ANovel2.3MbMicroduplicationof9q34.3Inserted … · 2019. 7. 31. · 1Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand 2Genetic Health

Hindawi Publishing CorporationCase Reports in PediatricsVolume 2012, Article ID 459602, 7 pagesdoi:10.1155/2012/459602

Case Report

A Novel 2.3 Mb Microduplication of 9q34.3 Insertedinto 19q13.4 in a Patient with Learning Disabilities

Shalinder Singh,1 Fern Ashton,1 Renate Marquis-Nicholson,1 Jennifer M. Love,1

Chuan-Ching Lan,1 Salim Aftimos,2 Alice M. George,1 and Donald R. Love1, 3

1 Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand2 Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand3 School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

Correspondence should be addressed to Donald R. Love, [email protected]

Received 1 July 2012; Accepted 27 September 2012

Academic Editors: L. Cvitanovic-Sojat, G. Singer, and V. C. Wong

Copyright © 2012 Shalinder Singh et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Insertional translocations in which a duplicated region of one chromosome is inserted into another chromosome are very rare. Wereport a 16.5-year-old girl with a terminal duplication at 9q34.3 of paternal origin inserted into 19q13.4. Chromosomal analysisrevealed the karyotype 46,XX,der(19)ins(19;9)(q13.4;q34.3q34.3)pat. Cytogenetic microarray analysis (CMA) identified a∼2.3Mbduplication of 9q34.3 → qter, which was confirmed by Fluorescence in situ hybridisation (FISH). The duplication at 9q34.3 is thesmallest among the cases reported so far. The proband exhibits similar clinical features to those previously reported cases withlarger duplication events.

1. Clinical Report

The proband was born prematurely at 35 weeks gestationwith a birth weight of 2040 g. She required nasogastric tubefeeding during the first week of life. During infancy, shewas investigated for hypotonia and associated plagiocephaly;a brain MRI scan showed no abnormalities. She also haddifficulties swallowing solids until the age of 2 years withongoing tendency to drooling and keeping her mouth open.She walked at 2 years and 3 months of age. Her speech begandeveloping at around that time. At school, she demonstratedage appropriate reading and writing skills, but requiredadditional help in maths. However, the degree of her learningdifficulty was minimal and psychometric assessment wasnot deemed to be necessary. She was also noted to havedifficulties in gross motor and particularly fine motor skillsand required assistance from an occupational therapist. Anophthalmic assessment at 16 years of age demonstratedmyopia, with visual acuity of 6/24 in the right eye and 6/12 inthe left eye. Fundoscopy revealed the presence of pigmentarychanges in both posterior poles.

She was reviewed at the genetics clinic at 16.5 yearsof age. At that time, she was continuing to make goodacademic progress although she was receiving some inputfrom the learning support unit attached to her school. Herheight was at the 50th centile, weight at the 25th centile,and head circumference between the 25th and 50th centiles.Facial dolichocephaly and asymmetry were noted. The eyeswere mildly deep set. She had a short philtrum and mildmicroganthia (Figures 1(a) and 1(b)), with a high archedpalate. There was distal tapering of the fingers with radialclinodactyly of the middle three fingers (Figure 1(c)). Shehad long halluces, curly toes, and bilateral hallux valgus(Figure 1(d)). A mild scoliosis was also noted.

2. Chromosome Analysis

Conventional G-banded chromosome analysis was per-formed on peripheral blood samples taken from the probandand her parents.

2 Case Reports in Pediatrics

(a) (b)

(c) (d)

Figure 1: Clinical features of the patient at the age of 16.5 years. Frontal view (a) shows the short philtrum. Lateral view (b) shows mildmicrognathia. (c) shows distal tapering of the fingers with radial clinodactyly of the middle three fingers, and (d) shows Long halluces, curlytoes, and bilateral hallux valgus.

