Complex chromosome rearrangements related 15q14 microdeletion plays a relevant role in phenotype expression and delineates a novel recurrent syndrome
© Roberti et al; licensee BioMed Central Ltd. 2011
Received: 27 October 2010
Accepted: 19 April 2011
Published: 19 April 2011
Complex chromosome rearrangements are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints. These are rarely seen in the general population but their frequency should be much higher due to balanced states with no phenotypic presentation. These abnormalities preferentially occur de novo during spermatogenesis and are transmitted in families through oogenesis.
Here, we report a de novo complex chromosome rearrangement that interests eight chromosomes in eighteen-year-old boy with an abnormal phenotype consisting in moderate developmental delay, cleft palate, and facial dysmorphisms.
Standard G-banding revealed four apparently balanced traslocations involving the chromosomes 1;13, 3;19, 9;15 and 14;18 that appeared to be reciprocal. Array-based comparative genomic hybridization analysis showed no imbalances at all the breakpoints observed except for an interstitial microdeletion on chromosome 15. This deletion is 1.6 Mb in size and is located at chromosome band 15q14, distal to the Prader-Willi/Angelman region. Comparing the features of our patient with published reports of patients with 15q14 deletion this finding corresponds to the smallest genomic region of overlap. The deleted segment at 15q14 was investigated for gene content.
Chromosomal abnormalities are the most commonly recognized causes of developmental delay and mental retardation, accounting for approximately 10% of cases .
High-resolution molecular methods, i.e. array-based comparative genomic hybridization (array-CGH) allow a careful characterization of unbalanced rearrangements, enabling a more explicit genotype/phenotype correlation  and enhancing the capacity to map disease-causing genes .
Complex chromosome rearrangements (CCRs) are defined as constitutional structural chromosomal rearrangements with at least three cytogenetically visible breakpoints and exchange of genetic material between two or more chromosomes . These are rare, although clinically important to recognize, because carriers can have phenotypes spanning from normal individuals, infertile males, mental retardation, to congenital abnormalities and they can be responsible for recurrent miscarriages in females [5–7].
The alterations can arise de novo or be familial; familial CCRs tend to involve less chromosomes and fewer breakpoints than de novo CCRs . A survey of 269371 prenatal studies reported a total of 246 apparently cytogenetically balanced anomalies; among them, 3% were de novo presumably balanced CCRs . There is a high prevalence of maternal origin in familial CCRs and a high incidence of mental retardation and phenotypic abnormalities in de novo CCRs, but in rare occasions they can be found in phenotypically normal individuals . These rearrangements preferentially occur de novo during spermatogenesis and are transmitted in families through oogenesis.
In de novo CCRs, associated with mental retardation, the degree of severity correlates with the number of breakpoints [5, 8, 10, 11]. According to the number of chromosomes breaks, CCRs are classified as type I (3 or 4 breaks) and type II (5 or more breaks) [10, 12].
In the past, size and banding pattern of the interested segments as well as the number of chromosomes involved could hamper delineation of the correct karyotype. Moreover, the conventional cytogenetics was of limited use in determining whether a CCR was balanced or unbalanced. Despite the importance of refining the multiple rearrangement breakpoints at the sequence level in CCR cases, virtually no breakpoints have been sequenced and no molecular mechanisms have been proposed for how they might occur. To date, most of the breakpoints have been mapped using conventional cytogenetic G-banded karyotyping, multi-subtelomeric fluorescence in situ hybridization (FISH), whole chromosome painting FISH, multicolor FISH (M-FISH) or spectral karyotyping (SKY) or multicolor banding (MCB) [5, 6, 13].
More recent studies have used array-CGH to uncover cryptic rearrangements . Deletions at the breakpoint regions are a common finding, but duplications are also detected [6, 14]. Importantly, when the resolution of the analysis methods used to examine CCRs improves, the initially identified number of breakpoints tends to increase [14–16]. This observation suggests that many, and possibly the majority of CCRs detected to date might actually be more complex than initially thought. In fact, De Gregori et al.  reported that 40% of patients observed as 'balanced translocations' were unbalanced and, remarkably, 18% of the reciprocal translocations were, instead, complex rearrangements.
