molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure...

� 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1594–1600 (2006)

Clinical Report

Molecular Cytogenetic Analysis of De Novodup(5)(q35.2q35.3) and Review of the Literature of

Pure Partial Trisomy 5q

Chih-Ping Chen,1,2,3,4* Shuan-Pei Lin,2,5 Chyi-Chyang Lin,6 Yann-Jang Chen,7,8 Schu-Rern Chern,2

Yueh-Chun Li,9 Lie-Jiau Hsieh,6 Chen-Chi Lee,1 Chen-Wen Pan,1 and Wayseen Wang21Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China

2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China3Institute of Clinical Nursing, School of Nursing, National Yang-Ming University, Taipei, Taiwan, Republic of China

4College of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China5Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China

6Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan, Republic of China7Faculty of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China

8Department of Pediatrics, Veteran General Hospital, Taipei, Taiwan, Republic of China9Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, Republic of China

Received 27 February 2006; Accepted 25 April 2006

An 11-year-old girl presented with the phenotype ofmicrocephaly, moderate mental retardation, motor retarda-tion, short stature, strabismus, brachydactyly, and facialdysmorphism. She had undergone surgery for inguinalhernias. Detailed examinations of the heart and otherinternal organs revealed normal findings. Her karyotypewas 46,XX,dup(5)(q35.2q35.3) de novo. Molecular cytoge-netic analysis showed a paternally derived 5q35.2! q35.3direct duplication and led to a correlation between theparticular genotype and phenotype. This is the first descrip-tion of a direct duplication of 5q35.2!q35.3. Our caserepresents the smallest distal duplication of chromosome5q that is not associated with congenital heart defects. Our

case also represents the smallest distal duplication ofchromosome 5q that is associated with short stature andmicrocephaly. Mutations or deletions of the NSD1 gene,mapped to 5q35.2! q35.3, has been known to cause Sotossyndrome with cerebral gigantism, macrocephaly, advancedbone age and overgrowth. Our case provides evidence thatthe gene dosage effect of the NSD1 gene causes a reversedphenotype of microcephaly and short stature.� 2006 Wiley-Liss, Inc.

Key words: chromosome 5q; duplication; NKX2-5 gene;NSD1 gene; partial trisomy 5q

How to cite this article: Chen C-P, Lin S-P, Lin C-C, ChenY-J, Chern S-R, Li Y-C, Hsieh L-J, Lee C-C, Pan C-W,WangW. 2006. Molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure

partial trisomy 5q. Am J Med Genet Part A 140A:1594–1600.

INTRODUCTION

A partial duplication of the distal long arm ofchromosome5 has beenwell known tobe associatedwith the specific phenotype of growth and mentalretardation, microcephaly, strabismus, a prominentwidened nasal bridge, a long philtrum, a long thinupper lip with down-turned corners, micrognathia,large low-set dysplastic ears, a downward palpebralslant, epicanthal folds, hypertelorism, facial clefts,brachydactyly, umbilical and inguinal hernias,ambiguous genitalia, hypospadias, undescended

Grant sponsor: National Science Council; Grant numbers: NSC-93-2314-B-195-017, NSC-93-2314-B-195-018; Grant sponsor: National HealthResearch Institute; Grant number: NHRI-EX92-9207SI; Grant sponsor:Bureau of Health Promotion, Department of Health; Grant number:BH92-GC03-1; Grant sponsor: Mackay Memorial Hospital, Taipei,Taiwan; Grant number: MMH-E-95004.

*Correspondence to: Chih-Ping Chen, M.D., Department of Obstetricsand Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-ShanNorth Road, Taipei, Taiwan, Republic of China.E-mail: [email protected]

DOI 10.1002/ajmg.a.31329

testes, pulmonary hypertension, atrial and ventricu-lar septal defects, cardiac conduction pathwayabnormalities, congenital hip dysplasia, dental car-ies, and eczema [Curry et al., 1979; Jones et al., 1979;Abuelo et al., 2000]. Most cases with a partial 5qduplication were the results of inherited unbalancedtranslocations and thus were not reflective of purepartial trisomy 5q. Pure partial trisomy 5q is un-common. Pure partial trisomy for 5q35.2!q35.3 hasnot previously been described. In this report, wepresent a girl with a de novo direct duplication of5q35.2!q35.3 and informative clinical findings.

