BACKGROUND: Inversions are balanced structural chromosome rearrangements, which can influence gene expression and the risk of unbalanced chromosome constitution in offspring. Many examples of inversion polymorphisms exist in human, affecting both heterochromatic regions and euchromatin. RESULTS: We describe a novel, 15 Mb long paracentric inversion, inv(21)(q21.1q22.11), affecting more than a third of human 21q. Despite of its length, the inversion cannot be detected using karyotyping due to similar band patterns on the normal and inverted chromosomes, and is therefore likely to escape attention. Its identification was aided by the repeated observation of the same pair of 150 kb long duplications present in cis on chromosome 21 in three Czech families subjected to microarray analysis. The finding prompted us to hypothesise that this co-occurrence of two remote duplications could be associated with an inversion of the intervening segment, and this speculation turned out to be right. The inversion was confirmed in a series of FISH experiments which also showed that the second copy of each of the duplications was always located at the opposite end of the inversion. The presence of the same pair of duplications in additional individuals reported in public databases indicates that the inversion may also be present in other populations. Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660. Although the breakpoints affect protein-coding genes, the occurrence of the inversion in normal parents and siblings of our patients and the occurrence of the duplications in unaffected controls in databases indicate that this rare variant is rather non-pathogenic. The inverted segment carried an identical shared haplotype in the three families studied. The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion. CONCLUSIONS: The identification of inv(21)(q21.1q22.11) supports the notion that paracentric inversions are the most common form of chromosomal variation and that some of them may still remain undetected.

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Gennet Prague Czech Republic

Zobrazit více v PubMed

Walzer S, Breau G, Gerald PS. A chromosome survey of 2,400 normal newborn infants. J Pediatr. 1969;74:438–448. doi: 10.1016/S0022-3476(69)80202-7. PubMed DOI

Feuk L. Inversion variants in the human genome: role in disease and genome architecture. Genome Med. 2010;2:11. doi: 10.1186/gm132. PubMed DOI PMC

Salm MP, Horswell SD, Hutchison CE, Speedy HE, Yang X, Liang L, Schadt EE, Cookson WO, Wierzbicki AS, Naoumova RP, Shoulders CC. The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism. Genome Res. 2012;22:1144–1153. doi: 10.1101/gr.126037.111. PubMed DOI PMC

Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, Ohashi H, Voullaire L, Larizza D, Giorda R, Weber JL, Ledbetter DH, Zuffardi O. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet. 2001;68:874–883. doi: 10.1086/319506. PubMed DOI PMC

Gilling M, Dullinger JS, Gesk S, Metzke-Heidemann S, Siebert R, Meyer T, Brondum-Nielsen K, Tommerup N, Ropers HH, Tumer Z, Kalscheuer VM, Thomas NS. Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans. Am J Hum Genet. 2006;78:878–883. doi: 10.1086/503632. PubMed DOI PMC

Fickelscher I, Liehr T, Watts K, Bryant V, Barber JC, Heidemann S, Siebert R, Hertz JM, Tumer Z, Simon Thomas N. The variant inv(2)(p11.2q13) is a genuinely recurrent rearrangement but displays some breakpoint heterogeneity. Am J Hum Genet. 2007;81:847–856. doi: 10.1086/521226. PubMed DOI PMC

Youings S, Ellis K, Ennis S, Barber J, Jacobs P. A study of reciprocal translocations and inversions detected by light microscopy with special reference to origin, segregation, and recurrent abnormalities. Am J Med Genet A. 2004;126A:46–60. doi: 10.1002/ajmg.a.20553. PubMed DOI

Martinez-Fundichely A, Casillas S, Egea R, Ramia M, Barbadilla A, Pantano L, Puig M, Caceres M. InvFEST, a database integrating information of polymorphic inversions in the human genome. Nucleic Acids Res. 2014;42:D1027–D1032. doi: 10.1093/nar/gkt1122. PubMed DOI PMC

Macdonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42:D986–D992. doi: 10.1093/nar/gkt958. PubMed DOI PMC

Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet. 1993;5:236–241. doi: 10.1038/ng1193-236. PubMed DOI

Kleczkowska A, Fryns JP, Van den Berghe H. Pericentric inversions in man: personal experience and review of the literature. Hum Genet. 1987;75:333–338. doi: 10.1007/BF00284103. PubMed DOI