After reviewing 226 CCRs reported in the literature, it is possible to observe a clear chromosome preference in CCRs events. In fact, the most common chromosomes involved in CCRs reported in the literature are 2, 3, 4, 7, 11 with frequencies of approximately 10-12% .
Here, we describe a de novo complex chromosome rearrangement, involving eight chromosomes, with a submicroscopic deletion in 15q14 in a boy with moderate mental retardation, cleft palate and facial anomalies. We discuss the implications of this deletion for identifying candidate genes related to the clinical features.
This boy is the second child of healthy, nonconsanguineous Caucasian parents. At birth the mother was 31 years old, the father 29. Family history showed mental retardation in the sister of the proband's maternal grandfather. The patient was born by Cesarean section at term of an uneventful pregnancy. Birth weight was 3100 g (25th centile), length 49 cm (25th centile), head circumference 34 cm (25th centile). Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Cleft palate was diagnosed at birth, and repaired at 8 months of age. Developmental milestones were retarded (sitting at 12 months, walking at 30 months). Language was delayed. Learning difficulties were recorded and the patient needed special assistance at school.
The boy was evaluated only by cerebral CT scan and it showed hypoplasic frontal lobes. The patient's parents refused cerebral MRI. Electroencephalogram, color-Doppler echocardiography and renal ultrasonography were normal. Ophthalmological and audiological examinations revealed no anomalies. Bone age at 8 years was corresponding to chronological age. Vertebral column X-ray showed mild kyphoscoliosis.
Classical and molecular cytogenetic studies
Phytohemagglutinin stimulated peripheral blood lymphocytes from the patient and his parents were short term cultured and the metaphases obtained were karyotyped with GTG banding. The karyotypes were described according to the International System for Human Cytogenetic Nomenclature (ISCN, 2005) .
To better recognize the chromosome segments involved in the rearrangements a panel of commercially available probes was used in Fluorescence In Situ Hybridization (FISH) experiments. DNA probes selected were: Prader-Willi Syndrome (PWS) on 15q11-13 (Vysis); Retinoblastoma (RB1) on 13q14 (Vysis); whole painting probes specific for chromosomes 1, 3, 9, 13, 14, 15, 18, 19 (Metasystems, Altlussheim, Germany); α-satellite probes for centromeres of chromosomes 13/21 (Q-BIOgene, Illkirch, France).
List of the probes used in FISH experiments
FISH experiments were carried out as previously described . The probes were directly labeled with Cy3-dUTP or fluorescein-dUTP (Perkin Elmer Life Sciences, Boston, MA, USA). Digital images were obtained using a Nikon Eclipse E1000 epifluorescence microscope equipped with a cooled CCD Photometrics CoolSNAP FX camera. Pseudocoloring and merging of images were performed with Genikon software v3.6.16.
DNA was extracted from peripheral blood of the patient and his parents with High Pure PCR Template Preparation Kit (Roche, Mannheim, Germany) according to the producer's instructions.
Molecular experiments were performed in order to assess the parental origin of the chromosome 15q14 deletion with a panel of short tandem repeats (STRs) using multiple primer pairs (available upon request) obtained from UniSTS database included in NCBI [http://www.ncbi.nlm.nih.gov/unists/]. DNA was amplified following standard protocol by means of GeneAmp PCR System 2700 (Applied Biosystems, Foster City, CA, USA) following standard protocol. One primer from each pair was fluorescently labelled and PCR products were run on an ABI Prism 310 (Applied Biosystems), using GeneMapper v 3.0 as software.