CLINICAL REPORT

The 11-year-old girl presented with speech delayand mental retardation. She was born at 39 gesta-tional weeks with a birth weight of 2,100 g(<3rd centile) as the third child of healthy unrelatedparents. Her two elder brothers were normal.The mother was 34 years of age, and the father was38 years of age at time of her birth. She underwentbilateral herniorrhaphy for inguinal hernias at 2 yearsof age. On examination at 5 years of age, shemanifested microcephaly with a head circumferenceof 44.7 cm (<3rd centile), short stature, moderatemental retardation with a full intelligence quotientof 54, motor retardation, strabismus, speech delay,learning difficulty, and brachydactyly with short anddeformed 5th fingers. She could sit at 9months, crawlat 10 months, stand at 15 months of age, and walk at17 months. Cytogenetic analysis of the peripheralblood lymphocytes revealed an aberrant chromo-some 5 with an additional material in the terminalinterstitial portion of 5q (Fig. 1A). No further studyhad been made to investigate the nature of theaberrant chromosome 5. On examination at 11 yearsof age, she manifested a small oval face, a shortreceding forehead, a small nose with a high nasalbridge, a prominent nasal tip, a small mouth withdown-turned mouth angles, microstomia, a thin up-per lip, and almond-shaped eyes. Her body weightwas 23.5 kg (<3rd centile), height was 130 cm(<3rd centile), and head circumference was 47.8 cm(<3rd centile). There was no craniosynostsis.Detailed examination of the heart by echocardio-graphy revealed normal findings. Serial brain sono-grams revealed neither ventriculomegaly nor corpuscallosum abnormalities.

MATERIALS AND METHODS

G-banded chromosomes were prepared fromperipheral blood lymphocytes of the patient andher parents. The aberrant chromosome 5 wascharacterized by fluorescence in situ hybridization(FISH) using the 5p/5q subtelomeric probes (TelVy-sion 5p/5q, Vysis, Downers Grove, IL). The DNA ofthe patient and parents was isolated from the

peripheral blood. Quantitative fluorescent polymer-ase chain reaction (QF-PCR) using polymorphicshort tandem repeat (STR) markers specific for distal5q was carried out to verify the parental origin,the location, and the extent of the duplication ofthe chromosome 5. For FISH determination of theorientation of the duplication, BAC clones mappingto the genomic region of the duplication of distalchromosome 5q were used. BAC clones RP11-125L2(173447703–173616629) encompassing the band5q35.2 and RP11-2I16 (177590853–177742910)encompassing the band 5q35.3 were applied.

RESULTS

The parental karyotypes were normal. FISHshowed the presence of two signals of the 5qsubtelomeric probe on the aberrant chromosome 5

FIG. 1. A: Partial G-banded karyotype of the patient shows one normalchromosome 5 and one aberrant chromosome 5 that contains a duplicatedsegment between bands 5q35.2 and 5q35.3. B: Fluorescence in situ hybridiza-tion (FISH) study using a 5p-specific subtelomeric probe (green) and a5q-specific subtelomeric probe (red) shows two distinctive red signals of the5q-specific subtelomeric probe on the aberrant chromosome 5, dup(5), with apartial duplication of 5q35.2-35.3.

PURE PARTIAL TRISOMY 5q 1595

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

(Fig. 1). The G-banding showed a duplication of5q35.2-q35.3. The patient’s karyotype was 46,XX,dup(5)(q35.2q35.3) de novo. The polymorphic DNAmarker analysis confirmed the paternal origin of theduplication (Table I). With the markers D5S1766(5q31.1) and D5S1401 (5q35.1), two alleles present-ing with two peaks of equal intensity (paternal:maternal ratio¼ 1:1) were seen in the proband.With the markers D5S1398 (5q35.2) (175251224–175251613) and D5S408 (5q35.3) (179920845–179921099), two alleles presenting with two peaksof unequal intensity (paternal: maternal ratio¼ 2:1)were seen. In the duplicated segment, the probandhad inherited two copies of the same paternal allele,indicating that an intra-chromosomal event betweensister chromatids of the paternal chromosome 5 hadtaken place (Fig. 2). FISH mapping of the orientationof the duplication revealed that the rearrangementwas a direct duplication with a linear tandem orien-tation (Fig. 3). The duplicated segment between5q35.2 and 5q35.3 was estimated to be at least 6.4 Mb

calculated from the distance between RP11-125L2and D5S408.