Madan K. Paracentric inversions: a review. Hum Genet. 1995;96:503–515. PubMed

Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, Costa T, Grebe T, Cox S, Tsui LC, Scherer SW. A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet. 2001;29:321–325. doi: 10.1038/ng753. PubMed DOI PMC

Antonacci F, Kidd JM, Marques-Bonet T, Ventura M, Siswara P, Jiang Z, Eichler EE. Characterization of six human disease-associated inversion polymorphisms. Hum Mol Genet. 2009;18:2555–2566. doi: 10.1093/hmg/ddp187. PubMed DOI PMC

Thomas NS, Bryant V, Maloney V, Cockwell AE, Jacobs PA. Investigation of the origins of human autosomal inversions. Hum Genet. 2008;123:607–616. doi: 10.1007/s00439-008-0510-z. PubMed DOI

Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–846. doi: 10.1038/ng.909. PubMed DOI PMC

Vogler C, Gschwind L, Rothlisberger B, Huber A, Filges I, Miny P, Auschra B, Stetak A, Demougin P, Vukojevic V, Kolassa IT, Elbert T, de Quervain DJ, Papassotiropoulos A. Microarray-based maps of copy-number variant regions in European and sub-Saharan populations. PLoS One. 2010;5:e15246. doi: 10.1371/journal.pone.0015246. PubMed DOI PMC

Morel F, Laudier B, Guerif F, Couet ML, Royere D, Roux C, Bresson JL, Amice V, De Braekeleer M, Douet-Guilbert N. Meiotic segregation analysis in spermatozoa of pericentric inversion carriers using fluorescence in-situ hybridization. Hum Reprod. 2007;22:136–141. PubMed

Jaarola M, Martin RH, Ashley T. Direct evidence for suppression of recombination within two pericentric inversions in humans: a new sperm-FISH technique. Am J Hum Genet. 1998;63:218–224. doi: 10.1086/301900. PubMed DOI PMC

Bhatt SS, Manvelyan M, Moradkhani K, Hunstig F, Mrasek K, Puechberty J, Lefort G, Sarda P, Weise A, Liehr T, Pellestor F. Inverted segment size and the presence of recombination hot spot clusters matter in sperm segregation analysis. Cytogenet Genome Res. 2014;142:145–149. doi: 10.1159/000356142. PubMed DOI

O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012;338:1619–1622. doi: 10.1126/science.1227764. PubMed DOI PMC

de Jong S, Chepelev I, Janson E, Strengman E, van den Berg LH, Veldink JH, Ophoff RA. Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner. BMC Genomics. 2012;13:458. doi: 10.1186/1471-2164-13-458. PubMed DOI PMC

Courtens W, Grossman D, Van Roy N, Messiaen L, Vamos E, Toppet V, Haumont D, Streydio C, Jauch A, Vermeesch JR, Speleman F. Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion. Hum Genet. 1998;103:497–505. doi: 10.1007/s004390050857. PubMed DOI

Barbi G, Kennerknecht I, Wohr G, Avramopoulos D, Karadima G, Petersen MB. Mirror-symmetric duplicated chromosome 21q with minor proximal deletion, and with neocentromere in a child without the classical Down syndrome phenotype. Am J Med Genet. 2000;91:116–122. doi: 10.1002/(SICI)1096-8628(20000313)91:2<116::AID-AJMG7>3.0.CO;2-Q. PubMed DOI

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. 2003;103:14–16. doi: 10.1159/000076284. PubMed DOI

Mau UA, Petruch UR, Kaiser P, Eggermann T. Familial robertsonian translocation 15;21 and rare paracentric inv(21): unexpected re-inversion in a child with translocation trisomy 21. Eur J Hum Genet. 2000;8:815–819. doi: 10.1038/sj.ejhg.5200544. PubMed DOI

Entesarian M, Carlsson B, Mansouri MR, Stattin EL, Holmberg E, Golovleva I, Stefansson H, Klar J, Dahl N. A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population. Am J Med Genet A. 2009;149A:380–386. doi: 10.1002/ajmg.a.32663. PubMed DOI

Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, Bassett AS, Seller A, Holmes CC, Ragoussis J. QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 2007;35:2013–2025. doi: 10.1093/nar/gkm076. PubMed DOI PMC