American Journal of Medical Genetics 139A:146–150 (2005)

Clinical ReportA Paternally Derived Inverted Duplication ofDistal 14q With a Terminal 14q DeletionChih-Ping Chen,1,2,3,4* Schu-Rern Chern,2 Shuan-Pei Lin,2,5 Chyi-Chyang Lin,6 Yueh-Chun Li,7

Tzu-Hao Wang,8 Chen-Chi Lee,1 Chen-Wen Pan,1 Lie-Jiau Hsieh,6 and Wayseen Wang2

1Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China3Department of Medical Technology, Yuanpei University of Science and Technology, Hsinchu, Taiwan, Republic of China4College of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China5Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China6Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan, Republic of China7Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, Republic of China8Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang-Gung Memorial Hospital, Tao-Yuan,Taiwan, Republic of China

A girl presented with a phenotype includingneonatal hypotonia, psychomotor retardation,mental retardation, short stature, and facial dys-morphism. She demonstrated common features ofboth 14q31-qter duplication and terminal 14qdeletion. She had undergone surgery for patentductus arteriosus and pyloric stenosis in infancy.Her karyotype was 46,XX,der(14) dup(14)(q32.3q31.3)del(14)(q32.3). Molecular cytogenetic analy-sis showed a paternally derived 14q31.3-q32.3duplication and a terminal 14q deletion and ledto the correlations between a particular genotypeand phenotype. This is the first description of adeletion and inverted duplication of 14q, and adds14q to the growing list of the inverted duplicationassociated with a terminal deletion.� 2005 Wiley-Liss, Inc.

KEY WORDS: chromosome 14q; deletion 14q;inverted duplication 14q; pyloricstenosis

INTRODUCTION

The inverted duplication associatedwith a terminal deletionhas been observed at a number of chromosome ends but neverat the end of 14q. In this report, we present a girl with a de novodistal 14q duplication and a terminal 14q deletion.

CLINICAL REPORT

This female patient was born at 39weeks of gestation, with abirthweight of 3,580 g, to a 26-year-oldwoman. The pregnancywas uneventful. The patient was the third child of healthynon-consanguineous parents. There was no family history ofcongenital heart defects, pyloric stenosis, and other congenitalmalformations. Her eldest sister had died of neuroblastoma atthe age of 7 years. Her elder brother is normal.

After birth, the patient was found to have cardiac decom-pensation and feeding difficulties because of patent ductusarteriosus and pyloric stenosis. When she was 45 days old, thepatent ductus arteriosus and pyloric stenosis were surgicallyrepaired. Cytogenetic analysis revealed a derivative chromo-some 14 with additional material at the end of the long arm ofone chromosome 14 (Fig. 1a). However, no further study wasmade to investigate the nature of the aberrant chromosome.

At the age of 2.5 years, the patient was transferred to ourhospital for evaluation of the psychomotor developmentaldelay. Her bodyweight was 9.8 kg (<3rd centile), and her headcircumference was 45 cm (3rd centile). She manifested hyper-telorism, epicanthal folds, macrostomia, oligodontia, mentalretardation, psychomotor retardation, hypotonia, micro-cephaly, a high and prominent forehead, blepharophimosis,sparse eyebrows and lashes, a broad philtrum, a prominentnasal bridge, a carp-shaped mouth, low-set ears, and clin-odactyly of bilateral fifth fingers.

When she was 4.5 years old, cerebral computed tomographyscan showedno abnormalities of the brain tissues. At the age of11 years and 8 months, the patient manifested microcephaly,short stature, mental retardation, psychomotor retardation,and facial dysmorphism (Fig. 2). Her body weight was 33 kg(3rd centile), body length was 117 cm (<3rd centile), boneage was 8.5 years, and head circumference was 52 cm(<3rd centile).

MATERIALS AND METHODS

G-banded chromosomes were prepared from peripheralwhite blood cells of the patient and her parents. The derivativechromosome 14 was characterized by spectral karyotyping(SKY) analysis using 24-color SKY probes (Applied SpectralImaging, Migdal HaEmek, Israel), fluorescence in situ hybri-dization (FISH) with a 14q specific subtelomeric probe(TelVysion 14q, Vysis, Downers Groove, IL), and microarray-based comparative genomic hybridization (CGH) (CMRCLHuman 15K, version 1) [Wang et al., 2004]. The DNA of thepatient and parents were isolated from the peripheral blood.

