Case Report
Prenatal diagnosis and molecular cytogenetic characterization of a de novo
interstitial duplication of 14q (14q31.3
q32.12) associated with abnormal
maternal serum biochemistry
Chih-Ping Chen a,b,c,d,e,f,g *, Kwui-Shuai Hwang h, Her-Young Su h, Shuan-Pei Lin b,c,i,j, Yi-Ning Su k,
Schu-Rern Chern c, Jun-Wei Su a,l, Yu-Ting Chen b, Wen-Lin Chen a and Wayseen Wang b,m
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 Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical
Center, Taipei, Taiwan
i Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
j Mackay Medicine, Nursing and Management College, Taipei, Taiwan
k Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical
University, Taipei, Taiwan
l Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
m 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]
Abstract
Objective: To present prenatal diagnosis and molecular cytogenetic characterization of a de
novo interstitial duplication of 14q (14q31.3q32.12) in a pregnancy associated with
abnormal maternal serum biochemistry.
Case Report: A 19-year-old woman underwent amniocentesis in the second trimester because of
abnormal maternal serum biochemistry. Her husband was 33 years old. At 16 weeks of gestation, the levels of -fetoprotein (AFP), unconjugated estriol (uE3), total -human chorionic gonadotrophin (-hCG) and inhibin-A were 0.8 multiples of median (MoM), 0.84 MoM, 3.06 MoM and 1.14 MoM, respectively, consistent with a positive trisomy 21 risk of 1/269. Amniocentesis revealed a small de novo interstitial duplication of 14q encompassing 14q31-q32.1. Array comparative genomic hybridization analysis detected a 6.6-Mb duplication at chromosome 14q31.3-q32.12. Fluorescence in situ hybridization analysis showed a direct duplication of interstitial 14q. The karyotype was 46,XY,dup(14) (q31.3q32.12). Level II ultrasound was unremarkable. The parents decided to continue the pregnancy. A 3,805-g healthy male baby was delivered at 39 weeks of gestation. When examined at 6 months of age, the neonate was normal in growth and psychomotor development with no apparently phenotypic abnormalities, although long-term follow-ups are required.
Conclusion: Abnormal maternal serum biochemistry in the second-trimester may be a distinctive prenatal feature in pregnancy associated with fetal chromosome 14q duplication.
Key words: 14q31.3q32.12, duplication 14q, interstitial duplication, maternal serum biochemistry, prenatal diagnosis
Introduction
Partial trisomy 14q with a duplication of 14q (14q22q32) has been associated with a distinct 14q duplication syndrome characterized by craciofacial dysmorphisms of high forehead, wide sutures and fontanels, sparse hair and eyebrows, board nasal bridge, hypertelorism, thin upper lip, abnormal ears, broad mouth and micrognathia, developmental delay, mild mental retardation, spasticity, hyperreflexia, premature puberty and primodial short stature [1-5].
Cases of partial trisomy 14q with a duplication of 14q31qter are rare and present only minor anomalies of an asymmetric face, frontal bossing, low-set and dysplastic ears, hypertelorism, sparse eyebrows and lashes, prominent nasal bridge, small mandible, growth retardation and moderate mental retardation [6-13]. Here, we present prenatal diagnosis and molecular cytogenetic characterization of a de novo interstitial duplication of 14q (14q31.3q32.12) in a pregnancy associated with abnormal maternal serum biochemistry but without apparently phenotypic abnormalities. To our knowledge, such a case has not previously been described.
