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Open Access 01-12-2009 | Research article

BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1

Authors: Anna Brunet, Lluís Armengol, Damià Heine, Jordi Rosell, Manel García-Aragonés, Elisabeth Gabau, Xavier Estivill, Miriam Guitart

Published in: BMC Medical Genetics | Issue 1/2009

Abstract

Background

Microdeletion of the chromosome 22q11.2 region is the most common genetic aberration among patients with velocardiofacial syndrome (VCFS) but a subset of subjects do not show alterations of this chromosome region.

Methods

We analyzed 18 patients with VCFS-like features by comparative genomic hybridisation (aCGH) array and performed a face-to-face slide hybridization with two different arrays: a whole genome and a chromosome 22-specific BAC array. Putative rearrangements were confirmed by FISH and MLPA assays.

Results

One patient carried a combination of rearrangements on 1q21.1, consisting in a microduplication of 212 kb and a close microdeletion of 1.15 Mb, previously reported in patients with variable phenotypes, including mental retardation, congenital heart defects (CHD) and schizophrenia. While 326 control samples were negative for both 1q21.1 rearrangements, one of 73 patients carried the same 212-kb microduplication, reciprocal to TAR microdeletion syndrome. Also, we detected four copy number variants (CNVs) inherited from one parent (a 744-kb duplication on 10q11.22; a 160 kb duplication and deletion on 22q11.21 in two cases; and a gain of 140 kb on 22q13.2), not present in control subjects, raising the potential role of these CNVs in the VCFS-like phenotype.

Conclusions

Our results confirmed aCGH as a successful strategy in order to characterize additional submicroscopic aberrations in patients with VCF-like features that fail to show alterations in 22q11.2 region. We report a 212-kb microduplication on 1q21.1, detected in two patients, which may contribute to CHD.

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McDermid HE, Morrow BE: Genomic disorders on 22q11. Am J Hum Genet. 2002, 70 (5): 1077-1088. 10.1086/340363.CrossRefPubMedPubMedCentral

Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O'Leary LA, Wong LY, Elixson EM, et al: A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003, 112 (1 Pt 1): 101-107. 10.1542/peds.112.1.101.CrossRefPubMed

Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H, Belohradsky B, Prieur M, et al: Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997, 34 (10): 798-804. 10.1136/jmg.34.10.798.CrossRefPubMedPubMedCentral

Cohen E, Chow EW, Weksberg R, Bassett AS: Phenotype of adults with the 22q11 deletion syndrome: A review. Am J Med Genet. 1999, 86 (4): 359-365. 10.1002/(SICI)1096-8628(19991008)86:4<359::AID-AJMG10>3.0.CO;2-V.CrossRefPubMedPubMedCentral

Gerdes M, Solot C, Wang PP, Moss E, LaRossa D, Randall P, Goldmuntz E, Clark BJ, Driscoll DA, Jawad A, et al: Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. Am J Med Genet. 1999, 85 (2): 127-133. 10.1002/(SICI)1096-8628(19990716)85:2<127::AID-AJMG6>3.0.CO;2-F.CrossRefPubMed

Hay BN: Deletion 22q11: spectrum of associated disorders. Semin Pediatr Neurol. 2007, 14 (3): 136-139. 10.1016/j.spen.2007.07.005.CrossRefPubMed

Kobrynski LJ, Sullivan KE: Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007, 370 (9596): 1443-1452. 10.1016/S0140-6736(07)61601-8.CrossRefPubMed

Perez E, Sullivan KE: Chromosome 22q11.2 deletion syndrome (DiGeorge and velocardiofacial syndromes). Curr Opin Pediatr. 2002, 14 (6): 678-683. 10.1097/00008480-200212000-00005.CrossRefPubMed

Robin NH, Shprintzen RJ: Defining the clinical spectrum of deletion 22q11.2. J Pediatr. 2005, 147 (1): 90-96. 10.1016/j.jpeds.2005.03.007.CrossRefPubMed

10.

Frohn-Mulder IM, Wesby Swaay E, Bouwhuis C, Van Hemel JO, Gerritsma E, Niermeyer MF, Hess J: Chromosome 22q11 deletions in patients with selected outflow tract malformations. Genet Couns. 1999, 10 (1): 35-41.PubMed

11.

Sivertsen A, Lie RT, Wilcox AJ, Abyholm F, Vindenes H, Haukanes BI, Houge G: Prevalence of duplications and deletions of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate. Am J Med Genet A. 2007, 143 (2): 129-134.CrossRef

12.