Genome-wide copy number analysis was determinedfrom genomic DNA samples using the Affymetrix Cytoge-netics Whole-Genome 2.7 M array, according to the manu-facturer’s instructions. Regions of copy number change werecalculated using the Affymetrix Chromosome Analysis Suitesoftware (ChAS) v.1.0.1 and interpreted with the aid of theUCSC genome browser (http://genome.ucsc.edu/; HumanMar. 2006 (hg18) assembly).

Chromosomal analysis showed a female karyotype46,XX,der(19)ins(19;9)(q13.4;q34.3q34.3) for the proband(Figure 2(a)). The father’s karyotype was 46,XY,ins(19;9)-(q13.4;q34.3q34.3) (Figure 2(d)) and the mother’s karyotypewas normal (data not shown). The array revealed a terminalduplication of approximately 2.3 Mb at 9q34.3, and theproband’s molecular karyotype was arr 9q34.3(137,864,059-140,171,337)x3 (Figure 3; UCSC Genome Browser-NCBIBuild 36, Mar. 2006 assembly).

FISH confirmed that a segment of region 9q34.3 wasinserted into the region 19q13.4 using the locus-specificprobe D9S325, with two signals on the chromosome 9homologues present in the proband (Figures 2(b) and2(c)). FISH using the probe specific for the 19q terminalregion confirmed that the subtelomeres of the derivativechromosome 19 were intact. FISH findings from the fatherdemonstrated an apparently balanced translocation: part ofregion 9q34.3 was inserted into 19q13.4, thus confirming

the parental origin of the derivative chromosome 19 (Fig-ures 2(e) and 2(f)). The duplicated region encompassesapproximately 92 genes, which are likely to contribute to theproband’s phenotypic features.

3. Discussion

Patients with 9q duplications have overlapping features,which include variable degrees of developmental delays,learning or intellectual deficits, facies characterised by dolic-ocephaly, asymmetry, deep set eyes or small palpebral fis-sures, high arched palate, micrognathia and digital anomaliesincluding arachnodactyly, camptodactyly and clinodactyly.Furthermore, the finding of long halluces appears to bea common and distinctive feature in patients with a pureduplication, although many other reported cases carry copynumber changes other than 9q duplications [1–8].

In this study, we report a small ∼2.3 Mb duplica-tion of 9q34.3 detected by CMA. Our patient displayeddolicocephaly and facial asymmetry, mildly deep-set eyes,short philtrum, mild microganthia, high arched palate, clin-odactyly, mild scoliosis, mild myopia, and digital anomalies.A comparison of phenotypic anomalies of our patient withpreviously reported cases is summarised in Table 1.

Recently, Gijsbers et al. [8] reported a 16-year-old girlwith a triplication and duplications in the 9q34.3 region.

Case Reports in Pediatrics 3

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Figure 2: Cytogenetics and FISH analysis of proband and father. ((a)–(c)) and (d-f) show the analysis of the proband and father, respectively.Ideograms of chromosomes 9 and 19 show that part of region 9q34.3 is inserted into region 19q13.4 in the proband (a), and the fatheris a carrier of a balanced insertional translocation (panel d). FISH analysis used probes for 9pter (305J7-T7), 9qter (D9S325), 19pter(129F16/SP6), 19qter (D19S238E), 19q13 (GLTSCR1/GLTSCR2/CRX), while 17cen and 17q used control probes ((b)–(c) for the proband,and panels (e)–(f) for the father). These panels confirm that the part of region 9q34.3 is inserted into region 19q13.4. The subtelomeres ofchromosome 19 were intact (the probes for 19pter (129F16/SP6) and 19qter (D19S238E) were used; image not shown).

The authors noted that the clinical features of their probandoverlapped with those in one previous report [2], whichwas a “pure” 9q34.3 duplication case. The same dysmorphicfeatures are shared with the proband reported here, butfeeding difficulties, scoliosis, and severe mental retardationare absent. The more severe phenotype reported by Gijsberset al. [8] may be attributed to a larger ∼2.9Mb region ofduplicated and triplicated subregions (chr9q34:137,265,834-140,207,437) that encompasses approximately 100 genes. Inour case, approximately 92 genes are duplicated in a∼2.3 Mbregion (chr9q34.3 : 137,864,059-140,171,337).

