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Chromosome 1P36 Deletion Syndrome: Prenatal Diagnosis, Molecular Cytogenetic Characterization and Fetal Ultrasound Findings

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Chromosome 1P36 Deletion Syndrome: Prenatal Diagnosis, Molecular Cytogenetic Characterization and Fetal Ultrasound Findings View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ■ SHORT COMMUNICATION ■ CHROMOSOME 1P36 DELETION SYNDROME: PRENATAL DIAGNOSIS, MOLECULAR CYTOGENETIC CHARACTERIZATION AND FETAL ULTRASOUND FINDINGS Chih-Ping Chen1,2,3,4,5,6*, Ming Chen7,8,9,10, Yi-Ning Su11, Chin-Yuan Hsu1, Fuu-Jen Tsai4,12,13, Schu-Rern Chern2, Pei-Chen Wu1, Chen-Chi Lee1, 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 prenatal diagnosis and molecular cytogenetic characterization of de novo partial mono- somy 1p (1p36.23pter) and partial trisomy 20p (20p12.1pter) associated with ventriculomegaly, ventricu- lar septal defect and midface hypoplasia. Materials, Methods and Results: A 31-year-old, primigravid woman was referred for amniocentesis at 20 ges- tational weeks because of ventriculomegaly, ventricular septal defect, and midface hypoplasia. Amniocentesis revealed an aberrant derivative chromosome 1, or der(1). Parental karyotypes were normal. Spectral karyotyping analysis revealed that the der(1) contained a segment of chromosome 20 in the distal end of the short arm of chromosome 1. Array comparative genomic hybridization demonstrated an 8.4-Mb distal 1p deletion and a 14-Mb distal 20p duplication. The karyotype was 46,XX,der(1)t(1;20)(p36.23;p12.1)dn. Polymorphic DNA marker analysis determined the paternal origin of the aberrant chromosome. The pregnancy was subsequently ter- minated. A 462-g malformed female fetus was delivered at 22 gestational weeks with a prominent forehead, midface hypoplasia, a flat nasal bridge, low-set ears, a long philtrum, a pointed chin and micrognathia. Conclusion: Spectral karyotyping, fluorescence in situ hybridization and array comparative genomic hybridiza- tion are useful for the prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial monosomy 1p (1p36.23pter) and partial trisomy 20p (20p12.1pter) are associated with ventriculomegaly, ventricular septal defect and midface hypoplasia on prenatal ultrasound. Prenatal diagnosis of ventriculomegaly, congenital heart defects and midface hypoplasia should alert clinicians to chromosome 1p36 deletion syndrome and prompt molecular cytogenetic analysis if necessary. [Taiwan J Obstet Gynecol 2010;49(4):473–480] Key Words: chromosome 1, chromosome 1p36 deletion syndrome, chromosome 20, monosomy 1p36, prenatal diagnosis, ultrasound *Correspondence to: Dr Chih-Ping Chen, Department Introduction of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Prenatal diagnosis of a de novo unbalanced reciprocal Taipei, Taiwan. E-mail: [email protected] translocation involving chromosomal segments with Accepted: September 1, 2010 a subtle difference in banding results in difficulties in Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 473 C.P. Chen, et al interpretation and genetic counseling, and requires ventriculomegaly, a ventricular septal defect (VSD) and molecular cytogenetic technologies such as spectral midface hypoplasia. karyotyping (SKY), fluorescence in situ hybridization (FISH), and array-based comparative genomic hybridi- zation (aCGH) to identify the nature of the aberrant Materials, Methods and Results chromosome. We previously reported the utility of SKY and FISH in the identification of a de novo aberrant A 31-year-old, primigravid woman was referred to the chromosome derived from an unbalanced reciprocal genetic counseling center for amniocentesis at 20 ges- translocation [1]. We additionally report here the pre- tational weeks because of abnormal ultrasound find- natal diagnosis and molecular cytogenetic characteri- ings of ventriculomegaly, VSD and midface hypoplasia zation of de novo partial monosomy 1p (1p36.23pter) (Figure 1). Amniocentesis revealed an aberrant deriva- and partial trisomy 20p (20p12.1pter) associated with tive chromosome 1, or der(1) (Figure 2). Chromosome A B C Figure 1. Prenatal ultrasound at 20 gestational weeks reveals (A) ventriculomegaly, (B) a ventricular septal defect and (C) midface hypoplasia. Figure 2. G-banded karyotype shows a derivative chromosome 1, or der(1). The proband’s karyotype is 46,XX,der(1)t(1;20)(p36.23;p12.1)dn. The arrows indicate the breakpoints. 