And Partial Monosomy 13Q (13Q33.3Qter) Associated with Dandy-Walker Malformation, Abnormal Skull Development and Microcephaly

■ SHORT COMMUNICATION ■

PRENATAL DIAGNOSIS AND MOLECULAR CYTOGENETIC CHARACTERIZATION OF DE NOVO PARTIAL TRISOMY 7P (7P15.3PTER) AND PARTIAL MONOSOMY 13Q (13Q33.3QTER) ASSOCIATED WITH DANDY-WALKER MALFORMATION, ABNORMAL SKULL DEVELOPMENT AND MICROCEPHALY

Chih-Ping Chen1,2,3,4,5,6*, Ming Chen7,8,9,10, Yi-Ning Su11, Fuu-Jen Tsai4,12,13, Schu-Rern Chern2, Chin-Yuan Hsu1, Pei-Chen Wu1, Dai-Dyi Town1, Dong-Jay Lee7,8, Gwo-Chin Ma7, Wayseen Wang2,14 Departments of 1Obstetrics and Gynecology and 2Medical Research, Mackay Memorial Hospital, 5Institute of Clinical and Community Health Nursing, 6Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, 10Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, 11Department of Medical Genetics, National Taiwan University Hospital, and 14Department of Bioengineering, Tatung University, Taipei; 3Department of Biotechnology, Asia University, 4School of Chinese Medicine, College of Chinese Medicine, China Medical University, and Departments of 12Medical Research and 13Medical Genetics, China Medical University Hospital, Taichung; Departments of 7Genomic Medicine, 8Medical Research and 9Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan.

SUMMARY Objective: To present the prenatal diagnosis and molecular cytogenetic characterization of de novo partial trisomy 7p (7p15.3pter) and partial monosomy 13q (13q33.3qter) associated with Dandy-Walker malformation (DWM), abnormal skull development, microcephaly and multiple congenital anomalies. Materials, Methods and Results: A 42-year-old woman, gravida 6, para 1, was referred for amniocentesis at 18 weeks of gestation because of her advanced maternal age. Amniocentesis revealed an aberrant derivative chromosome 13, or der(13). The parental karyotypes were normal. Spectral karyotyping showed that the der(13) was derived from a translocation of chromosomes 7 and 13. Fluorescence in situ hybridization using subtelomeric probes revealed three signals of 7pTEL and only one signal of 13qTEL, indicating a translocation between 7p and 13q in the der(13). Array-based comparative genomic hybridization demonstrated partial trisomy 7p (7p15.3- p22.3) and partial monosomy 13q (13q33.3-q34). The karyotype was 46,XY,der(13)t(7;13)(p15.3;q33.3). Polymorphic DNA marker analysis revealed the paternal origin of the aberrant chromosome. Level II ultrasound at 24 weeks of gestation revealed microcephaly, an irregular-shaped skull, DWM, nuchal edema and transposition of the great arteries. Conclusion: Spectral karyotyping, fluorescence in situ hybridization and array-based comparative genomic hybridization are useful for prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 7p (7p15.3pter) and partial monosomy 13q (13q33.3qter) can be associated with DWM,

*Correspondence to: Dr Chih-Ping Chen, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. E-mail: [email protected] Accepted: April 15, 2010

320 Taiwan J Obstet Gynecol • September 2010 • Vol 49 • No 3 Partial Trisomy 7p and Partial Monosomy 13q

microcephaly, abnormal skull development, nuchal edema and cardiovascular defects on prenatal ultrasound. [Taiwan J Obstet Gynecol 2010;49(3):320–326]

Key Words: chromosome 7, chromosome 13, Dandy-Walker malformation, monosomy 13q, microcephaly, trisomy 7p

