Case Report
Array comparative genomic hybridization characterization of prenatally detected de novo apparently balanced reciprocal translocations with or without genomic imbalance in other chromosomes
利用晶片式比較基因體分析法定性產前診斷之突變顯然是平衡性之互換染色體轉位併有或 不併有基因體不平衡於其它染色體
Chih-Ping Chen a,b,c,d,e,f,*, Ming Chen g,h, Gwo-Chin Ma g, Yi-Ning Su i, Tsang-Ming Ko j, Yi-Hui Lin k and
Wayseen Wang b,l 陳持平, 陳明, 馬國欽, 蘇怡寧, 柯滄銘, 林怡慧, 王偉信
aDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, ROC 馬偕紀念醫院婦產部
bDepartment of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, ROC 馬偕紀念醫院醫學研究部
cDepartment of Biotechnology, Asia University, Taichung, Taiwan, ROC 亞洲大學生物技術系
dSchool of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC 中國醫藥大學中醫學院中醫學系
eInstitute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan, ROC 陽明大學臨床社區健康護理研究所
fDepartment of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan, ROC 陽明大學婦產學系
g Departments of Medical Research, and Genomic Medicine, Center for Medical Genetic, Changhua Christian Hospital, Changhua, Taiwan, ROC 彰化基督教醫院遺傳諮詢中心醫學研究部暨基因醫學部 h Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan, ROC
彰化基督教醫院婦產部
iDepartment of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan, ROC 台灣大學附設醫院基因醫學部
jGenephile Bioscience Laboratory, Ko’s Obstetrics and Gynecology, Taipei, Taiwan, ROC 柯滄銘婦產科診所基因飛躍生命科學實驗室
kDepartment of Obstetrics and Gynecology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan, ROC 台北市立萬芳醫院婦產部
lDepartment of Bioengineering, Tatung University, Taipei, Taiwan, ROC 大同大學生物工程學系
* Correspondence to: Dr. Chih-Ping Chen,
Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei 104, Taiwan, ROC Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: cpc_mmh@yahoo.com
We present our experience of array comparative genomic hybridization (aCGH) characterization of two cases of prenatally detected de novo simple and complex apparently balanced reciprocal translocations. Amniocentesis of the first case revealed a complex chromosome rearrangement and a karyotype of 46,XY,t(5;8;6)(q11.2;p23.1;q22.32)dn. Array comparative genomic hybridization (aCGH) of amniocytes revealed no genomic imbalance. Ultrasound findings were unremarkable. The pregnancy was carried to term, and pediatric follow-ups were normal at 3 months of age. Amniocentesis of the second case revealed a simple reciprocal translocation and a karyotype of 46,XY,t(3;11)(q14;q23)dn. aCGH of amniocytes revealed a 1.32-Mb microduplication in chromosome 2p12 [arr cgh 2p12 (75,245,747-76,563,965)×3] encompassing the genes of TACR1, FAM176A, MRPL19 and C2orf3. Ultrasound findings were unremarkable. The pregnancy was carried to term, and the pediatric follow-ups were normal at 8 months of age. In cases of prenatally detected de novo apparently balanced reciprocal translocations, cryptic intrachromosomal rearrangements may exist in addition to the cytogenetically visible structural chromosome aberrations. aCGH is useful not only in identifying the genomic imbalances at the breakpoints but also in detecting unexpectedly complex rearrangements in other chromosomes.
Keywords: Array comparative genomic hybridization; Complex chromosome rearrangement;
1. Introduction
Amniocentesis may detect de novo simple and complex apparently balanced reciprocal translocations that give rise to difficulties in genetic counseling and require molecular cytogenetic technologies to identify deletions or duplications at the breakpoints of the involved chromosomes as well as additional genomic imbalances in other chromosomes.1-3 A simple balanced reciprocal
translocation is a two-way exchange between two chromosomes in which two chromosomal segments from two chromosomes break off, translocate and unite. A balanced complex chromosome translocation (CCR) has three or more breakpoints. The most common type of CCR is three-way exchange CCR in which three chromosomal segments from three chromosomes break off, translocate and unite. Here, we present our experience of array comparative genomic hybridization (aCGH) characterization of de novo simple and complex apparently balanced reciprocal translocations detected at amniocentesis.