The array-CGH (comparative genomic hybridization) studies of the patient and his parents were performed using Agilent Technologies Array-CGH Kits (Santa Clara, CA, USA). This platform is a 60-mer oligonucleotide-based microarray that allows molecular profiling of genomic aberrations with an overall median probe spatial resolution of 20 kb (105K) and a probe spacing in RefSeq Genes of 18.9 kb (105K).
Aliquots of 2000 ng of DNA from patient, parents and same-sex reference home made pool were double-digested with RsaI and AluI for 2 hours at 37°C. After heat inactivation of the enzymes at 65°C for 20 minutes, each digested sample was labelled by random priming (Agilent Technologies) for 2 hours using Cy5-dUTP for patient/parent DNAs and Cy3-dUTP for reference DNAs. Labelled products were column purified with Illustra CyScribe GFX purification kit (GE Healthcare, Buckinghamshire, UK). After probe denaturation and pre-annealing with 5-25 mg of Cot-1 DNA, hybridization was performed at 65°C with rotation for 40 hours (105K). After washing steps, following the manufacturer's instructions, the array was analyzed using an Agilent scanner and Feature Extraction software v.10.5. A graphical overview of the results was obtained using DNA Analytics software v.4.0. The chromosome aberration regions were calculated by ADM1 algorithm with moving average window of 1Mb.
In order to confirm the results obtained FISH experiment was performed using the BAC clones RP11-698F12 (accession number AC087487, chr15:33,659,677-33,839,903 bp) and RP11-203K2 (chr15:34,350,630-34,527,067 bp).
In order to evaluate if the Copy Number Variations (CNVs), detected by array-CGH, were polymorphic or potentially correlated with the clinical phenotype of our patient, bioinformatic analysis was carried out consulting the Database of Genomic Variants BioXRT [http://projects.tcag.ca/variation/].
With the aim to disclose the mechanisms underlying the chromosome interstitial microdeletion and to estimate if the genes included were imprinted, the Human Genome Segmental Duplication Database [http://projects.tcag.ca/humandup/] and the Gene Imprint Database [http://www.geneimprint.com/] were queried.
Investigation of gene contents in the deleted segment was carried out comparing the "UCSC Genes based on RefSeq, UniProt, GenBank, CCDS and Comparative Genomics" track (March 2006 release, hg18) with the corresponding interval in the "RefSeq Genes" track in the UCSC last release (Feb 2009, hg19).
Moreover, the deleted region was analyzed for the presence of segmental duplication and potentially imprinted genes but they were not found.
Additional information was obtained from microsatellite analysis carried out to assess the parental origin of the defect. The informative STRs (D15S1042 and D15S118) included in the deleted region, showed allelic loss of heterozygosity, revealing that this complex rearrangement arose in the paternal meiosis (Figure 4B).
Discussion and Conclusions
Abnormal phenotypes observed in persons who harbor apparently balanced chromosomal rearrangements are thought to result from disruption of gene(s) at chromosome breakpoint(s), from undetected additional genomic imbalance by routine karyotyping or from position effect . Recently, high resolution genome wide array-based analyses have enabled identification of previously unknown submicroscopic abnormalities at the traslocation breakpoints or in other genomic regions in patients with CCRs [6, 14, 20–22].
In the present paper, we reported a de novo complex cytogenetic profile interesting eight chromosomes. G-banding analysis showed eight chromosomes (1, 3, 9, 13, 14, 15, 18 and 19) involved in the CCR with four reciprocal traslocations and eight breakpoints. According to the number of chromosome breaks, our case would be classified as type II (5 or more breaks) [10, 23]. Zhang et al  reviewed the frequency of specific chromosomes in 226 CCR cases reported in the literature. Comparing the rearranged chromosomes of our patient with those listed by Zhang, they are rarely involved in CCRs, except for the chromosome 3 that shows a frequency of approximately 10%. The reason for this preference is not obvious.
