetic characterization of a familial der(1)del(1)(p36.33)dup(1)(p36.33p36.22) with variable phenotype. Am J Med Genet A 139:136–340 (2005).
20.
Tuck-Muller CM, Varela M, Li S, Pridjian G, Chen H, Wertelecki W: A complex five breakpoint intrachromosomal rearrangement ascertained through two recombinant offspring. Am J Med Genet 63:392–395 (1996).
21.
Van Esch H, Syrrou M, Lagae L: Refractory photosensitive epilepsy associated with a complex rearrangement of chromosome 2. Neuropediatrics 33:320–323 (2002).
22.
Vermeesch JR, Melotte C, Froyen G, Van Vooren S, Dutta B, Maas N, Vermeulen S, Menten B, Speleman F, De Moor B, Van Hummelen P, Marynen P, Fryns JP, Devriendt K: Molecular karyotyping: array CGH quality criteria for constitutional genetic diagnosis. J Histochem Cytochem 53:413–422 (2005).
23.
Weise A, Rittinger O, Starke H, Ziegler M, Claussen U, Liehr T: De novo 9-break-event in one chromosome 21 combined with a microdeletion in 21q22.11 in a mentally retarded boy with short stature. Cytogenet Genome Res 103:14–16 (2003).
24.
Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell G, Gribble SM, Burford DC, Carter NP, Hobson DL, Garbern JY, Kamholz J, Heng H, Hodes ME, Malcolm S, Hobson GM: Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombi- nation. Am J Hum Genet 77:966–987 (2005).
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