2. Case Report
Case 1
A 41-year-old, gravida 2, para 0, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis revealed a karyotype of 46,XY,t(5;8;6) (q11.2;p23.1;q22.32)dn. The parental karyotypes were normal. Simultaneously, oligonucleotide-based aCGH analysis by SurePrint G3 Human CGH Microarray Kit 60K (Agilent Technologies, Santa Clara, CA, USA) using cultured amniocytes showed no genomic imbalance and no loss or increase in the dosage of genetic probes specific for chromosomes 5, 6 and 8. Level II ultrasound revealed no structural abnormalities. The parents decided to continue the pregnancy. At 38 weeks of gestation, a healthy male baby was delivered with a body weight of 3,852 g. Pediatric examination of the infant during follow-ups at 3 months of age showed normal psychomotor development without phenotypic abnormalities.
Case 2
A 39-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis revealed a karyotype of 46,XY,t(3;11) (q14;q23)dn. The parental karyotypes were normal. Repeated amniocentesis was performed at 22 weeks of gestation. Oligonucleotide-based aCGH analysis by CytoScan v3 Microarray Kit (Agilent Technologies, Santa Clara, CA, USA) using cultured amniocytes showed no loss or
increase in the dosage of genetic probes specific for chromosomes 3 and 11 but a genomic imbalance in chromosome 2 (Fig. 1). There was a 1.32-Mb microduplication in chromosome 2p12 [arr cgh 2p12 (75,245,747-76,563,965)×3] encompassing the genes of TACR1, FAM176A,
MRPL19 and C2orf3. Level II ultrasound revealed no structural abnormalities. After genetic
counseling, the parents decided to continue the pregnancy. At 38 weeks of gestation, a healthy male baby was delivered with a body weight of 3,624 g. Pediatric examination of the infant during follow-ups at 8 months of age showed no abnormal psychomotor development and no phenotypic abnormalities.
3. Discussion
The present cases of de novo apparently balanced reciprocal translocations did not have genomic imbalances at the breakpoints and manifested no phenotypic abnormalities at birth. Warburton4
reported that 6.1% (10/163) of the cases with prenatally detected balanced simple balanced reciprocal translocations were associated with serious congenital anomalies. Chen et al.1 reported
that 55.6% (10/18) of the cases with prenatally detected de novo apparently balanced CCRs and multiple chromosome rearrangements (MCRs) manifested phenotypic abnormalities. Rapid genome-wide aneuploidy diagnosis can be achieved by aCGH using uncultured and/or cultured amniocytes.5-7 Precise definitions of de novo simple and complex apparently balanced reciprocal
translocations should include rapid genome-wide aneuploidy diagnosis such as aCGH using uncultured and/or cultured amniocytes.