DISCUSSION

We present the first report of a direct duplication ofthe distal chromosome 5q segment of 5q35.2-q35.3.Our case was caused by paternal sister chromatidrearrangement. The mechanisms of the directduplication include mismatched pairing of homo-logues and unequal crossover between non-sisterchromatids or sister chromatids [van Dyke, 1988;Kotzot et al., 2000]. Kotzot et al. [2000] in a study of 20cases with de novo tandem duplications of 18different autosomal chromosome segments foundthat two-thirds of the de novo tandem duplicationswere due to sister chromatid rearrangement, whilethe remainder involved non-sister chromatid rear-rangement. They also found that the occurrence inthe maternal origin and the occurrence in thepaternal origin were equal.

FIG. 2. Representative electrophoretograms of quantitative fluorescent polymerase chain reaction (QF-PCR) assay at short tandem repeat markers specific forchromosome 5q. With the microsatellite marker D5S408 (5q35.3), the presence of two peaks (249 bp: 261 bp) of unequal fluorescent activity (maternal: paternalratio¼ 1:2) in the proband indicates the occurrence of an intra-chromosomal event between sister chromatids of the paternal chromosome 5.

TABLE I. Genotypic Information of the Patients at Short Tandem Repeat Markers Specific forChromosome 5 Obtained by Quantitative Fluorescent Polymerase Chain Reaction Assays*

Markers Locus Father Mother Proband Regiona

D5S1766 5q31.1 252,252 252,260 252,260 134134571–134134822D5S1401 5q35.1 151,157 157,163 151,163 171841599–171841749D5S1398 5q35.2 393,393 399,399 393,393,399 175251224–175251613NSD1 5q35.2-q35.3 176493532–176655367D5S408 5q35.3 257,261 249,263 249,261,261 179920845–179921099

Note: D5S2907 (TelVysis 5qTEL) lies in the region of 180611001–180611189.*Alleles (basepair sizes) are listed below each individual.aAccording to Ensembl v32—March 2006, http://www.ensembl.org/Homo_sapiens/index.html.

1596 CHEN ET AL.


Our case had a direct duplication of 5q35.2-q35.3and was associated with microcephaly, strabismus,facial dysmorphism, psychomotor retardation, mod-erate mental retardation, short stature, brachydac-tyly, and inguinal hernias. To date, at least 28 caseswith mosaic or non-mosaic pure partial trisomy 5qhave been reported (Table II). Among these 28 cases,12 cases were caused by a de novo duplication, 7cases were caused by a parental balanced insertion,2 cases were caused by a paternal direct duplication,3 cases were caused by a maternal balanced trans-location involving the short arm of an acrocentricchromosome, 1 case was caused by the maternalinversion and insertion of chromosome 5, and 1 casewas caused by a direct duplication of unknownparental origin. The maternal origin was morecommon than the paternal origin, and the directduplication was more common than the invertedduplication. In general, there were growth, mental,and motor retardations. The common associatedstructural abnormalities included congenital heartdefects, microcephaly, brachydactyly, strabismus,umbilical hernia, and inguinal hernias. Otherreported abnormalities included craniostenosis,cryptorchidism, clinodactyly, a coccygeal pit, hypo-plastic corpus callosum, a small penis, renal andurinary tract anomalies, facial cleft, ectrodactyly,syndactyly, synostosis, polydactyly, ventriculome-galy, and cystic hygroma. Rodewald et al. [1980], in astudy of 14 patients with partial trisomy 5q suggestedthat patients with a distal duplication of 5q34!qtermight be associated with short stature, mild mentalretardation, delayed puberty, chronic eczema, her-nias, dysmorphic facies including short recedingforehead, a high nasal bridge, thick alae nasales, a

prominent nasal tip, dental caries, digital anomalies,and normal life expectancy. Hunter et al. [2005]suggested that the Hunter–McAlpine syndromeresults from a duplication of 5q35!qter. TheHunter–McAlpine syndrome is characterized by theconsistent findings of short stature, developmentaldelay, microcephaly, a small oval face, almond-shaped eyes, a small nose, a down-turned mouth andbrachydactyly, and less consistent signs of craniosy-nostosis, heart malformations, and decreased elbowextension [Hunter et al., 1977]. Our case manifestedthe common features of the Hunter–McAlpinesyndrome but lacked craniosynostosis or heartmalformations. A comparison of the present casewith the reported cases with mosaic or non-mosaicpure partial trisomy 5q encompassing 5q35.2-q35.3is shown in Table III.