Grant sponsor: National Science Council; Grant numbers: NSC-93-2314-B-195-017, NSC-93-2314-B-195-018; Grant sponsor:National Health Research Institute; Grant number: NHRI-EX92-920751; Grant sponsor: Bureau of Health Promotion,Department of Health; Grant number: BH92-GC03-1; Grantsponsor: Mackay Memorial Hospital, Taipei, Taiwan, R.O.C.;Grant number: MMH-E-93004.

*Correspondence to: Chih-Ping Chen, M.D., Department ofObstetrics and Gynecology, Mackay Memorial Hospital 92,Section 2, Chung-Shan North Road, Taipei, Taiwan, Republic ofChina. E-mail: cpc_mmh@yahoo.com

Received 20 January 2005; Accepted 29 August 2005

DOI 10.1002/ajmg.a.30997

� 2005 Wiley-Liss, Inc.

Quantitative fluorescent polymerase chain reaction (QF-PCR)using polymorphic short tandem repeat (STR)markers specificfor distal 14q was carried out to verify the parental origin, thelocation, and the extent of the deletion and duplication of thechromosome 14.

RESULTS

SKY showed that the additional chromosomal material onthe derivative chromosome 14 was of chromosome 14 in origin.Microarray-based CGH showed gain of the distal 14q. FISHshowedabsence of the 14q subtelomeric probe on thederivativechromosome 14 (Fig. 1b). The G-banding showed invertedduplication of 14q31.3-32.3. The parental karyotypes werenormal. The patient karyotype was 46,XX,der(14)(pter!q32.3::q32.3! q31.3:)de novo or 46,XX, der(14)dup(14)(q32.3q31.3)del(14)(q32.3). The polymorphic DNA marker analysisconfirmed paternal origin of the duplication of distal 14q(14q31.3!q32.3) and the deletion of terminal 14q (14q32.3!qter) (Table I). The duplication segment between 14q31.3 and14q32.3 was estimated to be between 16.7 Mb and 19.4 Mb.With themarkers D14S620 (14q24.2), D14S739 (14q31.1), and

Fig. 1. a: Partial G-banded karyotype of the patient shows one normal chromosome 14 and one derivative chromosome 14. The arrows indicate thebreakpoints. b: FISH study using a 14q specific subtelomeric probe (green) shows absence of the 14q subtelomeric probe on the derivative chromosome 14 order(14).

Fig. 2. The patient at the age of 11 years and 8 months.

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Deletion/Inv Duplication 14q31.3-q32.3 147

D14S616 (14q31.3), two alleles presenting with two peaks ofequal intensity (paternal:maternal ratio¼ 1:1) were seen inthe proband. With the markers D14S128 (14q31.3), D14S617(14q32.12), and D14S557 (14q32.32), two alleles presentingwith two peaks of unequal intensity (paternal:maternalratio¼ 2:1) were seen. The proband had inherited two copiesof the same paternal allele, indicating that an intrachromoso-mal event between sister chromatids of the paternal chromo-some had taken place. With the marker D14S543 (14q32.33),only one maternal allele was seen. The terminal 14q deletionwas of paternal origin.

DISCUSSION

The inverted duplication associatedwith a terminal deletionhas been observed at various chromosomal ends such as 1q

[Mewar et al., 1994; de Brasi et al., 2001], 2q [Bonaglia et al.,2000], 3p [Jenderny et al., 1998; Kennedy et al., 2000], 4p[Cotter et al., 2001; Kondoh et al., 2003], 4q [van Buggenhoutet al., 2004], 5p [Sreekantaiah et al., 1999], 7q [Hoo et al., 1995;Stetten et al., 1997], 8p [Dill et al., 1987; Mitchell et al., 1994;Florida et al., 1996; Giglio et al., 2001], 9p [Teebi et al., 1993],10p and 10q [Hoo et al., 1995], 11p [Fisher et al., 2002], 21q[Pangalos et al., 1992], andXp [Milunsky et al., 1999]. Since theparental karyotypes were normal, the inv dup(14q) associatedwith a terminal 14q deletion in this report might have beencaused by the simplestmodel involving aU-type exchange thatcaused an end-to-end fusion and that led to a dicentric chro-mosome; during anaphase, the dicentric chromosome couldbreak and result in a chromosomewith an inverted duplicationand loss of chromosomal material distal to the site of recombi-nation [Weleber et al., 1976; Mitchell et al., 1994; Bonaglia

TABLE I. Genotypic Information of the Patient and Parents at Short Tandem Repeat MarkersSpecific for Chromosome 14 Obtained by Quantitative Fluorescent Polymerase Chain

