Letter to the Editor
Rapid diagnosis of trisomy 21 by array comparative genomic hybridization
using uncultured amniocytes in a pregnancy with isolated ventriculomegaly in
the fetus
Chih-Ping Chen a,b,c,d,e,f,g*, Schu-Rern Chern c, Peih-Shan Wu h, Jun-Wei Su a,i, Li-Feng Chen a and Wayseen Wang b,j
a Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan b Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
c Department of Medicine, Mackay Medical College, New Taipei City, Taiwan d Department of Biotechnology, Asia University, Taichung, Taiwan
e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan f Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan g Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,
Taiwan
h Gene Biodesign Co. Ltd, Taipei, Taiwan
i Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan j Department of Bioengineering, Tatung University, Taipei, Taiwan
* Correspondence to: Chih-Ping Chen, MD
Department of Obstetrics and Gynecology, Mackay Memorial Hospital 92, Section 2, Chung-Shan North Road, Taipei, Taiwan
Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: [email protected]
Short title: Rapid diagnosis of trisomy 21
A 43-year-old, gravida 2, para 1, woman was referred for amniocentesis at 18 weeks of gestation because of advanced maternal age and fetal ventriculomegaly. Her husband was 45 years old. Prenatal ultrasound revealed a fetus with fetal biometry equivalent to 19 weeks and bilateral ventriculomegaly (Fig. 1). Other organs were unremarkable. About 28 mL amniotic fluid was aspirated, of which 10 mL was used for array comparative genomic hybridization (aCGH) analysis using uncultured amniocytes, and 16 mL for conventional cytogenetic analysis using cultured amniocytes. The aCGH investigation using whole-genome ISCA Plus Cytogenetic array (Roche NimbleGen, Madison, WI, USA) on uncultured amniocytes showed the result of trisomy 21 [arr cgh 21p11.2q22.3 (10,538,318 – 48,129,895)3] (Fig. 2). Conventional cytogenetic analysis using cultured amniocytes revealed a karyotype of 47,XX,+21 (Fig. 3). The pregnancy was terminated at 21 weeks of gestation, and a 434-g female fetus was delivered with facial dysmorphisms of Down syndrome. Postnatal quantitative fluorescent polymerase chain reaction (QF-PCR) analysis revealed a maternal origin of a heterologous duplication of chromosome 21, consistent with the result of meiosis I non-disjunction (Fig. 4).
Rapid prenatal diagnosis of chromosomal abnormalities can be achieved by interphase aCGH QF-PCR, interphase fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) without the need of cell cultures [1-6]. The present case shows the usefulness of aCGH for rapid aneuploidy diagnosis (RAD) in a pregnancy with fetal ventriculomegaly.
Prenatal diagnosis of ventriculomegaly should raise a suspicion of aneuploidy [7]. Ventriculomegaly occurs in 5-25 per 10,000 births and may be associated with aneuploidy, genetic disorders and syndromes, intrauterine hemorrhage, infections and neural tube defects [8]. Snijders et al [8] reported aneuploidy in 13% of the 690 fetuses with prenatally detected ventriculomegaly including trisomy 21, trisomy 18, trisomy 13, triploidy and other rearrangements. Snijders et al [8] reported ventriculomegaly in 16% of fetuses with trisomy 21 (n = 155), in 14% with trisomy 18 (n = 137), in 9% with trisomy 13 (n = 54), in 18% with triploidy (n = 50) and in 2% with Turner syndrome (n = 65). They also found that the prevalence of aneuploidy in fetal ventriculomegaly was 2% for fetuses with no other detectable abnormalities and 17% for those with additional abnormalities. Our case represents an interesting case of isolated ventriculomegaly associated with advanced maternal age and fetal trisomy 21.
Acknowledgements
This work was supported by research grant NSC-99-2628-B-195-001-MY3 from the National Science Council and MMH-E-101-04 from Mackay Memorial Hospital, Taipei, Taiwan.
References
1. Chen C-P, Su Y-N, Tsai F-J, Chern S-R, Hsu C-Y, Huang M-C, 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.
2. Chen C-P, Su Y-N, Wu P-C, Lee C-C, Pan C-W, Wang W. Rapid aneuploidy diagnosis by array comparative genomic hybridization using uncultured amniocytes in a pregnancy with fetal nuchal edema and mild ascites. J Med Ultrasound 2011; 19: 64-9.
3. Chen C-P, Su Y-N, Lin S-Y, Chang C-L, Wang Y-L, Huang J-P, 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.
4. Chen C-P, Hsu C-Y, Chern S-R, Wu P-S, Su J-W, Lee C-C, et al. Rapid diagnosis of monosomy X using uncultured amniocytes in amniotic fluid and cultured lymphocytes in cystic fluid in a pregnancy with fetal cystic hygroma and hydrops. J Med Ultrasound 2012; 20: 129-32.
5. Chen C-P, Su Y-N, Chang C-L, Chen Y-Y, Su J-W, Chern S-R, et al. Rapid aneuploidy diagnosis by multiplex ligation-dependent probe amplification using uncultured amniocytes in pregnancy with major fetal structural abnormalities. Taiwan J Obstet Gynecol 2012; 51: 123-8.
6. Chen C-P, Chen Y-Y, Liou J-D, Chern S-R, Wu P-S, Su J-W, et al. Rapid diagnosis of trisomy 18 using uncultured amniocytes in late second trimester in a pregnancy with fetal congenital heart defects, arthrogryposis, omphalocele and mega cisterna magna. J Med Ultrasound 2012; 20: in press.
7. Chen C-P. Prenatal sonographic features of the fetuses in trisomy 13 pregnancies (II). Taiwan J Obstet Gynecol 2009; 48: 218-24.
8. Snijders RJM, Farrias M, von Kaisenberg C, Nicolaides KH. Fetal abnormalities. In: Snijders RJM, Nicolaides KH, eds. Ultrasound Markers for Fetal Chromosomal Defects. New York: Parthenon Publishing Group, 1996; 1-62.
Figure Legends
Fig. 1. Prenatal ultrasound at 18 weeks of gestation shows (A) an enlarged ventricle with a width of 1.12 cm and (B) an enlarged contralateral ventricle with a width of 1.28 cm.
Fig. 2. (A) Whole genome view and (B) chromosomal view of array comparative genomic hybridization analysis on uncultured amniocytes show a duplication of chromosome 21 (arrows), consistent with the diagnosis of trisomy 21.
Fig. 3. A karyotype of 47,XX,+21 in the fetus.
Fig. 4. Representative electrophoretograms of quantitative fluorescent polymerase chain reaction assays at short tandem repeat markers specific for chromosome 21q. Three peaks (186 bp: 200 bp: 204 bp) of equal fluorescence activity at a ratio of 1:1:1 are detected in the fetal tissues. Two of which are of maternal origin, indicating a heterologous duplication of chromosome 21 as the result of meiosis I non-disjunction.