A duplication of the distal part of chromosome 5qhas been known to be associated with congenitalheart defects. Brewer et al. [1999] described theassociation of a duplication of 5q31!q35 with anatrial septal defect, prenatal microcephaly, andinguinal hernia. Fryns et al. [1987] reported a 3.5-year-old female with a duplication of 5q32!q35.2,marked cardiomegaly, valvular aortic stenosis, multi-ple peripheral pulmonary vessels stenoses, and asmall ventricular septum defect. Elias-Jones et al.[1988] reported a 3-year-old female with a duplica-tion of 5q31!qter and a secundum atrial septaldefect. Kriplani et al. [1998] reported a second-trimester fetus with a mosaic duplication of 5q33!qter and an atrial septal defect. Witters et al. [1998]reported a fetus with an inverted duplication of5q33.3!q35.3 and a complex cardiopathy includ-ing double outlet right ventricle, a ventricular septum

FIG. 3. FISH study using a 5q35.2-specific BAC clone probe (red) (RP11-125L2) and a 5q35.3-specific BAC clone probe (green) (RP11-2I16) shows a directduplication with a linear orientation of red-green-red-green. The inset shows the amplified dup(5)(q35.2q35.3).



defect, a right turning aortic arch, hypoplastic trun-cus and pulmonary artery, a left ductus arteriosusbetween the left subclavian artery and the pulmon-ary truncus, and absence of a right ductus arteriosus.Paoloni-Giacobino et al. [1999] reported a 14-year-old male with a duplication of 5q33!q35 and aventricular septal defect. Martin et al. [2003] reporteda 2-day-old male with a duplication of 5q31.1!q35.1 and the complex congenital heart defects of aninterrupted aortic arch and aortic stenosis. However,Sanchez-Garcia et al. [2001] reported a 2-year-oldmale with a duplication of 5q31.3!q33.3 withoutany cardiac defect.Our case additionally shows that adirect duplication of 5q35.2! q35.3 is not associatedwith congenital heart defects. The human NKX2-5gene, mapped to chromosome 5q34, is crucial to theheart development [Schott et al., 1998; Reamon-Buettner and Borlak, 2004]. Mutations or deletions ofthe NKX2-5 gene has been known to cause non-syndromic human heart diseases [Schott et al., 1998;Schafer et al., 2001; Rauch et al., 2003; Reamon-Buettner and Borlak, 2004]. The high frequency ofcongenital heart defects in patients with a duplica-tion of chromosome 5q involving the region of5q34!q35.1 indicates a role for the cardiac-specificgene dosage effects in this region. Dosage reductionor increase of the NKX2-5 gene may lead to a similarphenotype. Our case represents the smallest distal

duplication of chromosome 5q that is not associatedwith congenital heart defects. Carriers of cryptictranslocations involving the distal chromosome 5qmay carry a risk of having an abnormal child withcongenital heart defects in thepresence of aneusomyfor 5q34! q35.1. Prenatal diagnosis of duplicationor deletion of distal 5q should alert the genotype–phenotype correlation between the presence ofaneusomy for 5q34!q35.1 and sonographicallydetectable congenital heart defects. A few cases withduplication of 5q including 5q34!q35.1, however,have been reported to manifest no apparent cardiacabnormalities [Wysocka et al., 2002]. There may beincomplete penetrance of the candidate heart genewithin this region.

A duplication of the distal part of chromosome 5qhas been known to be associated with short statureand microcephaly. Our case represents the smallestdistal duplicationof chromosome5q (5q35.2! 35.3)that is associated with short stature and microce-phaly. Mutations or deletions of the NSD1 gene, anuclear receptor SET domain-containing proteingene located at 5q35.2-q35.3, causes Sotos syndrome(OMIM 117550) with cerebral gigantism, macroce-phaly, advanced bone age and overgrowth [Kurotakiet al., 2002, 2003]. The present case providesevidence that the gene dosage effect of the NSD1gene causes short stature and microcephaly. It is

TABLE II. Reported Cases With Mosaic or Non-Mosaic Pure Partial Trisomy 5q

ReportPatient’s age at

evaluation Sex Duplicated segment Origin of duplicationParental origin

(cytogenetic study)

Jalbert et al. [1975] 3 y 7 m F q11-q22 ins(1;5) matRojas-Martinez et al. [1990] 3.5 y M q11.1-q15 dir dup de novoYip et al. [1989] 2 y 9 m M q11.2-q13.1 ins(20;5) patBreslau-Siderius et al. [1993] 8 y M q11.2-q14 dir dup de novoKessel and Pfeiffer [1979] 6 y F q13-q22 dir dup de novoGilgenkrantz et al. [1981]