Reaction Assaysa

Markers Locus Regionb Father Mother Patient

D14S620 14q24.2 72401116–72401231 118,118 114,126 118,126D14S739 14q31.1 81336367–81336556 189,197 197,201 197,201D14S616 14q31.3 84263655–84263874 215,227 219,231 215,219D14S128 14q31.3 85450372–85450704 342,350 334,354 342,342,354D14S617 14q32.12 91272543–91272683 156,156 144,160 144,156,156D14S557 14q32.32 102189847–102190162 335,343 323,339 339,343,343D14S543 14q32.33 103658598–103658852 263,271 283,283 283

aAlleles (basepair sizes) are listed below each individual.bAccording to Ensembl v32, Jul 2005, http://www.ensembl.org/Homo_sapiens/index.html.

TABLE II. Comparison of the Present Case With the Reported Cases With a Terminal Deletion of14q32.3! qter or a Duplication of 14q31! qter

FeaturesA terminal deletion of

14q32.3! qter*A duplication of14q31! qter** Present case

No. of cases 7 9Male 2 5Female 5 4

Mental retardation 7/7 7/7 þHypotonia 5/7 5/9 þGrowth retardation 3/7 7/8 þMicrocephaly 4/7 6/9 þClinodactyly 0/2 7/9 þHypertelorism 1/4 7/9 þStrabismus 3/5 1/7 �Blepharophimosis 5/6 0/7 þPtosis 4/7 0/7 �Downslanting palpebral fissures 3/6 7/9 þEpicanthi 5/7 2/9 þDysmorphic nose 6/6 6/9 þHigh arched palate 5/6 3/9 �Abnormal ears 2/6 7/9 þMicrognathia 3/6 8/9 �Congenital heart defect 2/6 6/9 þUmbilical and diaphragmatichernia

0 1/9 �

Hiatal hernia 0 1/9 �Hypoplasia of thymus 0 2/9 �Intestinal malrotation andectopic spleen

0 1/9 �

Cleft palate 0 1/9 �Radio-ulnar synostosis 0 1/9 �Pyloric stenosis 0 0/9 þ

*van Karnebeek et al., 2002.**Trunca and Optitz [1977]; Weinstein et al. [1977]; Sklower et al. [1984]; Carr et al. [1987]; Wakita et al. [1988];Masada et al. [1989]; Schinzel [2001]; Sonoda et al. [2001].

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148 Chen et al.

et al., 2000; Kondoh et al., 2003; van Buggenhout et al.,2004].

Since the first report of a pure terminal 14q deletion[Hreidarsson and Stamberg, 1983], many additional patientswith terminal 14q deletions due to either a linear deletion or aring chromosome 14 have been described. Common featureshave been described in patients in whom a terminal 14qdeletion of 14q32.3!qter is associated with a duplication of14q31! qter [Trunca and Optitz, 1977; Weinstein et al., 1977;Sklower et al., 1984; Carr et al., 1987; Wakita et al., 1988;Masada et al., 1989; Schinzel, 2001; Sonoda et al., 2001; vanKarnebeek et al., 2002]. Our patient demonstrated commonfeatures of both distal 14q duplication and terminal 14qdeletion (Table II). Genomic imprinting effects have beenobserved in chromosome 14 [Ledbetter and Engel, 1995;Papenhausen et al., 1995; Miyoshi et al., 1998; Hordijk et al.,1999]. Paternal UPD 14 is associated with severe mentalretardation, seizures, coarse facial appearance, and rib andspine anomalies [Papenhausen et al., 1995], whereasmaternalUPD 14 has a Prader–Willi syndrome-like phenotype. How-ever, van Karnebeek et al. [2002] suggested that there is noimprinting effect at 14qter.

The present case was associated with pyloric stenosis.Pyloric stenosis has not been described in cases with distal14q duplications or in cases with terminal 14q deletions,although pyloric stenosis is a common feature in cases withpartial trisomy 9q involving bands q22.1-q31.3 [Yamamotoet al., 1988; Heller et al., 2000], and susceptibility to infantilehypertrophic pyloric stenosis is associated with a promoterpolymorphism inNOS1 gene (gene map locus 12q24.2-q24.31)that encodes nitric oxide synthase-1 [Chung et al., 1996; Sauret al., 2004]. The pyloric stenosis in the present case may be acoincidental event. Whether or not there is a correlationbetween duplication/deficiency of distal 14q and pyloricstenosis is unclear, and more cases for study are required.

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