A 17q duplication prenatally detected lable at ScienceDirect Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 326e329 Contents lists avai Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com Research Letter A 17q duplication prenatally detected Rossella Bruno, Angelo Valetto*, Veronica Bertini, Cinzia Cosini, Benedetta Toschi, Caterina Congregati, Simona Rossi, Paolo Simi Cytogenetics and Molecular Genetic Unit, Azienda Ospedaliera Universitaria Pisana, S. Chiara Hospital, 56100 Pisa, Italy a r t i c l e i n f o Article history: Accepted 27 May 2014 This report is about an isolated de novo interstitial duplication of chromosome 17q detected in prenatal diagnosis. The duplication spans about 15.6 Mb, and contains at least 15 OMIM genes. As far as we know, this is the first case which has been detected prenatally; postnatal cases with a similar chromosomal anomaly are rare and the phenotype has been associated with a wide spectrum of clinical signs. This phenotypic variability may be due to the different extents of the duplicated regions, thus an accurate molecular definition of the chromosomal breakpoints is necessary to make better genotype-phenotype correlations [1]. The mother was a 36-year-old healthy woman with two healthy children; amniocentesis was performed at the 16th week of gesta- tion because of her advanced age. Ultrasound gynecological ex- amination did not show any fetal abnormalities except for a slight hypertelorism. Conventional banding chromosome analysis on cultured amniotic fluid cells, with a resolution of about 400 bands, revealed an apparent terminal duplication of chromosome 17q (Fig. 1), that was better characterized using molecular cytogenetic techniques. Array-comparative genomic hybridization (Array-CGH) using a 44 K oligo platform (Agilent Technologies, Santa Clara, CA, USA) revealed that the duplication was not terminal but interstitial, from position 55,354,004 bp (17q23) to position 71,053,979 bp (17q25) (NCBI36/hg18 map) (Fig. 2). The OMIM genes in the region can be seen in Table 1 and in Fig. 3. Fluorescent in situ hybridization, using the whole Chromosome Painting 17 probe (Cytocell, LTD Cambridge, UK), excluded additional cryptic rearrangements; Telvysion 17q (Vysis, Abbott S.p.A., Milan, Italy) probe for the 17q * Corresponding author. Molecular Genetic Unit, Azienda Ospedaliera Uni- versitaria Pisana, S. Chiara Hospital, via Roma 57, 56100 Pisa, Italy. E-mail address: a.valetto@ao-pisa.toscana.it (A. Valetto). http://dx.doi.org/10.1016/j.tjog.2014.05.008 1028-4559/Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published subtelomeric regions showed two normal signals (Fig. 4), con- firming array-CGH data. Parental karyotypes and array CGH profiles were normal. Pregnancy was terminated at the 21st week of gestation. Anal- ysis of the fetal anatomy showed minor facial dimorphisms with hypertelorism, a wide nasal base, a wide mouth and a thin upper lip (Figs. 5e6), along with no specific signs such as microcalcinosis in the adrenal and hepatic parenchyma that can be associated with many other chromosomal anomalies, such as Di George Syndrome, Edwards Syndrome, Patau Syndrome, Down Syndrome, and mosaicism for partial trisomy of chromosome 8 [2e5]. Partial 17q duplication is a rare anomaly, and most of the pa- tients reported in literature have undergone postnatal analysis using classic cytogenetic techniques. The resolution of cytogenetic banding is about 10 Mb, thus a detailed analysis of breakpoints is missing. Duplication 17q has been associated with a severe phenotype but the clinical consequences of this anomaly are far from being clarified, and extensive variability is present among the reported patients. Manifestations of this anomaly include psycho- motor/mental retardation, growth retardation, and dysmorphic features such as facial asymmetry with hypertelorism, frontal bossing and temporal narrowness, a broad nasal bridge, epicanthal folds, wide mouth with a thin upper lip, micrognathia, webbed neck, low-set posteriorly angulated ears, and an abnormal hairline. Moreover partial trisomy 17q is associated with polydactyly, long fingers, abnormal