research article diagnosis of familial wolf-hirschhorn...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 209204 8 pageshttpdxdoiorg1011552013209204

Research ArticleDiagnosis of Familial Wolf-Hirschhorn Syndrome due toa Paternal Cryptic Chromosomal Rearrangement byConventional and Molecular Cytogenetic Techniques

Carlos A Venegas-Vega12 Fernando Fernaacutendez-Ramiacuterez1 Luis M Zepeda1

Karem Nieto-Martiacutenez2 Laura Goacutemez-Laguna1 Luz M Garduntildeo-Zarazuacutea1

Jaime Berumen23 Susana Kofman12 and Alicia Cervantes12

1 Servicio de Genetica Hospital General de Mexico Dr Balmis No 148 Colonia Doctores 06726 Mexico DF Mexico2 Facultad de Medicina Universidad Nacional Autonoma de Mexico Mexico DF Mexico3 Departamento deMedicina Genomica Hospital General deMexico Dr Balmis No 148 Colonia Doctores 06726Mexico DFMexico

Correspondence should be addressed to Alicia Cervantes acervantunammx

Received 26 October 2012 Accepted 13 December 2012

Academic Editor Ozgur Cogulu

Copyright copy 2013 Carlos A Venegas-Vega et alThis 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

The use of conventional cytogenetic techniques in combination with fluorescent in situ hybridization (FISH) and single-nucleotidepolymorphism (SNP) microarrays is necessary for the identification of cryptic rearrangements in the diagnosis of chromosomalsyndromes We report two siblings a boy of 9 years and 9 months of age and his 7-years- and 5-month-old sister with theclassicWolf-Hirschhorn syndrome (WHS) phenotype Using high-resolution GTG- and NOR-banding karyotypes as well as FISHanalysis we characterized a pure 4p deletion in both sibs and a balanced rearrangement in their father consisting in an insertion of4pmaterial within a nucleolar organizing region of chromosome 15 Copy number variant (CNV) analysis using SNP arrays showedthat both siblings have a similar size of 4p deletion (sim65 Mb) Our results strongly support the need for conventional cytogeneticand FISH analysis as well as high-density microarray mapping for the optimal characterization of the genetic imbalance in patientswithWHS parents must always be studied for recognizing cryptic balanced chromosomal rearrangements for an adequate geneticcounseling

1 Introduction

Current diagnosis of chromosomal syndromes should in-clude a combination of conventional cytogenetic techniqueswith molecular cytogenetic methods particularly fluorescentin situ hybridization (FISH) as well as modern genomicapplications such as copy number variations (CNVs) analysisby single-nucleotide polymorphism (SNP) or comparativegenomic hybridization (aCGH) microarray techniques Thelaboratory methods employed to achieve an adequate diag-nosis of a familial case ofWolf-Hirschhorn syndrome (WHSOMIM194190) exemplifies how the conventional molecularand genomic techniques are complementary and useful toprovide an appropriate genetic counseling in chromosomalsyndromes

Wolf-Hirschhorn syndrome affects at least 150000 new-borns and presents a broad range of clinical manifestationsWHS is characterized by a typical craniofacial appearancegrowth delay mental retardation hypotonia and seizures[1] In the majority of cases (50ndash60) WHS is caused byldquopurerdquo de novo terminal or interstitial deletions in 4p16unbalanced translocations (45) either de novo or inheritedfrom a balanced rearrangement (sim15) and other complexcytogenetic findings (gt1) such as a chromosome 4 ringdel(4p) mosaicism or a duplicationdeletion rearrangementderived from a chromosome 4 inversion [2 3] have beenobserved as well In a high proportion of the WHS patients(25ndash30) the chromosomal abnormality is cryptic and notdetectable by conventional cytogenetic techniques In cases ofclinical suspicion ofWHS in a patient with normal karyotype

2 BioMed Research International

Table 1 Phenotype traits of our patients with a 4p deletion of sim65Mb compared with the frequencies of the main clinical features associatedwith 4p deletions of an average size between 5 and 18Mb from Zollino et al [5]

II-2 II-4 Sex Male FemaleAge at examination (years Months) 99 75Preterm delivery (lt38 weeks) + +Hypotonia + + 91Mildmoderate mental retardation minus minus 24Severe mental retardation + + 80Seizures + + 80Prenatal growth delay + + 84Postnatal growth delay + + 91Microcephaly + + 95Typical facial dysmorphisms + + 100

Cranial asymmetry + +Round-broad face + +High-diffuse frontal hair line + +High forehead + +Prominent glabella + +Sparse eyebrows + +Long eyelashes + +Downslanting palpebral fissures + minus