The peculiar aspect of case 2 in this presentation is the prenatal detection of a de novo microduplication in chromosome 2 which was not involved in the translocation of t(3;11) (q14;q23). De novo apparently balanced reciprocal translocations have been reported to be associated with genomic imbalances in other chromosomes. Turleau et al.8 reported mental
retardation, bilateral glaucoma, hypospadias and cryptorchidism in a patient with a deletion of 11p13p14 and a CCR involving chromosomes 4, 7 and 15. Gribble et al.9 reported an
8-year-old girl with autism, dry skin, absent tears, developmental delay and a de novo t(2;5) (q31.1;q23.2). aCGH analysis detected a de novo 2.2-3.4-Mb deletion of 6q21. Chen et al.1
reported a de novo apparently balanced CCR of t(2;18;14)(q33.1;q12.2;q31.2) associated with de
novo duplication of 5q34, deletion of 7p21.1 and deletion of 10q25.3. The fetus manifested facial
novo balanced chromosomal translocations including 41 de novo reciprocal translocations and 18
de novo CCRs, De Gregori et al.10 found 42 deletions by aCGH in 27 cases, indicating 45.8% of
the patients with an apparently balanced translocation were in fact unbalanced. De Gregori et al.10 reported three patients with de novo balanced reciprocal translocations in association with de novo genomic imbalances in other chromosomes. In their report, one case was a female with
growth retardation, ataxic gaits, absence of language, t(1;7)(q24;p13) and del(6)(q14.3-q15); the second case was a female with hypotonia, ataxic gaits, facial dysmorphism, mental retardation, ventricle asymmetry, t(8;14)(q13;q13) and del(9)(pter-p24.2); and the third case was a female with mental retardation, facial dysmorphism, t(1;9)(q44;p13.3) and del(4)(p15.2). Baptista et al.11
reported a female with premature ovarian failure, a karyotype of 46,X,t(X;8)(q22.1;q24.13) and a 200-kb deletion in 2p13.2 detected by aCGH. Schluth-Bolard et al.12 reported two patients with de novo balanced reciprocal translocations in association with de novo genomic imbalances in
other chromosomes. In their report, one case was a male with mental retardation, macrosomia, leukodystrophy, hexadactyly, t(1;18)(q11.1;q12.1) and del(14)(q32.3q32.3); the other case was a male with mental retardation, autistic troubles, growth retardation, t(7;12)(p11;p11) and del(2) (q33.1q33.1). Tzschach et al.13 reported a female patient with mental retardation, psychosis,
obesity, facial dysmorphism, strabismus, t(2;5)(p21;q12.1) and an interstitial 4q32 deletion. The present case 2 had a de novo 1.32-Mb microduplication in 2p12 encompassing the genes of TACR1, FAM176A, MRPL19 and C2orf3. TACR1 [Online Mendelian Inheritance in Man (OMIM) 162323], or tachykinin receptor 1, is a neurokinin 1 receptor mediating behavioral stress responses. FAM176A, or family with sequence similarity 176, member A, is a regulator of programmed cell death mediating both autophagy and apoptosis. MRPL19 (OMIM 611832), or mitochondrial ribosomal protein L19, participates in mitochondrial energy metabolism. C2orf3 (OMIM 189901), or chromosome 2 open reading frame 3, or transcription factor 9 (TCF-9) acts as a factor that represses transcription. MRPL19 and C2orf3 have been associated with dyslexia. Association studies of positional candidate genes have implicated MRPL19 and C2orf3 as relevant candidates for the DYX3 locus,14,15 although recently, some data did not support
MRPL19/C2orf3 as a locus involved in reading abilities.16 At least two to three years are needed
to follow up the psychomotor development of case 2 to define the 1.32-Mb microdeletion in 2p12 as a copy number variation of benign nature.
In conclusion, the present cases provide evidence that in cases of prenatally detected de novo apparently balanced reciprocal translocations, cryptic intrachromosomal rearrangements may exist in addition to the cytogenetically visible structural chromosome aberrations. In this regard, aCGH is useful not only in identifying the genomic imbalances at the breakpoints but also in detecting unexpectedly complex rearrangements in other chromosomes.
Acknowledgements
This work was supported by research grants NSC-97-2314-B-195-006-MY3 and NSC-99-2628-B-195-001-MY3 from the National Science Council, and MMH-E-100-04 from Mackay Memorial Hospital, Taipei, Taiwan.
References
1. Chen CP, Chern SR, Lee CC, Lin CC, Li YC, Hsieh LJ, et al. Prenatal diagnosis of de novo t(2;18;14)(q33.1;q12.2;q31.2), dup(5)(q34q34), del(7)(p21.1p21.1), and del(10)(q25.3q25.3) and a review of the prenatally ascertained de novo apparently balanced complex and multiple chromosomal rearrangements. Prenat Diagn 2006;26:138–46.