positioned feet, cerebellar hypoplasia, multiple cardiac anomalies, limb shortness, hyperlaxity, genital abnormal- ities, and accessory spleen [6,7]. The partial trisomy of 17q has been described in complex chromosomal rearrangements (Table 2). King et al [8] reported a case of partial trisomy 17q2-qter, detected by amniocentesis which was performed because of polyhydramios and ultrasound diagnosis of fetal anomalies. The chromosome complement of the cultured amniotic fluid cells was 46,XX/46,XX,-21,þder(21),t(17; 21) (q21.1; q22.3) in a ratio of 1:15; the infant born showed the unique phenotypic features of mosaic partial trisomy 17q2: frontal bossing, large mouth, brachyrhizomelia, and hexadactyly. Babovic-Vuksanovic et al [9] presented a familial case of dup 17q24-q25.1, whose clinical characteristics resembled Ullrich- Turner syndrome, indicating the presence of genes involved in skeletal development. Kelly et al [6] described an adult with dup by Elsevier Taiwan LLC. All rights reserved. mailto:a.valetto@ao-pisa.toscana.it http://crossmark.crossref.org/dialog/?doi=10.1016/j.tjog.2014.05.008&domain=pdf www.sciencedirect.com/science/journal/10284559 http://www.tjog-online.com http://dx.doi.org/10.1016/j.tjog.2014.05.008 http://dx.doi.org/10.1016/j.tjog.2014.05.008 http://dx.doi.org/10.1016/j.tjog.2014.05.008 Fig. 1. Cytogenetic analysis of the cultured amniotic fluid cells by Q-banding. Karyotype shows a duplication of the long arm of chromosome 17. R. Bruno et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 326e329 327 17q24-q25, suffering with epilepsy, sensorineural hearing loss, long fingers, and overlapping toes. In a study Lukusa et al [1] reported a case of a 3 year-old girl, with pure 17q25.3 (2.46 Mb) duplication and a complex clinical presentation comprising main features of dup 17q syndrome and additionally striking distal arthrogryposis. Most cases of partial trisomy for the distal region of 17q are due to adjacent-1 segregation of reciprocal translocation which were derived from either one of the parents [10e12]; some cases are due to a familial chromosome 17 inversion [13,14], few are de novo events [8]. This report shows the first case of a de novo isolated 17q duplication detected in a fetus without ultrasound abnormalities. The results of the fetal autopsy did not show the typical phenotypic Fig. 2. Array-comparative genomic hybridization profile of the duplicated region. Array-com 17q23-q25 (red dots represent duplicated oligos). alterations observed in cases diagnosed postnatally thus the cor- relation of genotype-phenotype is difficult, particularly during prenatal investigations. The lack of specific data concerning the prognosis of fetuses with dup 17 q makes genetic counseling a difficult task. The 17q23-qter portion is the region most commonly duplicated in almost all the dup 17q cases reported in literature. This region includes OMIM genes involved in several diseases, such as retinitis pigmentosa, ciliarydyskenesia, microcephaly, and bradyopsia (Table 1). So far, the duplication we have found is the largest described in prenatal diagnosis and it is likely that it was not compatible with life; if the pregnancy had not been interrupted the infant would have probably shown the major clinical signs of dup 17q syndrome immediately after birth. parative genomic hybridization showing the presence of a duplication of chromosome Table 1 OMIM genes located in the duplicated region 17q 23-25. Gene Location Phenotype Carbonic anhydrase IV CA4 17q23.1 Retinitis pigmentosa 17 Small patella syndrome SPS 17q23.2 Small patella syndrome Angiotensin i-converting enzyme ACE 17q23.3 Renaltubulardysgenesis Angiotensin I-converting enzyme, benign serum in crease Alzheimer disease, susceptibility to Microvascular complications of diabetes 3 Myocardial infarction, susceptibility to SARS, progression of Stroke, hemorrhagic Ste20-related kinase adaptor alpha STRADA 17q23.3 Polyhydramnios, megalencephaly, and symptomatic epilepsy Growth hormone 1 GH1 17q23.3 Growth hormone deficiency, isolated, type IA Growth hormone deficiency, isolated, type IB Growth hormone deficiency, isolated, type