Ptosis +Lminus

Exophthalmos +R +Ocular coloboma minus minus 30

Strabismus + +Hypertelorism + +Broad nasal bridge + +Beaked nose + +Short nasal wings + +Short philtrum + +Prominent philtrum columns + +Downturned corners of mouth + +

Cleft lippalate +a +a 25Oligodontia + +Micrognathia + +Prominent ears + +Low set and malformed ears + +

OthersBrain anomalies +b +b

Hearing loss + +Congenital heart defects +c +d 52Renal abnormalities minus +e 37Hypospadias minus NA 41Skeletal anomalies +f +f 37

Sacral dimple + +Clinical findings + present minus absent R right L left NA not applicableaCleft palatebCorticalsubcortical atrophy enlargement of lateral ventricles and septum pellucidum agenesiscVentricular septal defect and pulmonary stenosisdAtrial septal defecteMalrotation of left kidneyfHip dislocation

BioMed Research International 3

additional FISH studies of the sub-telomeres and the WHScritical region (WHSCR) must be performed [4]

The high degree of variation in the clinical presentationof WHS has been attributed to differences in the size ofthe 4p deletion the presence of a partial trisomy from thesegregation of a chromosomal translocation or inversionallelic differences or multifactorial inheritance [2ndash5] Themajority of familial cases have been associated with parentalchromosomal balanced translocations particularly t(4p 8p)which represents a distinct genetic entity [2 5 6] Chromo-somes 7p 11p 12p and DpGp have also frequently beenimplicated in 4p inherited or de novo rearrangements [2 5 7ndash10] We describe two sibs with a classic WHS phenotype and4p161-p163 deletions (sim65Mb) due to the segregation of apaternal balanced rearrangement characterized by karyotyp-ing FISH and microarray copy-number analysis

2 Materials and Methods

21 Clinical Report The family pedigree is shown in Figure 1The parents were a healthy young non-consanguineouscouple II1 is a healthy 11-year old girl The propositus (II2)is a 9 years and 9 months of age boy born at 375 gestationweeks by cesarean section due to fetal distress birth weight2125 g height 43 cm (both lt3rd centile) Hypotonia wasnoted at birth At 7 months of age the patient developedgeneralized tonic-clonic seizures Clinical examination at 9years and 9 months of age revealed psychomotor retardationheight 124 cm weight 15 kg and OFC 453 (all lt3rd centile)He displayed facial features typical of WHS (Figure 1(a))Psychological examination by WISC-R revealed a global IQof 25 II4 is a 7-years and 5-month old girl born at 372 weeksby cesarean section birth weight 2100 g and height 42 cm(both lt3rd centile) She showed clinical findings similarto those of her brother (Figure 1(b)) and renal ultrasoundreported left kidney malrotation Her global IQ was 30 Theclinical features of both patients are described in Table 1Initial conventional cytogenetic analysis by GTG banding(400ndash700 bands) revealed a 4p16 deletion in both sibssuggesting a parental chromosomal balanced rearrangement

22 Cytogenetic and FISH Analysis Chromosome analyseson lymphocytes by GTG (400ndash700 bands) and NOR bandingwere performed according to standard protocols FISH wasperformed using LSI WHSCR1 Spectrum Orange and CEP 4Spectrum Green probes and ToTelVysion Mixtures number4 (4p Spectrum Green 4q Spectrum Orange 21q SpectrumGreenOrange and LSI AML1 Spectrum Aqua) and number10 (10p Spectrum Green 10q Spectrum Red 15q SpectrumGreenOrange and LSI PML Spectrum Aqua) from VysisAbbot Inc (Abbot Park IL USA) according to the proce-dures described by the manufacturer

23 Microarray Analysis High purity genomic DNA wasextracted from 3mL whole blood using the Versagene DNAPurification kit (Gentra Systems Inc Minneapolis MNUSA) Genomic mapping was performed on the affectedsibs and parents using the Genome-wide human SNP array

1

1

(a) (b)

2

2 3 4

I

II

Figure 1 Family pedigree and patient profiles (a) II2 at the age of 9years 9 months (b) II4 at the age of 7 years 5 months Both patientsexhibited typical WHS phenotypes

50 set (Affymetrix Inc Santa Clara CA USA) accord-ing to the protocol supplied by the manufacturer Geno-typing Console 41 (Affymetrix Inc) was used for qualityassessment and genotyping of the data The QC call rateby the BRLMM-P algorithm was over 93 CNV analysiswas performed using SNP amp Variation Suite 756 software(Golden Helix Inc Bozeman MT USA) Patientsrsquo datawere normalized against a reference set generated in ourlaboratory consisting of 71 healthy subjects including thepatientsrsquo parentsThe copy number analysismethod (CNAM)was used to identify the CNV segments with a movingwindow of 10000 markers in a univariate basis Mappingwas carried out based on the human genome assembly Feb2009 (GRCh 37hg19) (NCBI Reference Sequence (RefSeq)httpwwwncbinlmnihgovRefSeq)