Introduction Amniocentesis revealed an aberrant derivative chromosome 13, or der(13) (Figure 1). Chromosomal prepara- Prenatal diagnosis of a de novo unbalanced reciprocal tions of the blood lymphocytes from the parents revealed translocation involving chromosomal segments with normal karyotypes. The derivative chromosome was subtle difference in banding gives rise to difficulties in characterized by SKY using 24-color SKY probes (Applied interpretation and genetic counseling. Diagnosis also Spectral Imaging, Carlsbad, CA, USA) and by FISH using requires molecular cytogenetic techniques such as spec- DNA probe mixtures containing the 6p, 6q, 7p, 7q, tral karyotyping (SKY), fluorescence in situ hybridization 13q, and 14q subtelomeric probes (TelVysion, Downers (FISH) and array-based comparative genomic hybridiza- Grove, IL, USA) and whole-chromosome paint 7 tion (aCGH) to identify the nature of the aberrant (Cytocell, Adderbury, UK). SKY analysis revealed that chromosome. Here, we report prenatal diagnosis and the der(13) contained a segment of chromosome 7 in molecular cytogenetic characterization of de novo par- the distal end of the long arm of chromosome 13 tial trisomy 7p (7p15.3pter) and partial monosomy (Figure 2). The FISH analyses showed that the chro- 13q (13q33.3qter) presenting with Dandy-Walker mosome 7 segment in the distal end of the long arm of malformation (DWM), abnormal skull development, chromosome 13 was of 7p in origin and the distal end microcephaly, nuchal edema, and transposition of the of 13q was deleted (Figure 3). great arteries as salient prenatal sonographic findings Level II ultrasound at 24 weeks of gestation showed in the second trimester. microcephaly with a biparietal diameter and a head cir- cumference less than the 5th centile, an irregular-shaped skull, DWM, nuchal edema, and transposition of the Materials, Methods and Results great arteries (Figure 4). The parents opted to termi- nate the pregnancy. A 568 g malformed male fetus was A 42-year-old woman, gravida 6, para 1, was referred delivered with a sloping forehead, trigonocephaly, a large to our hospital for amniocentesis at 18 weeks of gesta- anterior fontanelle, prominent sutures, hypertelorism, tion because of her advanced maternal age. The woman short palpebral fissures, a short nose with a broad nasal had experienced three spontaneous abortions and bridge, a small mouth, micrognathia, a long philtrum, one artificial abortion. She had a 1½-year-old pheno- large low-set ears, clenched hands with flexion defor- typically normal son. Her husband was 43 years old. mity of the fingers, overriding the fifth toe of the right

1 23 45

p15.3

6 7 8 9 10 11 12

q33.3 13 der(13) 14 15 16 17 18

19 20 21 22 YX Figure 1. The G-banded karyotype shows a derivative chromosome 13, or der(13). Arrows indicate the breakpoints.

Taiwan J Obstet Gynecol • September 2010 • Vol 49 • No 3 321 C.P. Chen, et al

1 23 4 5

6 789101112

13 14 15 16 17 18

Figure 2. Spectral karyotyping using 24-color probes shows that the der(13) 19 20 21 22 XY is due to a translocation between chromosomes 7 and 13.

A B

der(13) 7pter

wcp 7

14qter 7qter

13qter

6qter Figure 3. (A) Fluorescence in situ hybridization (FISH) using a whole chromosome paint (WCP) 7 probe (pink) shows that the der(13) is stained with a pink signal by the probe. (B) FISH using chromosome 7p terminal (ter) probe, 7qter probe and 14qter probe, with the 7pTEL (green)/7qTEL (red) probes and 14qTEL (yellow) probe shows three green signals corresponding to the 7pTEL probe, indicating partial trisomy 7p. (C) FISH using chromosome 6pter probe, 6qter probe and 13qter probe with the 6pTEL (green)/6qTEL (red) probes and 13qTEL (yellow) probe shows only one yellow signal corresponding to the 6pter 13qTEL probe, indicating partial monosomy 13q. foot, and overriding the third and the fifth toes of the RP11-34M9)×3, 13q33.3q34 (RP11-313L9RP11- left foot secondary to short metatarsal bones (Figure 5). 450H16)×1] (Figure 6). The karyotype was 46,XY,der The external genitalia were unremarkable. (13)t(7;13)(p15.3;q33.3) (Figure 1). Oligonucleotide- Bacterial artificial chromosome (BAC)-based aCGH based aCGH using HumanCytoSNP-12vl BeadChips of fetal DNA using CMDX CA2500 chips (CMDX, Irvine, (Illumina, San Diego, CA, USA) showed a 19.9-Mb du- CA, USA) demonstrated partial trisomy 7p and partial plication of distal 7p and a 7.38-Mb deletion of distal monosomy 13q [arr cgh 7p22.3p15.3 (RP11-90P13 13q (Figure 7). Quantitative fluorescent polymerase