Of the genes contained within the duplicated regiondetected in our patient, eleven are present in the OnlineMendelian Inheritance in Man (OMIM; http://www.ncbi.nlm.nih.gov/omim) morbid map, and of these, all butNOTCH1 are associated with autosomal recessive diseaseand homozygosity for terminating mutations (Table 2). Asa consequence, these OMIM genes do not appear to play arole in the clinical phenotype reported here which is likely tobe caused by gene overexpression, due to the increased copynumber of the 2.3 Mb region of chromosome 9, rather thanhaploinsufficiency.

In the mouse, upregulation of NOTCH activity appearsto be associated with an increase in the number of interneu-ronal contacts and the cessation of neurite growth [9]. In

addition, the NOTCH signalling pathway plays a pivotal rolein embryo development. It is likely, given the mathematicalmodelling undertaken by Raya et al. [10], that increasedexpression of NOTCH1 would have an impact on the levelof NOTCH1-associated subcomplexes, and hence alter devel-opmental and physiological outcomes. That NOTCH1 over-expression may be the principal underlying gene responsiblefor the phenotype of our patient remains speculative atthis stage. It is also possible that the site of insertion onchromosome 19 may affect the expression of chromosome19 genes, which may play a role in the phenotype reportedhere. Unfortunately, the array data does not provide anyclues regarding the specific site of insertion on chromosome19.

In summary, the proband reported here is a new additionto the rare collection of dup 9q34 cases. Our patient hasdeveloped a mild form of the clinical features describedin other 9q34 cases, possibly due to the smaller affectedregion. Patients with shorter dup 9q34 tend to have abetter prognosis and would benefit from special educationwith input from their parents [2]. It is hoped that withincreased reporting of similar cases, dosage changes andbreakpoints in this region can be more clearly correlated tophenotypic features to aid genetic counselling and medicalmanagement.


Scalechr9: 135500000 136000000 136500000 137000000 137500000 138000000 138500000 139000000 139500000 140000000