Array-CGH studies were needed to obtain a more precise delineation of the structural abnormalities and they revealed a cryptic microdeletion at 15q14, 1.6 Mb in size, overlapping with the breakpoint previously identified by means of G-banding analysis. The parental origin of this deletion was found to be paternal, the CCR occurring during spermatogenesis. Interestingly, the origin of de novo CCR and reciprocal translocation cases are frequently reported as paternal [8, 14, 21, 23, 24]. The cause of CCRs is unknown, however, the fact that all reported cases have been non-mosaic and have involved only one chromosome of a homologous pair suggests a 'catastrophic' meiotic event in one of the parental gametes rather than a post-zygotic event. One considered aspect is the influence of the environment on the genome. In fact, some authors  have observed a correlation between the exposure to radiations and CCRs. In our case, no particular risks for radiation damage had been reported by the parents.
The deleted segment at 15q14 was investigated for gene content. Three known genes (ATPBD4, ATP binding domain 4; C15orf41, 15 open reading frame 41; MEIS2, Meis homeobox 2), one pseudogene (CSNK1A1P, casein kinase 1, alpha 1 pseudogene) and one predicted gene (LOC145845) were found.
The protein encoded by ATPBD4, located on the minus strand, has a domain conserved from chimpanzee to yeast forming an alpha/beta/alpha fold which binds to adenosine nucleotide.
C15orf41 encodes the predicted protein LOC84529, with two isoforms, one 281 and two 183 aminoacids in size, whose functions still remain unclear.
MEIS2 encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs. Multiple transcript variants encoding distinct isoforms have been described for this gene and the longest one contains 12 exons. The gene is transcribed on minus strand and is about 200 kb in size. The breakpoint in our case is located in a short segment of about 20 kb between the last deleted probe (A_16_P2021458; 35,072,417-35,072,476) and the first conserved probe (A_14_P124780; 35,094,819-35,094,878) producing the deletion of about half the gene with the loss of 4 exons mapping at the 3' end. Although the deletion is about 100 kb, the first 8 exons were conserved.
The deletion of MEIS2 has been recently reported in patients with cleft palate and congenital heart defects  suggesting its involvement also in the clinical phenotype of our patient. Moreover, Stankunas et al  showed that disruptions of MEIS1, a gene belonging to the same family of MEIS2 and interacting with PBX1-2-3 through the formation of a heteroligomeric complexes, produces heart defects in mice because it controls a subset of target genes that regulate cardiac outflow tract formation.
Clinical features of the patients with deletions including cytogenetic band 15q1 4
SIZE AND POSITION OF CHROMOSOME 15 DELETION
ADDITIONAL CHROMOSOME ABERRATION
del(15)(q14) (submicroscopic, 1,6 Mb)
Chen et al., 2008
del(15)(q14) (submicroscopic, 5,6 Mb)
Epilepsy; speech and language disorder
Brunetti-Pierri et al., 2008 case 1
del(15)(q14) (submicroscopic, 4,2 Mb)
+ (Bifid uvula)
Bilateral inguinal hernias, autistic spectrum behavior
Brunetti-Pierri et al., 2008 case 2
del(15)(q13-q14) (submicroscopic, 8,9 Mb)
Erdogan et al., 2007
del(15)(q14) (submicroscopic, 5,3 Mb)
Low-set ears, OFC 3rd percentile
Galan et al., 1991
+ (Bifid uvula)
Pulmonary valve stenosis
Right cryptorchidism, hearing deficency
Tonk et al., 1995
VSD, PDA, ischemic cardiomyopathy
Large fontanelles, hearing deficency
Autio et al., 1988
Cryptorchidism, kidney defect, corpus callosum agenesis
Herva and Vuorinen, 1980
Mosaic with 46, XY
VSD, hypoplastic pulmonary artery, atretic tricuspid valve
Died at 7 days
Pauli et al., 1983
+ (Bifid uvula)
Cryptorchidism, unilateral renal ptosis
Windpassinger et al., 2003
Persistent foramen ovale, PDA
Cryptorchidism, clubfeet, strabismus
Kucerova et al., 1979
Duckett and Roberts, 1981
Trisomy 13(pter-q32 or 33)
+ (Bifid uvula)
VSD, ASD, PDA, transposition of great vessels
Died at 14 hr
Microphthalmia, tracheo-oesophageal fistula
Ming et al., 1977
Died at 3 days
Schwartz et al., 1985
Coarctation of aorta, PDA
Cleft alveolar ridge, hydronephrosis
Matsumura et al., 2003
Renal failure, cryptorchidism
Our patient exhibits only some clinical features in common with the cases with partially overlapping deletions, particularly mental retardation, speech defect and cleft palate (Figure 5). Specific facial anomalies in patients with 15q14 microdeletions include bitemporal narrowing, smooth philtrum, pointed chin and dysmorphic ears. Short stature is a characteristic feature. The present patient has normal birth parameters, whereas most previous reports have intrauterine growth retardation. Congenital heart defects or epilepsy are absent being probably related to patients with larger deletions. Thus, excluding epilepsy, which was reported only in Chen's paper, the unique clinical difference between the present case and the other three (Erdogan, Brunetti-Pierri -patient 1- and Chen) is the absence of cardiac malformations.