474 Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 Chromosome 1p36 Deletion Syndrome preparations of blood lymphocytes from the parents uncultured amniocytes. Bacterial artificial chromosome revealed normal karyotypes. The derivative chromosome (BAC)-based aCGH using CMDX BAC-based aCGH was characterized by SKY using 24-color SKY probes CA2500 chips (CMDX, Irvine, CA, USA) demonstrated (Applied Spectral Imaging, Carlsbad, CA, USA). SKY partial monosomy 1p and partial trisomy 20p [arr analysis revealed that the der(1) contained a segment 1p36.33p36.23 (RP11-668E2RP11-81J7)×1, 20p of chromosome 20 in the distal end of the short arm 13p12.1 (RP11-530N10RP11-238I2)×3] (Figure 4). of chromosome 1 (Figure 3). Repeat amniocentesis Oligonucleotide-based aCGH using HumanCytoSNP- was performed at 22 gestational weeks, and 20 mL of 12vl BeadChips (Illumina, San Diego, CA, USA) further aspired amniotic fluid was applied for aCGH using demonstrated an 8.4-Mb distal 1p deletion and a 14-Mb 12345 6 789101112 13 14 15 16 17 18 Figure 3. Spectral karyotyping using 24-color SKY probes shows a 19 20 21 22 X Y der(1) derived from a translocation between chromosomes 1 and 20. Chromosome 1 Chromosome 20 0 0 10 50 20 100 30 150 40 50 200 Figure 4. Bacterial artificial chromosome-based array comparative genomic hybridization shows a distal 1p 60 deletion [arr 1p36.33p36.23 (RP11-668E2RP11- 81J7)×1] and a distal 20p duplication [arr 20p13p12.1 .22.33 .567 1 1.52 3 4.5 .22.33 .567 1 1.52 3 4.5 (RP11-530N10RP11-238I2)×3]. Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 475 C.P. Chen, et al Known reg A Found reg B Allele freq 0.0 0.25 0.5 0.75 1.0 1 p31 p31 Known reg Found reg B Allele freq q12 0.0 0.25 0.5 0.75 1.0 1 742,430 Detected region 1,581,470 CHR 1 2,420,510 p31 3,259,550 Start 742429 4,098,590 End 9132849 4,937,630 q12 q32 Length 8390420 5,776,670 q41 Value 1 6,615,710 7,454,750 Loss G/L 8,293,790 Conf 1706,878 9,132,830 − − 3.62 −2.74−1.37 0.001.37 2.74 3.62 1.81 0.00 1.81 Smoothed log R Smoothed log R Known reg B Found reg B Allele freq 0.0 0.25 0.5 0.75 1.0 20 p13 p12 p11 p11 Known reg Found reg q11 B Allele freq 0.0 0.25 0.5 0.75 1.0 20 q11 457,700 p13 q11 Detected region 1,867,450 p12 CHR 20 3,267,200 p11 4,666,950 q13 Start 467697 p11 6,066,700 q11 q13 End 14465220 7,466,450 q11 Length 13997523 8,866,200 q13 10,265,950 Value 3 q13 11,665,700 Gain q13 G/L 13,065,450 q13 q13 Conf 7696.879 14,485,200 −2.00 −1.00 0.00 1.00 2.00 −2.33 −1.16 0.00 1.16 2.33 Smoothed log R Smoothed log R Figure 5. Oligonucleotide-based array comparative genomic hybridization shows (A) an 8.4-Mb distal 1p deletion [arr 1p36.33p36.23 (742,429-9,132,849)×1] and (B) a 14-Mb distal 20p duplication [arr 20p13p12.1 (467,697-14,465,220)×3]. distal 20p duplication [arr 1p36.33p36.23 (742,429- Discussion 9,132,849)×1, 20p13p12.1 (467,697-14,465,220)×3] (Figure 5). The karyotype was 46,XX,der(1)t(1;20) Chromosome 1p36 deletion syndrome (OMIM 607872), (p36.23;p12.1)dn (Figure 2). Polymorphic DNA marker or monosomy 1p36 syndrome, is the most common sub- analysis determined the paternal origin of the aberrant telomeric terminal deletion syndrome, and it is associ- chromosome. The parents opted to terminate the preg- ated with multiple congenital anomalies and mental nancy. A 462-g malformed female fetus was delivered retardation [2]. Chromosome 1p36 deletion syndrome with a prominent forehead, midface hypoplasia, a flat has an estimated frequency of 1 in 5,000 live births [3] nasal bridge, low-set ears, a long philtrum, a pointed and is characterized by a typical craniofacial dysmor- chin and micrognathia (Figure 6). phism of straight eyebrows, deep-set eyes, midface 476 Taiwan J Obstet Gynecol • December 2010 • Vol 49 • No 4 Chromosome 1p36 Deletion Syndrome A B Figure 6. Anterior and lateral views of the craniofacial appearance of the proband. hypoplasia, a broad nasal bridge, a long philtrum, 1p36 and a karyotype of 46,XY,der(1)t(1;20)(p36;p13) a pointed chin, large anterior fontanel, microbrachy- in a fetus conceived by a carrier mother who had a previ- cephaly, epicanthal folds, low-set ears, brachydactyly, ous aneuploid child with 46,XX,der(1)t(1;20)(p36;p13) camptodactyly, short feet, developmental delay, men- and multiple anomalies. The male fetus prenatally man- tal retardation, hypotonia, seizures, structural brain ifested hydrocephalus and complex congenital heart abnormalities, congenital heart defects, eye problems, defects during prenatal ultrasound at 16 gestational hearing loss and skeletal, renal and genital abnormali- weeks, and postnatally manifested truncus arteriosus, ties [4,5].
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