Genetic association studies of complex diseases and disorders

OMIM-associated genes

RefSeq genes

9q34.29q34.3

CELABOSURF1

DBH COL5A1 NOTCH1 PTGDSABCA2

GRIN1

602930 602777110300

612277231050

604455268900

600428601541 180245

130010130000120215

608167190198

601895602012

606946

601012607341

605284191100604383604890114840601619606074604606

185642185641185640256000220110185620185630185660

604134274150235400

606813609312223360

601541609012601429

180245

601624

601252605366

611971151675164320173310

612903610224

608129600577262600612860

609491607212

613036613037612854

608582608594603100

612904

609379

612902

610615610167605107

609072

120930612905176803606533600047602030605798612057

604346610537138249

610882606073

609826

241530

602660611180

611255608137

146110

612122

611846611424

610253607001

601012

TSC1TSC1TSC1

GFI1BGFI1B

GTF3C5GTF3C5

CELCELP

RALGDSRALGDS

GBGT1OBP2B

ABOSURF6MED22MED22RPL7A

SNORD24SNORD36BSNORD36ASNORD36C

SURF1SURF2SURF4

C9orf96REXO4

ADAMTS13ADAMTS13ADAMTS13ADAMTS13

C9orf7C9orf7

SLC2A6

SLC2A6

TMEM8C

ADAMTSL2ADAMTSL2

FAM163B

DBH

SARDHSARDH

VAV2VAV2

NCRNA00094

BRD3

WDR5WDR5

RNU6ATAC

RXRACOL5A1

FCN2

FCN2FCN1

OLFM1OLFM1

KIAA0649C9orf116C9orf116

MRPS2LCN1

OBP2APAEPPAEP

LOC100130954LOC100130954

GLT6D1LCN9

SOHLH1SOHLH1

KCNT1CAMSAP1

UBAC1NACC2

C9orf69LHX3LHX3

QSOX2LOC26102

GPSM1

GPSM1GPSM1

DNLZCARD9CARD9

SNAPC4SDCCAG3SDCCAG3SDCCAG3

PMPCAINPP5ESEC16AC9orf163NOTCH1

EGFL7EGFL7

MIR126AGPAT2AGPAT2FAM69B

SNHG7

SNHG7SNHG7

SNORA43SNORA17

LCN10LCN6

LOC100128593

LCN8LCN15

TMEM141KIAA1984

LOC100131193C9orf86C9orf86C9orf86MIR4292C9orf172

PHPT1PHPT1

MAMDC4EDF1EDF1TRAF2FBXW5

C8G

LCN12

PTGDSLCNL1

C9orf142CLIC3

ABCA2

ABCA2C9orf139

FUT7

NPDC1

ENTPD2ENTPD2

C9orf140

UAP1L1

LOC100289341

MAN1B1DPP7GRIN1GRIN1GRIN1GRIN1GRIN1

LRRC26

ANAPC2

SSNA1TPRN

TMEM203

NDOR1NDOR1NDOR1

NDOR1RNF208

C9orf169LOC643596

SLC34A3SLC34A3SLC34A3

TUBB2CFAM166A

C9orf173

COBRA1

C9orf167

NRARP

EXD3

NOXA1

ENTPD8ENTPD8

NELFNELFNELF

NELFNELF

PNPLA7PNPLA7

MRPL41WDR85

ZMYND19

ARRDC1C9orf37EHMT1EHMT1

FLJ40292

MIR602CACNA1B

TUBBP5

chr9 (q34.13-q34.3) p23

Present case

2 MB

Gijsbers et al. [8]

Papadopoulou et al. [7]

Figure 3: Location and extent of 9q34 duplications. UCSC Genome Browser (March 2006 (hg18) assembly) view of the chromosomalregion 9q34.13-q34.3 (chr9:134,776,210-140,171,337) is shown, together with Refseq, OMIM, and GAD genes. The bottom panel shows thelocation and extent of the 9q34.3-qter region of the patient described here, and of other cases reported in the literature. Note: the regionhighlighted in yellow is the ∼2.3 Mb region duplicated in our case, and the thicker green block represents the triplicated region reported byGijsbers et al. [8].


Table 2: Duplicated region and OMIM genes.

OMIM Protein Gene Disorder Molecular genetics

600577 LIM/homeodomain protein LHX3 LHX3Combined pituitaryhormone deficiency-3

Homozygosity for intragenicdeletion/nonsense mutation

613037 Inositol polyphosphate-5-phosphatase INPP5E Joubert syndrome 1Homozygosity for mutations in theINPP5E gene that lead to decreasedphosphatase activity

Mental retardation, truncalobesity, retinal dystrophy,and micropenis

Homozygous nonsense mutation detectedin the INPP5E gene

607212Caspase recruitment domain-containingprotein 9

CARD9Autosomal recessive formof familial chronicmucocutaneous candidiasis

Homozygous nonsense mutation in theCARD9 gene

190198Notch, Drosophila, homolog of, 1,translocation associated Notch homolog;NOTCH1