Morover, all the patients displayed cleft palate, suggesting that the deletion of 15q14 is correlated with this defect.
The mechanisms underlying CCRs formation are still poorly understood; some studies propose models based upon the principle of parsimony and the minimum amount of breaks required for the formation of the CCRs. Moreover, the proximal region of the long arm of chromosome 15 has a complex organization and undergoes recurrent nonhomologous recombination events that are facilitated by large repeat units, known as duplicons . Another mechanism recently described as an alternative cause of genomic disorders with non-recurring breakpoints is Fork Stalling and Template Switching (FoSTeS), that initiates by a single strand DNA replication error in contrast to the meiotic recombination mechanisms . Other mechanisms have been proposed to explain CCRs and they have been summarized by Zhang et al . However, because the breakpoint sequences of CCRs have not yet been experimentally determined, the relationship between genomic architecture and the formation of the CCRs, along with the ability to infer the underlying mechanisms producing the rearrangements, remains elusive.
Interstitial deletion of chromosome 15 encompassing q14 is rare. Comparing the characteristics of our patient with those of cases currently reported in the literature, we have identified the smallest genomic region of overlap and we have recognized the related common phenotypic features. Both these observations suggest that this genetic lesion could reveal a novel recurrent syndrome.
Written informed consent was obtained from the patient's relatives for pubblication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
List of Abbreviations
complex chromosome rearrangement
array-based comparative genomic hybridization
fluorescence in situ hybridization
bacterial artificial chromosome
short tandem repeats
copy number variations.
We would like to thank Dr Alessandro Jenkner for critical reading of the manuscript.
- van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M, Hennekam RC: Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet. 2005, 13: 6-25. 10.1038/sj.ejhg.5201279.View ArticlePubMedGoogle Scholar
- Pinkel D, Albertson DG: Comparative genomic hybridization. Annu Rev Genomics. 2005, 6: 331-354. 10.1146/annurev.genom.6.080604.162140. Hum Genet.View ArticleGoogle Scholar
- Brunetti-Pierri N, Sahoo T, Frioux S, Chinault C, Zascavage R, Cheung SW, Peters S, Shinawi M: 15q13q14 Deletions: Phenotypic characterization and molecular delineation by Comparative Genomic Hybridization. Am J Med Genet A. 2008, 146A: 1933-1941. 10.1002/ajmg.a.32324.View ArticlePubMedGoogle Scholar
- Pai GS, Thomas GH, Mahoney W, Migeon BR: Complex chromosome rearrangements. Report of a new case and literature review. Clin Genet. 1980, 18: 436-444. 10.1111/j.1399-0004.1980.tb01790.x.View ArticlePubMedGoogle Scholar
- 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. 1998, 78: 44-51. 10.1002/(SICI)1096-8628(19980616)78:1<44::AID-AJMG9>3.0.CO;2-L.View ArticlePubMedGoogle Scholar
