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A De Novo Duplication of Chromosome 9Q34.13-Qter in a Fetus With

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A De Novo Duplication of Chromosome 9Q34.13-Qter in a Fetus With Liu et al. Molecular Cytogenetics (2016) 9:54 DOI 10.1186/s13039-016-0267-3 CASE REPORT Open Access A de novo duplication of chromosome 9q34.13-qter in a fetus with Tetralogy of Fallot Syndrome Jing Liu, Hao Hu, Na Ma, Zhengjun Jia, Yuchun Zhou, Jiancheng Hu and Hua Wang* Abstract Background: Partial duplications of the distal 9q have been rarely reported in literatures. The key features included characteristic facial appearance, long fingers and toes, slight psychomotor retardation, heart murmur et al. But rare severe congenital heart defects (CHD) such as TOF were reported to be associated with 9qter duplications. Case presentation: A 23-year-old woman was referred for genetic counseling and prenatal diagnosis at 253/7 weeks of gestation due to her male fetus, diagnosed as Tetralogy of Fallot Syndrome (TOF) by prenatal ultrasound. SNP (Single nucleotide polymorphism) array revealed that the male fetus had a de novo 5.47 Mb duplication at 9q34.13-qter. Meanwhile, non-invasive prenatal testing (NIPT) using low coverage whole genome massively parallel sequencing of circulating cell-free fetal DNA (cffDNA) showed consistent results. Multiplex ligation-dependent probe amplification (MLPA) also confirmed the duplication at 9qter. Conclusion: In this paper, we present an Asian fetus with TOF caused by a de novo 5.47 Mb duplication at 9q34. 13-qter. Duplication of 9q34.13-qter should be considered as an etiological diagnosis in the case of TOF. Our prenatal diagnostic findings provide important information for genetic counseling on the male fetus and future pregnancies in this family. Chromosomal microarray analysis (CMA) remains the first-tier clinical diagnostic test for prenatal fetus with suspicious syndromes. We also highlight the high potential application of NIPT in the screening of sub-chromosomal rearrangement. Keywords: TOF, 9qter duplication, SNP array, Non-invasive prenatal testing, Prenatal diagnosis Background locus in 9q + -associated CHD [3]. Here we present a male Partial duplications of the long arm of chromosome 9 fetus with TOF who was found to have a de novo 5.47 Mb have been rarely reported in literatures. Turleau et al. first duplication at 9q34.13-qter detected by SNP array, which reported this new syndrome in 1975 [1]. The duplications was confirmed by NIPT based on low coverage whole of the distal 9q are even rare, since Alldedice et al first genome massively parallel sequencing and MLPA. A lit- demonstrated the relationship between 9q34 duplications erature review was performed to refine correlation of and phenotypic abnormalities [2]. The key features in- CHD and 9q34 duplications. Our prenatal diagnostic find- cluded slight psychomotor retardation, characteristic facial ings provide important information for genetic counseling appearance, fingers and toes, heart murmur et al. But rare on the male fetus and future pregnancies in this family, severe congenital heart defects (CHD) such as TOF were and highlight the predictive values of NIPT in the screen- reported to be associated with these duplications. ing of sub-chromosomal rearrangement. Amarillo et al. first reported the disrupted RXRA and complex microduplication of 9q (9q+) in a patient with Case presentation TOF, suggesting that RXRA at 9q34.2 may be a critical A gravida 2, para 1 woman came to our clinical genetics center for genetic counseling at 253/7 weeks of gestation. * Correspondence: [email protected] This is her second pregnancy. A first round prenatal ultra- Prenatal Diagnosis Center of Province Hunan, The Maternal and Child Health Care Hospital of Hunan province, Changsha, Hunan 410008, People’s sound revealed that the male fetus (II:2) (Fig. 1a) had Republic of China multiple defects: ventricular septal defect (VSD) and © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Molecular Cytogenetics (2016) 9:54 Page 2 of 5 Fig. 1 a The pedigree of this family. The red arrow indicates the proband; b G-banded karyotype of the affected fetus shows a inv(9)(p11q13) which was inherited from his mother; c Anatomical features of heart: VSD; d MLPA result reveals that the peak height ratio of patient at 9q34.3 is 1.5, which means a duplication at this region pulmonary stenosis. Biparietal diameter was 6.76 cm and AC was 25 cm(~5th centile). Facial abnormalities:a (50 ~ 95th centile) and abdominal circumference (AC) round face with small jaw, normal eye distance (19 mm), was 23.0 cm (~95th centile). A second round prenatal flat