322 Taiwan J Obstet Gynecol • September 2010 • Vol 49 • No 3 Partial Trisomy 7p and Partial Monosomy 13q chain reaction using specific short tandem-repeat poly- Chromosome 7 Chromosome 13 p22.3 00 morphic DNA markers determined the paternal origin p22.2 p13 p22.1 of the aberrant derivative chromosome. p21.3 p12 p21.2 p11.2 p21.1 p15.3 p11.1 q11 p15.2 p15.1 q12.11 20 p14.3 q12.12 Discussion p14.2 q12.13 q12.2 p14.1 q12.3 p13 q13.1 p12.3 q13.2 p12.2 50 We previously reported the usefulness of SKY and FISH p12.1 q13.3 p11.2 p11.1 q14.11 40 to identify a small supernumerary marker chromo- q11.1 q14.12 q11.21 q14.13 q14.2 some [1]. In the present case, we also demonstrate the q11.22 q14.3 q11.23 utility of SKY and FISH to identify a de novo aberrant q21.1 q21.11 q21.2 60 q21.12 q21.31 q21.13 q21.2 q21.32 q21.3 q21.33 q22.1 100 q22.1 q22.2 q22.2 q22.3 q22.3 q31.1 80 q31.2 q31.1 q31.31 q31.32 q31.2 q31.33 q32.1 q31.3 q32.2 q32.3 q32.1 q33 q32.2 q32.3 q34 100 q33.1 q35 q33.2 q36.1 150 q33.3 q36.2 q34 q36.3 .22.33.5671 1.52 34.5 .22.33.5 1 1.52 3 4.5 Ratio Ratio Figure 6. Bacterial artificial chromosome based-array comparative genomic hybridization shows a duplication of distal 7p Figure 4. Prenatal ultrasound at 24 weeks of gestation shows [arr cgh 7p22.3p15.3 (RP11-90P13RP11-34M9)×3] and an irregular shape of the skull, Dandy-Walker malformation, an a deletion of distal 13q [arr cgh 13q33.3q34 (RP11-313L9 enlarged cisterna magna, and hypoplasia of cerebellar vermis. RP11-450H16)×1].

A B

Figure 5. (A) Facial appearance, (B) flexion deformity of the fingers of both hands, and (C) overriding the fifth toe of the right foot and overriding the third and the fifth toes of the left foot in the fetus.

Taiwan J Obstet Gynecol • September 2010 • Vol 49 • No 3 323 C.P. Chen, et al Known reg Found reg A 4554318330_R01C02 B Allele freq 0.0 0.25 0.5 0.75 1.0 7 Known reg Found reg 4554318330_R01C02 B Allele freq p21

0.0 0.25 0.5 0.75 1.0 7 p15 141,320 Detected region 2,133,210 4,125,100 CHR 7 6,116,990 Start 141322 8,108,880 q11 q11 End 20060166 q21 10,100,770 q11 Length 19918844 12,092,660 q21 14,084,550 Value 3 16,076,440 q22 G/L Gain 18,068,330 Conf 5028.312 20,080,180 −2.00 −1.00 2.001.000.00 Smoothed log R q33 q34

q35

−2.00 −1.00 0.00 1.00 2.00 Smoothed log R Known reg Found reg B 4554318330_R01C02 B Allele freq 0.0 0.25 0.5 0.75 1.0 13

q13

q11

q12

Known reg q14 Found reg 4554318330_R01C02 B Allele freq q14 0.0 0.25 0.5 0.75 1.0 13 q21 106,737,060 Detected region p11p11 107,475,860 108,214,660 CHR 13 q21 108,953,460 Start 106737065 109,692,260 q21 End 114125098 110,431,060 q31 Length 7388033 111,169,860 q31 111,908,660 q31 Value 1 112,647,460 q32 G/L Loss 113,386,260 q33

Conf 1607.139 114,125,060 q33 −2.00 −1.00 0.00 1.00 2.00 Smoothed log R q34 −4.12 −2.06 0.00 2.06 4.12 Smoothed log R Figure 7. Oligonucleotide-based array comparative genomic hybridization shows (A) a 19.9-Mb duplication in 7p22.3 7p15.3 [arr cgh 7p22.3p15.3 (141,322-20,060,166) × 3] and (B) a 7.38-Mb deletion of 13q33.313q34 [arr cgh 13q33.3q34 (106,737,065-114,125,098) × 1].