NOTCH1 Aortic valve diseaseHeterozygosity for nonsense/frameshiftmutations

Leukemia, T-cell acutelymphoblastic

6031001-Acylglycerol-3-phosphateO-acyltransferase 2

AGPAT2Lipodystrophy, congenitalgeneralised, type 1; CGL1

Homozygous or compound heterozygousmutations

613354 Taperin TPRNAutosomal recessivenonsyndromic deafness-79

Homozygous truncating mutations

604346 Mannosidase, alpha, class 1B member 1 MAN1B1Mental retardation,autosomal recessive 15

Homozygous mutations

138249Glutamate receptor, ionotropic,N-methyl D-aspartate 1

GRIN1Mental retardation,autosomal dominant 8

Missense mutation; in-frame duplicationof codon 560

609826Solute carrier family 34(sodium/phosphate cotransporter),member 3

SLC34A3Hypophosphatemic ricketswith hypercalciuria

Homozygous single-nucleotide deletion

608137Nasal embryonic luteinizinghormone-releasing hormone factor

NELFHypogonadotropichypogonadism

A thr480-to-ala mutation in the NELF gene

607001 Euchromatic histone methyltransferase 1 EHMT1 Kleefstra syndrome

Heterozygous nonsense/frameshiftmutation, in the EHMT1 gene; terminaldeletions, interstitial deletions, derivativechromosomes, and complexrearrangements

The entries in this table were taken from the OMIM database (http://www.ncbi.nlm.nih.gov/omim).

Acknowledgment

The details of this case have been deposited in Deci-pher (https://decipher.sanger.ac.uk); ID 254186. The authorswish to state that there is no conflict of interests withany organization regarding the material presented in thispaper.

References

[1] J. W. Hou and T. R. Wang, “Molecular cytogenetic studiesof duplication 9q32→q34.3 inserted into 9q13,” ClinicalGenetics, vol. 48, no. 3, pp. 148–150, 1995.

[2] P. W. Allderdice, B. Eales, H. Onyett et al., “Duplication 9q34syndrome,” American Journal of Human Genetics, vol. 35, no.5, pp. 1005–1019, 1983.

[3] N. B. Spinner, J. N. Lucas, M. Poggensee, M. Jacquette,and A. Schneider, “Duplication 9q34→qter identified bychromosome painting,” American Journal of Medical Genetics,vol. 45, no. 5, pp. 609–613, 1993.

[4] E. L. Youngs, T. McCord, J. A. Hellings, N. B. Spinner, A.Schneider, and M. G. Butler, “An 18-year follow-up reporton an infant with a duplication of 9q34,” American Journal ofMedical Genetics A, vol. 152, no. 1, pp. 230–233, 2010.

[5] T. Mattina, M. Pierluigi, D. Mazzone, S. Scardilli, C. Perfumo,and F. Mollica, “Double partial trisomy 9q34.1→qter and21pter→q22.11: FISH and clinical findings,” Journal of Medi-cal Genetics, vol. 34, no. 11, pp. 945–948, 1997.

[6] K. Gawlik-Kuklinska, M. Iliszko, A. Wozniak et al., “A girlwith duplication 9q34 syndrome,” American Journal of MedicalGenetics, Part A, vol. 143, no. 17, pp. 2019–2023, 2007.

[7] E. Papadopoulou, C. Sismani, C. Christodoulou, M. Ioan-nides, M. Kalmanti, and P. Patsalis, “Phenotype-genotypecorrelation of a patient with a “balanced” translocation9;15 and cryptic 9q34 duplication and 15q21q25 deletion,”American Journal of Medical Genetics A, vol. 152, no. 6, pp.1515–1522, 2010.

[8] A. C. J. Gijsbers, E. K. Bijlsma, M. M. Weiss et al., “A 400 kbduplication, 2.4 Mb triplication and 130 kb duplication of9q34.3 in a patient with severe mental retardation,” EuropeanJournal of Medical Genetics, vol. 51, no. 5, pp. 479–487, 2008.


[9] N. Šestan, S. Artavanis-Tsakonas, and P. Rakic, “Contact-dependent inhibition of cortical neurite growth mediated byNotch signaling,” Science, vol. 286, no. 5440, pp. 741–746,1999.

[10] Á. Raya, Y. Kawakami, C. Rodrı́guez-Esteban et al., “Notchactivity acts as a sensor for extracellular calcium duringvertebrate left-right determination,” Nature, vol. 427, no.6970, pp. 121–128, 2004.

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ANovel2.3MbMicroduplicationof9q34.3Inserted … · 2019. 7. 31. · 1Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand 2Genetic Health