Smith A, St Heaps L, Robson L: Apparently unrelated cytogenetic abnormalities among 462 probands referred for the detection of del(22q) by FISH. Am J Med Genet. 2002, 113 (4): 346-350. 10.1002/ajmg.10800.CrossRefPubMed

13.

Katzman PJ, Wang B, Sawhney M, Wang N: Differential detection of deletion 22q11.2 syndrome by specialty and indication. Pediatr Dev Pathol. 2005, 8 (5): 557-567. 10.1007/s10024-005-0056-1.CrossRefPubMed

14.

Brunet A, Gabau E, Perich RM, Valdesoiro L, Brun C, Caballin MR, Guitart M: Microdeletion and microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/Velocardiofacial syndrome. Am J Med Genet A. 2006, 140 (22): 2426-2432.CrossRefPubMed

15.

Fernandez L, Lapunzina P, Pajares IL, Palomares M, Martinez I, Fernandez B, Quero J, Garcia-Guereta L, Garcia-Alix A, Burgueros M, et al: Unrelated chromosomal anomalies found in patients with suspected 22q11.2 deletion. Am J Med Genet A. 2008, 146A (9): 1134-1141. 10.1002/ajmg.a.32256.CrossRefPubMed

16.

Daw SC, Taylor C, Kraman M, Call K, Mao J, Schuffenhauer S, Meitinger T, Lipson T, Goodship J, Scambler P: A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet. 1996, 13 (4): 458-460. 10.1038/ng0896-458.CrossRefPubMed

17.

Van Esch H, Groenen P, Fryns JP, Ven Van de W, Devriendt K: The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet Couns. 1999, 10 (1): 59-65.PubMed

18.

Berend SA, Spikes AS, Kashork CD, Wu JM, Daw SC, Scambler PJ, Shaffer LG: Dual-probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci. Am J Med Genet. 2000, 91 (4): 313-317. 10.1002/(SICI)1096-8628(20000410)91:4<313::AID-AJMG13>3.0.CO;2-U.CrossRefPubMed

19.

Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, et al: Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003, 362 (9393): 1366-1373. 10.1016/S0140-6736(03)14632-6.CrossRefPubMed

20.

Zweier C, Sticht H, Aydin-Yaylagul I, Campbell CE, Rauch A: Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am J Hum Genet. 2007, 80 (3): 510-517. 10.1086/511993.CrossRefPubMedPubMedCentral

21.

Miyake N, Shimokawa O, Harada N, Sosonkina N, Okubo A, Kawara H, Okamoto N, Kurosawa K, Kawame H, Iwakoshi M, et al: BAC array CGH reveals genomic aberrations in idiopathic mental retardation. Am J Med Genet A. 2006, 140 (3): 205-211.CrossRefPubMed

22.

Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, et al: Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet. 2004, 41 (4): 241-248. 10.1136/jmg.2003.017731.CrossRefPubMedPubMedCentral

23.

Thienpont B, Mertens L, de Ravel T, Eyskens B, Boshoff D, Maas N, Fryns JP, Gewillig M, Vermeesch JR, Devriendt K: Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur Heart J. 2007, 28 (22): 2778-2784. 10.1093/eurheartj/ehl560.CrossRefPubMed

24.

Vissers LE, Veltman JA, van Kessel AG, Brunner HG, et al: Identification of disease genes by whole genome CGH arrays. Hum Mol Genet. 2005, 14 (Spec No 2): R215-223. 10.1093/hmg/ddi268.CrossRefPubMed

25.

Cusco I, del Campo M, Vilardell M, Gonzalez E, Gener B, Galan E, Toledo L, Perez-Jurado LA: Array-CGH in patients with Kabuki-like phenotype: identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration. BMC Med Genet. 2008, 9: 27-10.1186/1471-2350-9-27.CrossRefPubMedPubMedCentral

26.

Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, et al: DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer. 2003, 36 (4): 361-374. 10.1002/gcc.10155.CrossRefPubMed

27.

Wang NJ, Liu D, Parokonny AS, Schanen NC: High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am J Hum Genet. 2004, 75 (2): 267-281. 10.1086/422854.CrossRefPubMedPubMedCentral

28.

Pantano L, Armengol L, Villatoro S, Estivill X: ProSeeK: A web server for MLPA probe design. BMC Genomics. 2008, 9 (1): 573-10.1186/1471-2164-9-573.CrossRefPubMedPubMedCentral

29.

Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002, 30 (12): e57-10.1093/nar/gnf056.CrossRefPubMedPubMedCentral

30.