324 Taiwan J Obstet Gynecol • September 2010 • Vol 49 • No 3 Partial Trisomy 7p and Partial Monosomy 13q chromosome derived from an unbalanced reciprocal deleted segment of 13q32.3-q33.1 for DWM. Walczak- translocation. Sztulpa et al [16] suggested that haploinsufficiency of The present case had an irregular-shaped skull and the ARHGEF7 gene in patients with chromosome dele- a large fontanelle. Delayed closure of the large fontanelle tions in 13q33-q34 is responsible for mental retardation and prominent sutures are characteristic clinical fea- and microcephaly. ARHGEF7 maps to 13q34 and en- tures of partial trisomy 7p [2,3]. The present case had codes ρ guanine nucleotide exchange factor 7. Muta- partial trisomy 7p (7p15.3pter) with a triple dose of tions in other ρ guanine nucleotide exchange factors such the TWIST gene. The TWIST gene is localized to chro- as ARHGEF6 and ARHGEF9 have been reported to be mosome 7p21.1 and encodes a transcription factor associated with X-linked mental retardation [17,18]. containing a basic helix–loop–helix domain. Mutations Partial trisomy 7p is associated with a characteris- or haploinsufficiency of the TWIST gene will cause cran- tic craniofacial phenotype of dolichocephaly or brachy- iosynostosis [4–6]. By contrast, the increased gene cephaly, large fontanelles, large low-set malformed ears, dosage effect of the TWIST gene may cause delayed hypertelorism, down-slanting palpebral fissures, a high closure of the large fontanelle and abnormal skull or prominent forehead, a broad or prominent nasal development [7–9]. bridge, micrognathia, and high arch palate [8,19–25]. The present case had DWM, microcephaly, and nu- Reish et al [23] restricted the critical region for this chal edema. Chromosome 13q deletions have been as- phenotype to 7p15pter. In a review of 37 cases with sociated with DWM, microcephaly, and nuchal edema. partial trisomy 7p, Kozma et al [26] found hydroceph- McCormack et al [10] reported two patients with alus in seven cases (19%), other central nervous system del(13q21-q23) and del(13q22-q33), and multiple con- anomalies in 13 cases (35%), cardiac anomalies in 16 genital anomalies including holoprosencephaly and cases (43%) and foot deformities in 18 cases (49%). DWM. Gul et al [11] reported prenatal diagnosis of Prenatal diagnosis of partial trisomy 7p is uncommon. del(13)(13q31.2/32.1qter) in a fetus with intrauterine Witters et al [27] reported prenatal diagnosis of par- growth restriction, DWM, microcephaly, right microph- tial trisomy 7p (7p22.1pter) and partial monosomy thalmia, micrognathia, marked nuchal edema, oligo- 18p (18p11.22pter) in a fetus with nuchal edema. dactyly, thumb aplasia, and ambiguous genitalia. Alanay Ozgun et al [28] reported prenatal diagnosis of partial et al [12] reported prenatal diagnosis of del(13)(q14 trisomy 7p (7p15.3pter) and partial monosomy 9p qter) in a fetus with intrauterine growth restriction, (9p24pter) in a fetus with corpus callosum agenesis, DWM, and bilaterally absent thumbs and first toes. an enlarged left kidney, single umbilical artery, hyper- Ballarati et al [13] reported three patients with DWM telorism, a depressed nasal bridge, frontal bossing, and 13q deletions, including del(13)(q22.3-q33.2), irregular maxillar alveolar composition, club feet, flexion del(13)(q31.1-qter) and del(13)(q32.2-qter), and found deformity of the upper extremities, and Epstein anom- that the minimal deletion interval associated with DWM aly. Chen et al [29] reported Dandy-Walker variant in was limited to the 13q32.2-q33.2 region in which the a boy with partial trisomy 7p (7p21.2pter) and par- ZIC2 and ZIC5 genes are located. Hindryckx et al [14] tial monosomy 12q (12q24.33qter). The present case reported a first-trimester diagnosis of del(13)(q31.1- also provides evidence that DWM is associated with q33.1) in a fetus with increased nuchal translucency, partial trisomy 7p (7p15.3pter). DWM, a small parietal encephalocele, agenesis of the corpus callosum, mild renal dysplasia, and the absence of lobulation of the lungs. In a study of 14 patients with Acknowledgments partial deletion of 13q, Kirchhoff et al [15] refined the smallest deletion linked to short stature (13q31.3), This work was supported by research grants NSC-96- microcephaly (13q33.3-q34), cortical development mal- 2314-B-195-008-MY3 and NSC-97-2314-B-195-006- formations (13q33.1-qter), DWM (13q32.2-q33.1), cor- MY3 from the National Science Council, and MMH- pus callosum agenesis (13q32.2-q33.1), meningocele/ E-99004 from Mackay Memorial Hospital, Taipei, encephalocele (13q31.3-qter), DWM, corpus callosum Taiwan. and neural tube defects taken together (13q32.3-q33.1), anophthalmia/microphthalmia (13q31.3-qter), cleft lip/palate (13q31.3-q33.1), lung hypoplasia (13q31.3- References q33.1), and thumb aplasia/hypoplasia (13q31.3-q33.1 and 13q33.3-q34). In the present case, the deletion of 1. Chen CP, Lin CC, Su YN, et al. Prenatal diagnosis and molec- 13q33.3-qter was associated with the phenotypic fea- ular cytogenetic characterization of a small supernumerary tures of microcephaly, but was outside the minimal marker chromosome derived from chromosome 18 and

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