II Kowarski syndrome CD79 B antigen CD79 B 17q23.3 A gamma globulinemia 6 Sodium channel, voltage-gated, type IV, alpha subunit SCN4A 17q23.3 Hyperkalemic periodic paralysis, type 2 Hypokalemic periodic paralysis, type 2 Myasthenic syndrome, acetazolamide-responsive Myotonia congenita, atypical, acetazolamide-responsive Paramyotonia congenita Polymerase, DNA, GAMMA-2 POLG2 17q23.3 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 Regulator of G protein signaling 9 RGS9 17q24.1 Bradyopsia Family with sequence similarity 20 member A FAM20 A 17q24.2 Amelogenesis imperfecta and gingival fibromatosis syndrome Sry-box 9 SOX9 17q24.3 Acampomelic campomelic dysplasia Campomelic dysplasia Campomelic dysplasia with autosomal sex reversal Component of oligomeric golgi complex 1 COG1 17q25.1 Congenital disorder of glycosylation, type IIg Dynein, axonemal, intermediate chain 2 DNAI2 17q25.1 Ciliary dyskinesia, primary, 9, with or without situs inversus Solute carrier family 9, member 3, regulator 1 SLC9A3R1 17q25.1 Nephrolithiasis/osteoporosis, hypophosphatemic, 2 Solute carrier family 25 (mitochondrial thiamine pyrophosphate carrier), member 19 SLC25A19 17q25.1 Microcephaly, amish type Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) Fig. 3. OMIM genes located in the duplicated region 17q23-25. Fig. 4. Fluorescence in situ hybridization performed using the probe Whole Chromo- some Painting 17 (Cytocell). Fig. 5. Hypertelorism and a wide nasal base. R. Bruno et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 326e329328 Fig. 6. Apparently normal fetal anatomy. Table 2 Duplication of 17q region as sole chromosome anomaly reported in literature and in our study. Study Duplicated 17q region Babovic-Vuksanovic et al 1998 [9] 17q24-q25.1 Kelly et al 2002 [6] 17q24-q25 Lukusa et al 2010 [1] From 17q 25.3 (2,46 Mb) Our study 17q23-q25 (15.6 Mb) R. Bruno et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 326e329 329 Conflict of interest The authors have no conflicts of interest relevant to this article. References [1] Lukusa T, Fryns JP. Pure de novo 17q25.3 micro duplication characterized by micro-array CGH in a dysmorphic infant with growth retardation, develop- mental delay and distal arthrogryposis. Genet Couns 2010;21:25e34. [2] Bertola G, Giambona S, Bianchi R, Girola A, Berra SA. Di George syndrome: not always a pediatric diagnosis. Recenti Prog Med 2013;104:69. [3] Simchen MJ, Toi A, Bona M, Alkazaleh F, Ryan G, Chitayat D. Fetal hepatic calcifications: prenatal diagnosis and outcome. Am J Obstet Gynecol 2002;187:1617e22. [4] Jay A, Kilby MD, Roberts E, Brackley K, Platt C, McHugo J, et al. Prenatal diagnosis of mosaicism for partial trisomy 8: a case report including fetal pathology. Prenat Diagn 1999;19:976e9. [5] Bronshtein M, Blazer S. Prenatal diagnosis of liver calcifications. Obstet Gynecol 1995;86:739e43. [6] Kelly BD, Becker K, Kermode V, Stallings RL, Murphy RP, Green AJ, et al. Dysmorphic features and learning disability in an adult male with pure partial trisomy 17q24-q25 due to a terminal duplication. Am J Med Genet 2002;112: 217e20. [7] Cordier AG, Braidy C, Levaillant JM, Brisset S, Maurin ML, Mas AE, et al. Cor- relation between ultrasound and pathological examination in a prenatal diagnosis of Cri du Chat syndrome associated with partial trisomy 17q. Prenat Diagn 2008;28:463e5. [8] King PA, Ghosh A, Tang M. Mosaic partial trisomy 17q2. J Med Genet 1991;28: 641e3. [9] Babovic-Vuksanovic D, Westman JA, Jalal SM, Lindor NM. Clinical character- istics associated with dup17(q24q25.1) in a mosaic mother and two non- mosaic daughters. Clin Dysmorphol 1998;7:171e6. [10] Ohdo S, Madokoro H, Sonoda T, Ohba K. Sibs lacking characteristic features of duplication of distal 17q. J Med Genet 1989;26:465e8. [11] Cotter PD, Stewart NL. Partial trisomy 17q and monosomy 9p due to a familial translocation. Ann Genet 1990;33:231e3. [12] Barros Nu~nez P, Rolon A, Lizcano LA, Rivera H. Pure trisomy 17q from a 17;21 translocation. Genet Couns 1993;4:227e9. [13] Greenberg F, Stratton RF, Lockhart LH, Elder FF, Dobyns WB, Ledbetter DH. 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