nasal bridge, high-arched palate. Anatomical features ultrasound was performed at 31 weeks of gestation, of heart: VSD (Fig. 1c) and displacement of the aorta to which indicated TOF. the right side over the right ventricle (about 1/2). The The mother (I:2) was 23 years old and her husband right outflow tract (pulmonary) was 0.7 cm, the left out- (I:1) was 27 years old. Both of them were healthy non- flow tract (aorta) was 1.2 cm, the thickness of right ven- consanguineous Chinese. Their first child (II:1) was a tricle was 0.5 cm, left was 1.03 cm, bicuspid valve was 2.5 years old girl, born at term by vaginal delivery after 1.8 cm and tricuspid valve was 2.1 cm. an uneventful pregnancy. Her birth weight was 3.4 kg (50 ~ 97th centile). No significant history of anoxia was Materials and methods recorded at birth. When she was 1 year old, her parents After culturing amino fluid cells and peripheral blood found that her pupils of each eye were not in the same lymphocytes obtained from the fetus and the other size. After a series of examinations, she was diagnosed three family members separately, routine chromosome as optic nerve hypoplasia, but no genetics testing was G-banded (320–400 bands) karyotyping analyses were followed up. performed on metaphase cells according to standard Amino fluid and blood samples were obtained from protocols. the fetus and the family separately after receiving in- SNP array analysis: Genomic DNA was extracted from formed consent. According to the genetics diagnosis and the amino fluid cells and peripheral blood lymphocytes ultrasound results, this pregnancy was subsequently ter- by using DNA Extraction Kit (Tissue and cells) and minated at 32 weeks, followed by an autopsy. The male QIAamp DNA Blood Mini Kit (QIAGEN, Hilden, fetus’ weight was 2052 g, height was 44.5 cm, head cir- Germany) separately. SNP array was performed using cumference was 30.6 cm, bust circumference was 26 cm, Affymetrix CytoScan®750 K Array (Affymetrix Inc, CA, Liu et al. Molecular Cytogenetics (2016) 9:54 Page 3 of 5 USA), according to the manufacturer’s protocol. Array Results results were analyzed using Chromosome Analysis Suite G-banded analysis of this family showed that the fetus (ChAS; version 2.1). All genomic coordinates were taken inherited an inverted chromosome from his mother: from the February 2009 (hg19) human reference se- 46, XY, inv(9)(p11q13), mat (Fig. 1b). The other two quence (NCBI Build 37). Genes and Online Mendelian showed normal karyotypes. The SNP array result of Inheritance in Man (OMIM) references were from the fetus was: arr[hg19] 9q34.13q34.3(135,550,093– RefSeq and OMIM entries, respectively. 141,018,648) × 3, 16p11.2(32,564,735–33,814,547) × 1 The maternal peripheral blood was collected into (Fig. 2a). The proximal duplication boundary was mapped Cell-Free DNA BCT (Streck, Inc., Omaha, NE, USA) within a 2.8-kb region between (nt. 135547269- prior to amniocentesis and centrifuged according to 135550093) at 9q34.13. The elder sister had a similar dele- the protocol. The plasma was shipped to Berry tion at 16p11.2 as the fetus. No other pathogenic CNVs or Genomics in Beijing for DNA extraction and down- variants of uncertain significance were identified in the stream low coverage whole genome massively parallel parents. NIPT found a 5.6 Mb duplication in the fetus at sequencing for detection of fetal sub-chromosomal 9q34 (Fig. 2b). MLPA analysis confirmed the duplication anomalies. at 9q34.3 (Fig. 1d). The SALSA MLPA P070 kit was performed to de- termine the DNA copy number of a single DNA se- Discussion quence in each of 41 human subtelomeric regions. TOF occurs in three of every 10,000 live births. It is the MLPA analysis was performed following the manu- most common cause of cyanotic cardiac disease in pa- facturer’sinstructions.Theproductswereexamined tients beyond the neonatal age, and accounts for up to by ABI 3500dx genetic analyzer (Thermo Fisher, one-tenth of all congenital cardiac lesions [4]. According USA). Quantitative data were analyzed using the to previous study, about 10 % of CHD in children with software of Coffalyser V8.0 (https://www.mlpa.com). multiple congenital defects and/or intellectual disability Fig. 2 The ideograph of chromosome 9 in our patient with 9q34.13-34.3 gain. a CMA (Affymetrix ChAS Browser) detects a copy number gain at 9qter. The black frame region shows: 9q34.13q34.3(135,550,093-141,018,648) x3; weighted log2 ratio (WLR) is 0.5; copy number state (CN) is 3; allele differences (AD) (1.5, 0.5, −0.5, −1.5); smooth signal (SS) is 3; b NIPT via low coverage whole genome massively parallel sequencing of cffDNA in maternal plasma.
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