Case 1 4 y F q13-q22 ins(10;5) matCase 2 Fetus F q13-q22 ins(10;5) mat

Held et al. [1980] 4 y F q13-q31 dir dup de novoRauen et al. [2001] 9 d M q13-q33 (12–30%) dir dup de novoLi et al. [1998]

Father 35 y M q15-q21 dir dup NATwin 1 3 w F q15-q21 dir dup patTwin 2 6 m F q15-q21 dir dup pat

Mowat et al. [1999] 16 m M q15-q23.1 dir dup de novoOsztovics and Kiss [1982] 1 y 8 m F q15-q31 ins(6;5) matEvans et al. [1984] 14 y M q22-q33 ins(2;5) matMartin et al. [1985] 4 m M q22-q33 inv ins(5) matKotzot et al. [2000] ? F q22-q35 dir dup de novoMartin et al. [2003] 2 d M q31-q35.1 ins(20;5) matSanchez-Garcia et al. [2001] 2 y M q31.3-q33.3 dir dup de novoFryns et al. [1987] 3.5 y F q32-q35.2 inv dup de novoPaoloni-Giacobino et al. [1999] 14 y M q33-q35 t(5;14)(q33;p12) patKriplani et al. [1998] 25 gw M q33-qter (25%) dir dup de novoWitters et al. [1998] 19 gw F q33.3-q35.3 inv dup de novode Albuquerque Coelho et al. [1996] ? F q35-qter dir dup de novoHunter et al. [2005] 68 y (42 y) F q35-qter t(5;13)(q35;p11.2) NA

57 y (31 y) M q35-qter t(5;13)(q35;p11.2) NA29 y (3 y) F q35-qter t(5;13)(q35;p11.2) mat

31 y (6.5 y) F q35-qter t(5;13)(q35;p11.2) mat

ins, insertion; dir dup, direct duplication; inv, inversion; inv dup, inverted duplication; mat, maternal; pat, paternal; NA, no analysis; F, female; M, male; y, year(s); m,month(s); d, day(s); w, week(s); gw, gestational week(s); ?, unknown.

1598 CHEN ET AL.


likely that dosage reduction or increase of the NSD1gene may lead to a reversed phenotype.

ACKNOWLEDGMENTS

The authors thank Professor Teresa L. Yang-Fengfor her critical review, support, and encouragement.

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TABLE III. Clinical Findings of the Reported Cases With Mosaic or Non-Mosaic Pure Partial Trisomy 5q Encompassing 5q35.2-q35.3

AuthorsCases Fryns et al. [1987]

Paoloni-Giacobinoet al. [1999] Kriplani et al. [1998] Witters et al. [1998]

de AlbuquerqueCoelho et al. [1996]

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(cytogenetic study)de novo pat de novo de novo de novo

Parental origin(molecular study)

NA NA NA NA

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ventriculomegalyCubitus valgus Polycystic kidneys Cystic hygroma,

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Authors Hunter et al. [2005]Cases Patient IV. 11 Patient IV. 5 Patient V. 13 Patient V. 14 Present case

Duplicated segment q35qter q35qter q35qter q35qter q35.2q35.3Origin of duplication t(5;13)(q35;p11.2) t(5;13)(q35;p11.2) t(5;13)(q35;p11.2) t(5;13)(q35;p11.2) dir dupParental origin

(cytogenetic study)possibly paternal possibly maternal maternal maternal de novo

Parental origin(molecular study)

pat

Birth weight (g) ? ? 3,230 2,325 2,100Birth age (gw) ? ? ? ? 39Sex M F F F FAge at examination 31 y and 57 y 42 y and 68 y 3 y and 29 y 6.5 y and 31 y 11 yGrowth retardation þ þ þ þ þMental retardation þ þ þ þ þMotor retardation ? ? ? ? þMicrocephaly þ þ þ þ þAntimongoloid slant � � � � þEpicanthal folds � � � � �Hypertelorism � � � � �Strabismus � � � � þThin upper lip þ þ þ þ þDown-turned mouth þ þ þ þ þMicrognathia � � � � �Ear anomaly � � � � �Brachydactyly þ þ þ þ þCongenital heart defects þ � � þ �Others Craniosynostosis Inguinal hernias

dir dup, direct duplication; inv, inversion; inv dup, inverted duplication; pat, paternal; NA, no analysis; F, female; M, male; y, year(s); gw, gestational week(s); ?, unknown.



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molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure...

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