- Astbury C, Christ LA, Aughton DJ, Cassidy SB, Fujimoto A, Pletcher BA, Schafer IA, Schwartz S: Delineation of complex chromosomal rearrangements: evidence for increased complexity. Hum Genet. 2004, 114: 448-457. 10.1007/s00439-003-1079-1.View ArticlePubMedGoogle Scholar
- Giardino D, Corti C, Ballarati L, Colombo D, Sala E, Villa N, Piombo G, Pierluigi M, Faravelli F, Guerneri S, Coviello D, Lalatta F, Cavallari U, Bellotti D, Barlati S, Croci G, Franchi F, Savin E, Nocera G, Amico FP, Granata P, Casalone R, Nutini L, Lisi E, Torricelli F, Giussani U, Facchinetti B, Guanti G, Di Giacomo M, Susca FP, Pecile V, Romitti L, Cardarelli L, Racalbuto E, Police MA, Chiodo F, Rodeschini O, Falcone P, Donti E, Grimoldi MG, Martinoli E, Stioui S, Caufin D, Lauricella SA, Tanzariello SA, Voglino G, Lenzini E, Besozzi M, Larizza L, Dalpra L: De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn. 2009, 29: 257-265. 10.1002/pd.2215.View ArticlePubMedGoogle Scholar
- Batista DA, Pai GS, Stetten G: Molecular analysis of a complex chromosomal rearrangement and a review of familial cases. Am J Med Genet. 1994, 53: 255-263. 10.1002/ajmg.1320530311.View ArticlePubMedGoogle Scholar
- Kleczkowska A, Fryns JP, Van den Berghe H: Complex chromosomal rearrangements (CCR) and their genetic consequences. J Genet Hum. 1982, 30: 199-214.PubMedGoogle Scholar
- Kousseff BG, Nichols P, Essig YP, Miller K, Weiss A, Tedesco TA: Complex chromosome rearrangements and congenital anomalies. Am J Med Genet. 1987, 26: 771-782. 10.1002/ajmg.1320260403.View ArticlePubMedGoogle Scholar
- Madan K, Nieuwint AW, van Bever Y: Recombination in a balanced complex translocation of a mother leading to a balanced reciprocal translocation in the child. Review of 60 cases of balanced complex translocations. Hum Genet. 1997, 99: 806-815. 10.1007/s004390050453.View ArticlePubMedGoogle Scholar
- Kousseff BG, Papenhausen P, Neu RL, Essig YP, Saraceno CA: Cleft palate and complex chromosome rearrangements. Clin Genet. 1992, 42: 135-142. 10.1111/j.1399-0004.1992.tb03225.x.View ArticlePubMedGoogle Scholar
- Zhang F, Carvalho CM, Lupski JR: Complex human chromosomal and genomic rearrangements. Trends Genet. 2009, 25: 298-307. 10.1016/j.tig.2009.05.005.PubMed CentralView ArticlePubMedGoogle Scholar
- De Gregori M, Ciccone R, Magini P, Pramparo T, Gimelli S, Messa J, Novara F, Vetro A, Rossi E, Maraschio P, Bonaglia MC, Anichini C, Ferrero GB, Silengo M, Fazzi E, Zatterale A, Fischetto R, Previdere C, Belli S, Turci A, Calabrese G, Bernardi F, Meneghelli E, Riegel M, Rocchi M, Guerneri S, Lalatta F, Zelante L, Romano C, Fichera M, Mattina T, Arrigo G, Zollino M, Giglio S, Lonardo F, Bonfante A, Ferlini A, Cifuentes F, Van Esch H, Backx L, Schinzel A, Vermeesch JR, Zuffardi O: Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients. J Med Genet. 2007, 44: 750-762. 10.1136/jmg.2007.052787.PubMed CentralView ArticlePubMedGoogle Scholar
- Giardino D, Corti C, Ballarati L, Finelli P, Valtorta C, Botta G, Giudici M, Grosso E, Larizza L: Prenatal diagnosis of a de novo complex chromosome rearrangement (CCR) mediated by six breakpoints, and a review of 20 prenatally ascertained CCRs. Prenat Diagn. 2006, 26: 565-570. 10.1002/pd.1460.View ArticlePubMedGoogle Scholar