2. Chen CP, Wu PC, Su YN, Chern SR, Tsai FJ, Lee CC, et al. Balanced reciprocal translocations at amniocentesis. Taiwan J Obstet Gynecol 2010;49:455–67.
3. Lee NC, Chen M, Ma GC, Lee DJ, Wang TJ, Ke YY, et al. Complex rearrangements between chromosomes 6, 10, and 11 with multiple deletions at breakpoints. Am J Med Genet 2010;152A:2327–34.
4. Warburton D. De novo balanced chromosome rearrangements and extra marker chromosome identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 1991;49:995–1013.
5. Chen CP, Su YN, Tsai FJ, Lin HH, Chern SR, Lee MS, et al. Terminal 2q deletion and distal 15q duplication: prenatal diagnosis by array comparative genomic hybridization using uncultured amniocytes. Taiwan J Obstet Gynecol 2009;48:441–5.
6. Chen CP, Su YN, Tsai FJ, Chern SR, Hsu CY, Huang MC, et al. Rapid genome-wide aneuploidy diagnosis using uncultured amniocytes and array comparative genomic hybridization in pregnancy with abnormal ultrasound findings detected in late second and third trimesters. Taiwan J Obstet Gynecol 2010;49:120–3.
7. Chen CP, Su YN, Lin SY, Chang CL, Wang YL, Huang JP, et al. Rapid aneuploidy diagnosis by multiplex ligation-dependent probe amplification and array comparative genomic hybridization in pregnancy with major congenital malformations. Taiwan J Obstet Gynecol 2011;50:85–94.
8. Turleau C, de Grouchy J, Dufier JL, Phuc LH, Schmelck PH, Rappaport R, et al. Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and del 11p13. Hum Genet 1981;57:300–6.
9. Gribble SM, Prigmore E, Burford DC, Porter KM, Ng BL, Douglas EJ, et al. The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes. J Med Genet 2005;42:8–16.
10. De Gregori M, Ciccone R, Magini P, Pramparo T, Gimelli S, Messa J, et al. Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients. J Med Genet 2007;44:750–62.
11. Baptista J, Mercer C, Prigmore E, Gribble SM, Carter NP, Maloney V, et al. Breakpoint mapping and array CGH in translocations: comparison of a phenotypically normal and an abnormal cohort. Am J Hum Genet 2008;82:927–36.
12. Schluth-Bolard C, Delobel B, Sanlaville D, Boute O, Cuisset JM, Sukno S, et al. Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases. Eur J Med Genet 2009;52:291–6.
13. Tzschach A, Menzel C, Erdogan F, Istifli ES, Rieger M, Ovens-Raeder A, et al. Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement. Am J Med Genet 2010;152A:1008–12.
14. Anthoni H, Zucchelli M, Matsson H, Müller-Myhsok B, Fransson I, Schumacher J, et al. A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia. Hum Mol Genet 2007;16:667–77.
15. Petryshen TL, Pauls DL. The genetics of reading disability. Curr Psychiatry Rep 2009;11:149–55. 16. Scerri TS, Morris AP, Buckingham LL, Newbury DF, Miller LL, Monaco AP, et al. DCDC2,
KIAA0319 and CMIP are associated with reading-related traits. Biol Psychiatry 2011;doi:10.1016/ j.biopsych.2011.02.005.
Figure Legend
Fig. 1. (A) Oligonucleotide-based aCGH shows a de novo 1.32-Mb duplication in chromosome 2p12 [arr cgh 2p12 (75,245,747-76,563,965)×3] in the fetus. aCGH: array comparative genomic hybridization. (B) The duplicated region encompasses the genes of TACR1, FAM176A, MRPL19 and C2orf3.