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, et al: Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008, 359 (16): 1685-1699. 10.1056/NEJMoa0805384.CrossRefPubMedPubMedCentral

31.

Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C: Detection of large-scale variation in the human genome. Nat Genet. 2004, 36 (9): 949-951. 10.1038/ng1416.CrossRefPubMed

32.

Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, et al: Global variation in copy number in the human genome. Nature. 2006, 444 (7118): 444-454. 10.1038/nature05329.CrossRefPubMedPubMedCentral

33.

Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, Sprysak KA, Tomaszewski R, Haase SM, Vicen-Wyhony LM, et al: Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res. 2004, 94 (11): 1429-1435. 10.1161/01.RES.0000130528.72330.5c.CrossRefPubMed

34.

Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, et al: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008, 320 (5875): 539-543. 10.1126/science.1155174.CrossRefPubMed

35.

Cheroki C, Krepischi-Santos AC, Szuhai K, Brenner V, Kim CA, Otto PA, Rosenberg C: Genomic imbalances associated with mullerian aplasia. J Med Genet. 2008, 45 (4): 228-232. 10.1136/jmg.2007.051839.CrossRefPubMed

36.

Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, et al: Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007, 39 (3): 319-328. 10.1038/ng1985.CrossRefPubMedPubMedCentral

37.

Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, et al: Large recurrent microdeletions associated with schizophrenia. Nature. 2008, 455 (7210): 232-236. 10.1038/nature07229.CrossRefPubMedPubMedCentral

38.

International Schizophrenia Consortium: Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008, 455 (7210): 237-241. 10.1038/nature07239.CrossRef

39.

Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, et al: Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008, 40 (12): 1466-1471. 10.1038/ng.279.CrossRefPubMedPubMedCentral

40.

Gu H, Smith FC, Taffet SM, Delmar M: High incidence of cardiac malformations in connexin40-deficient mice. Circ Res. 2003, 93 (3): 201-206. 10.1161/01.RES.0000084852.65396.70.CrossRefPubMed

41.

Ni X, Valente J, Azevedo MH, Pato MT, Pato CN, Kennedy JL: Connexin 50 gene on human chromosome 1q21 is associated with schizophrenia in matched case control and family-based studies. J Med Genet. 2007, 44 (8): 532-536. 10.1136/jmg.2006.047944.CrossRefPubMedPubMedCentral

42.

Barbi G, Spaich C, Adolph S, Rossier E, Kehrer-Sawatzki H: Supernumerary der(1) marker chromosome derived from a ring chromosome 1 which has retained the original centromere and euchromatin from 1q21.1 --> q21.3 with substantial loss of 1q12 heterochromatin in a female with dysmorphic features and psychomotoric developmental delay. Am J Med Genet A. 2005, 132 (4): 419-424.CrossRef

43.

Finelli P, Cavalli P, Giardino D, Gottardi G, Natacci F, Savasta S, Larizza L: FISH characterization of a supernumerary r(1)(::cen-->q22::q22-->sq21::) chromosome associated with multiple anomalies and bilateral cataracts. Am J Med Genet. 2001, 104 (2): 157-164. 10.1002/ajmg.10019.CrossRefPubMed

44.

Giardino D, Bettio D, Gottardi G, Rizzi N, Pierluigi M, Perfumo C, Cali A, Dagna Bricarelli F, Larizza L: FISH characterization of two supernumerary r(1) associated with distinct clinical phenotypes. Am J Med Genet. 1999, 84 (4): 377-380. 10.1002/(SICI)1096-8628(19990604)84:4<377::AID-AJMG14>3.0.CO;2-U.CrossRefPubMed

45.

Ramirez-Duenas ML, Gonzalez GJ: fra(1) (p11), fra(1) (q22) and r(1) (p11q22) in a retarded girl. Ann Genet. 1992, 35 (3): 178-182.PubMed

46.

Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, et al: Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007, 80 (2): 232-240. 10.1086/510919.CrossRefPubMed

47.

Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, Verschuuren-Bemelmans CC, Vernon E, Brown KW, Newbury-Ecob RA: Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002, 39 (12): 876-881. 10.1136/jmg.39.12.876.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/10/144/prepub

Title: BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1
Authors: Anna Brunet
Lluís Armengol
Damià Heine
Jordi Rosell
Manel García-Aragonés
Elisabeth Gabau
Xavier Estivill
Miriam Guitart
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-10-144

Keynote webinar | Spotlight on medication adherence

Springer Medicine

BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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