- Ballarati L, Recalcati MP, Bedeschi MF, Lalatta F, Valtorta C, Bellini M, Finelli P, Larizza L, Giardino D: Cytogenetic, FISH and array-CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient. Eur J Med Genet. 2009, 52: 218-223. 10.1016/j.ejmg.2009.02.004.View ArticlePubMedGoogle Scholar
- Shaffer LG, Tommerup N: ISCN (2005): An International System for Human Cytogenetic Nomenclature. Basel: S. Karger Publishers; 2005.Google Scholar
- Lichter P, Tang CJ, Call K, Hermanson G, Evans GA, Housman D, Ward DC: High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science. 1990, 247: 64-69. 10.1126/science.2294592.View ArticlePubMedGoogle Scholar
- Borg K, Nowakowska B, Obersztyn E, Cheung SW, Brycz-Witkowska J, Korniszewski L, Mazurczak T, Stankiewicz P, Bocian E: Complex balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) and two microdeletions del(1)(p31.1p31.1) and del(7)(p14.1p14.1) in a patient with features of Greig cephalopolysyndactyly and mental retardation. Am J Med Genet A. 2007, 143A: 2738-2743. 10.1002/ajmg.a.32017.View ArticlePubMedGoogle Scholar
- Kirchhoff M, Rose H, Lundsteen C: High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet. 2001, 38: 740-744. 10.1136/jmg.38.11.740.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 2005, 42: 8-16. 10.1136/jmg.2004.024141.PubMed CentralView ArticlePubMedGoogle Scholar
- Borg K, Stankiewicz P, Bocian E, Kruczek A, Obersztyn E, Lupski JR, Mazurczak T: Molecular analysis of a constitutional complex genome rearrangement with 11 breakpoints involving chromosomes 3, 11, 12, and 21 and a approximately 0.5-Mb submicroscopic deletion in a patient with mild mental retardation. Hum Genet. 2005, 118: 267-275. 10.1007/s00439-005-0021-0.View ArticlePubMedGoogle Scholar
- Patsalis PC: Complex chromosomal rearrangements. Genet Couns. 2007, 18: 57-69.PubMedGoogle Scholar
- Baptista J, Mercer C, Prigmore E, Gribble SM, Carter NP, Maloney V, Thomas NS, Jacobs PA, Crolla JA: Breakpoint mapping and array CGH in translocations: comparison of a phenotypically normal and an abnormal cohort. Am J Hum Genet. 2008, 82: 927-936. 10.1016/j.ajhg.2008.02.012.PubMed CentralView ArticlePubMedGoogle Scholar
- Stankunas K, Shang C, Twu KY, Kao SC, Jenkins NA, Copeland NG, Sanyal M, Selleri L, Cleary ML, Chang CP: Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circ Res. 2008, 103: 702-709. 10.1161/CIRCRESAHA.108.175489.PubMed CentralView ArticlePubMedGoogle Scholar
- Ming PM, Goodner DM, Park TS: Chromosome 6/15 translocation with multiple congenital anomalies. Obstet Gynecol. 1977, 49: 251-253.PubMedGoogle Scholar
- Kucerova M, Strakova M, Polivkova Z: The Prader-Willi syndrome with a 15/3 translocation. J Med Genet. 1979, 16: 234-235. 10.1136/jmg.16.3.234.PubMed CentralView ArticlePubMedGoogle Scholar
- Herva R, Vuorinen O: Congenital heart disease with del(15q) mosaicism. Clin Genet. 1980, 17: 26-28. 10.1111/j.1399-0004.1980.tb00108.x.View ArticlePubMedGoogle Scholar