Case Report
A 19-year-old, gravida 2, para 1, woman underwent second-trimester screening for chromosome abnormalities using maternal serum biochemistry at 16 weeks of gestation. Her husband was 33 years old. The levels of -fetoprotein (AFP), unconjugated estriol (uE3), total -human chorionic gonadotrophin (-hCG) and inhibin-A were 0.8 multiples of median (MoM), 0.84 MoM, 3.06 MoM and 1.14 MoM, respectively, consistent with a positive for a positive trisomy 21 risk of 1/269. At 18 weeks of gestation, she underwent amniocentesis which revealed a small interstitial duplication of 14q encompassing 14q31-q32.1 (Fig. 1). Prenatal ultrasound findings were unremarkable. A repeated amniocentesis was performed at 20 weeks of gestation. Oligonucleotide-based array comparative genomic hybridization (aCGH) using CytoChip Oligo Array (BlueGnome, Cambridge, UK) on uncultured amniocytes detected a 6.6-Mb duplication at chromosome 14q31.3-q32.12, or arr cgh 14q31.3q32.12 (84,238,307-90,839,109)3 (UCSC hg18, NCBI build 36, March 2006) (Fig. 2). The parental karyotypes were normal. For fluorescence in
situ hybridization (FISH) determination of the orientation of the duplication of the chromosome 14
[dup(14)], the bacterial artificial chromosome (BAC) clone probes mapping the genomic region of 14q31.3-q32.1 were used. The BAC clone probes RP11-35P13 (85,596,133-85,731,472) (UCSC hg18, NCBI build 36) (spectrum green) at 14q31.3 and RP11-99C24 (89,927,464-90,094,722)
(spectrum red) at 14q32.11 were used to determine the orientation of the duplication. FISH analysis showed an orientation of green-red-green-red (Fig. 3), consistent with a direct duplication of interstitial 14q. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype of 46,XY,dup(14)(q31.3q32.12) (Fig. 1). Level II ultrasound was unremarkable. The parents opted to continue the pregnancy. At 39 weeks of gestation, a healthy male baby was delivered with a body weight of 3,805 g (85th centile), a body length of 51 cm (85th centile) and a head
circumference of 36 cm (85th centile). There was no dysmophism. Ultrasound examinations of
internal organs showed normal findings. When examined at 6 months of age, he was normal in growth and psychomotor development with no apparently phenotypic abnormalities, although long-term follow-ups are required.
Discussion
Abnormal maternal serum biochemistry in the first or second trimester may result in incidental detection of rare fetal chromosomal abnormalities [14-16]. The present pregnant woman was 19 years old. She underwent amniocentesis because of a positive screen risk of 1/269 for trisomy 21 calculated by relatively low levels of AFP and uE3, and an abnormally high level of -hCG. The present case shows that fetuses with an interstitial duplication of 14q may present abnormal maternal serum biochemistry in the second trimester, and suggests that abnormal maternal serum biochemistry may be a distinctive prenatal feature in pregnancy associated with fetal chromosome 14q duplication.
Our case is the first report of a de novo tandem duplication encompassing the chromosomal bands from 14q31.3 to 14q32.12 without involving 14q32.2. The present case did not have the phenotype of uniparental disomy (UPD) 14 and 14q duplication syndrome. Maternal UPD 14 manifests a phenotype of short stature, growth retardation, muscular hypotonia, joint laxity, truncal obesity, small hands, hyperextensible joints, scoliosis and mild dysmorphic features of the face, whereas paternal UPD 14 manifests intrauterine growth restriction, polyhydramnios, severe psychomotor retardation, mild contractures of the fingers, cardiomyopathy and the “coat-hanger sign” of the thoracal ribs [17,18]. Genomic imprinting effects have been observed in chromosome 14 because human chromosome 14q32.2 region harbors paternally expressed genes such as DLK1 and RTL1, maternally expressed genes such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8, and the differentially methylated region (DMR) of intergenic DMR
(IG-DMR) and MEG3-DMR [19-22]. Our case did not involve duplication of the imprinting genes. However, our case did involve with duplication of other genes such as FLRT2, GALC, GPR65,
KCNK10, SPATA7, PTPN21, ZC3H14, EML5, TTC8, FOXN3, C14orf143, TDP1, KCNK13, PSMC1, C14orf102, CALM1, TTC7B, RPS6KA5, C14orf159, SNORA11B, GPR68 and CCDC88C.
The gene dosage increase effect of those genes is unknown at the present time. Although the present neonate was normal in growth and psychomotor development with no apparently phenotypic abnormalities, long-term follow-ups are required for delineating the genotype-phenotype correlation of dup(14)(q31.3q32.12).
Acknowledgements
This work was supported by research grants NSC-99-2628-B-195-001-MY3 and NSC-101-2314-B-195-011-MY3 from the National Science Council and MMH-E-101-04 from Mackay Memorial Hospital, Taipei, Taiwan.
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Figure Legends
Fig. 1. A karyotype of 46,XY,dup(14)(q31.3q32.12)
Fig. 2. Oligonucleotide-based array comparative genomic hybridization on uncultured amniocytesshows a 6.6-Mb duplication at 14q31.3-q32.12 (arrow).
Fig. 3 Fluorescence in situ hybridization using bacterial artificial chromosome clone probes RP11-35P13 (85,596,133-85,731,472) (spectrum green) at 14q31.3 and RP11-99C24 (89,927,464-90,094,722) (spectrum red) at 14q32.11. A direct duplication of 14q in the orientation of green-red-green-red is evident in the dup(14). The inset shows the amplified dup(14) and chromosome 14. dup(14) = the chromosome 14 with a duplication.