- Duckett DP, Roberts SH: Adjacent 2 meiotic disjunction. report of a case resulting from a familial 13q;15q balanced reciprocal translocation and review of the literature. Hum Genet. 1981, 58: 377-386. 10.1007/BF00282819.View ArticlePubMedGoogle Scholar
- Pauli RM, Meisner LF, Szmanda RJ: 'Expanded' Prader-Willi syndrome in a boy with an unusual 15q chromosome deletion. Am J Dis Child. 1983, 137: 1087-1089.PubMedGoogle Scholar
- Schwartz S, Max SR, Panny SR, Cohen MM: Deletions of proximal 15q and non-classical Prader-Willi syndrome phenotypes. Am J Med Genet. 1985, 20: 255-263. 10.1002/ajmg.1320200208.View ArticlePubMedGoogle Scholar
- Autio S, Pihko H, Tengstrom C: Clinical features in a de novo interstitial deletion 15q13 to q15. Clin Genet. 1988, 34: 293-298. 10.1111/j.1399-0004.1988.tb02881.x.View ArticlePubMedGoogle Scholar
- Galan F, Aguilar MS, Gonzalez J, Clemente F, Sanchez R, Tapia M, Moya M: Interstitial 15q deletion without a classic Prader-Willi phenotype. Am J Med Genet. 1991, 38: 532-534. 10.1002/ajmg.1320380406.View ArticlePubMedGoogle Scholar
- Tonk V, Wyandt HE, Osella P, Skare J, Wu BL, Haddad B, Milunsky A: Cytogenetic and molecular cytogenetic studies of a case of interstitial deletion of proximal 15q. Clin Genet. 1995, 48: 151-155. 10.1111/j.1399-0004.1995.tb04076.x.View ArticlePubMedGoogle Scholar
- Windpassinger C, Petek E, Wagner K, Langmann A, Buiting K, Kroisel PM: Molecular characterization of a unique de novo 15q deletion associated with Prader-Willi syndrome and central visual impairment. Clin Genet. 2003, 63: 297-302. 10.1034/j.1399-0004.2003.00059.x.View ArticlePubMedGoogle Scholar
- Matsumura M, Kubota T, Hidaka E, Wakui K, Kadowaki S, Ueta I, Shimizu T, Ueno I, Yamauchi K, Herzing LB, Nurmi EL, Sutcliffe JS, Fukushima Y, Katsuyama T: 'Severe' Prader-Willi syndrome with a large deletion of chromosome 15 due to an unbalanced t(15,22)(q14;q11.2) translocation. Clin Genet. 2003, 63: 79-81. 10.1034/j.1399-0004.2003.630114.x.View ArticlePubMedGoogle Scholar
- Erdogan F, Ullmann R, Chen W, Schubert M, Adolph S, Hultschig C, Kalscheuer V, Ropers HH, Spaich C, Tzschach A: Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay. Am J Med Genet A. 2007, 143: 172-178.View ArticleGoogle Scholar
- Chen CP, Lin SP, Tsai FJ, Chern SR, Lee CC, Wang W: A 5.6-Mb deletion in 15q14 in a boy with speech and language disorder, cleft palate, epilepsy, a ventricular septal defect, mental retardation and developmental delay. Eur J Med Genet. 2008, 51: 368-372. 10.1016/j.ejmg.2008.02.011.View ArticlePubMedGoogle Scholar
- Amos-Landgraf JM, Ji Y, Gottlieb W, Depinet T, Wandstrat AE, Cassidy SB, Driscoll DJ, Rogan PK, Schwartz S, Nicholls RD: Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am J Hum Genet. 1999, 65: 370-386. 10.1086/302510.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee JA, Carvalho CM, Lupski JR: A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007, 131: 1235-1247. 10.1016/j.cell.2007.11.037.View ArticlePubMedGoogle Scholar
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