3 Results

31 Cytogenetic and FISH Analysis High-resolution GTGbanding on the affected children revealed a 4p161 dele-tion (Figures 2(a) and 2(b)) FISH using WHSCR1 and 4psubtelomeric probes confirmed the loss of both sequences(Figures 2(g) and 2(h)) The motherrsquos karyotype was normalwhile the phenotypically normal father carries a deriva-tive chromosome 4 and an apparent heteromorphism inboth chromosomes 15 (Figure 2(c)) FISH using ToTelVy-sion Mixtures 4 and 10 showed that 4p subtelomeric sig-nal was located on the short arm of one chromosome 15


der (15)

der (15)

15 15

(a)

(b)

(c)

(d) (e)

(f)

(g) (h) (i)

Figure 2 Partial karyotypes from the family (a) II2 (b) II4 and (c) I1 chromosomes 4 and 15 with GTG banding (d) and (e) Partialmetaphases from the father showing chromosome 15 and der(15) associated with acrocentric chromosomes (f) Group D metaphasechromosomes from the father demonstrating active Ag-NOR in all chromosomes including der(15) (g) II2 and (h) II4 FISH with LSIWHSCR1 (orange) subtelomeric 4p (green) probes and controls CEP 4 (green) 4q subtelomeric (orange) 21q (orangegreen) and LSI AML1(aqua) showing the absence of both 4p signals on one chromosome 4 (i) I2 (father) FISH with ToTelVysion mixtures 4 and 10 showing agreen 4p subtelomeric signal on 15p

(Figure 2(i)) Ag-NOR banding was negative on 4p andno association of der(4) with acrocentric chromosomeswas observed der(15) was positive for Ag-NOR and acro-centric association (Figures 2(d) 2(e) and 2(f)) confirm-ing an insertion from 4p to 15p The other chromosome15 showed an increased stalk on its short arms (Fig-ures 2(e) and 2(f)) Both affected children inherited thischromosome 15pstk+ (Figures 2(a) and 2(b)) The fatherrsquosfinal karyotype was 46XYins(154)(p12p161p163)ish ins(154) (D4S3359+PML+D15S936+ D4S3359-D4S2930+) II 1inherited the same balanced rearrangement from her father(data not shown)

32 Microarray Analysis CNV analysis confirmed a similar4p deletion in both siblings 648Mb in the propositus and650 Mb in his affected sister The minimal deletion positionswere from nt69535 to 6546304 and from nt58388 to6560313 respectively (Figure 3(a)) These include WHSCRand WHSCR2 The telomeric break points affected theZNF718 and ZNF595 genes in both sibs however an 111 Kb

difference was observed between these (Figure 3(b)) Thedistal region of 4p is highly variable (database of GenomicVariants httpprojectstcagcavariation) and the childreninherited a different chromosome 4 from their motheras documented by the SNP genotyping analysis (data notshown)The centromeric break point differs by 14Kb betweensibs and in both cases the gene MAN2B2 maps outside thedeletion at least 152 Kb from its start point (Figure 3(c))Acrocentric p arms are not represented in the 50 SNP array

4 Discussion

Three clinical categories ofWHShave been defined accordingto the size of the 4p deletion (1) lt35Mb linked to amild form (2) between 5 and 18Mb associated with theclassical phenotype observed in our patients and (3) gt22Mbcausing a severe form [5] The pathogenesis of WHS ismultigenic and genotype-phenotype correlation studies mayclarify the role of specific genes on 4p in the disease etiology[2 4] CNV analysis in our patients revealed a similar 4p


minus 04

0

04

Log2

R

1 25 4 55 67(Mb)

163 162 161

Position (Chr4)

Chromosome 4p bands

(a)

minus 04

0

Log2

R

6 46 85 125(Kb)

Genes

CNV

Position (Chr4)

ZNF595

ZNF718

(b)

minus 04

0

Log2

R

6528 65846556 6613(Kb)

Position (Chr4)

Genes

CNV

MAN2B2

(c)

Figure 3 (a) Deletion involving chromosome bands 4p161-p163 was confirmed by microarray mapping of the propositus (998787) his youngersister (998771) and both parents (father (◼) and mother (∙)) (b) The affected patients display differential telomeric break points which occur at avariable region including genes ZNF718 and ZNF595 (c) The centromeric break points in both patients were located gt15 kb upstream of theMAN2B2 transcriptional start site (pos 6576902) Gene (RefSeq) and CNV (DGV) annotation maps are shown below CNV gain regions areindicated in red losses in green and gainlosses in gray Log2R logarithmic value of the sample to reference ratio

deletion of sim65 Mb with the common deleted segmentspanning from 69535 Kb to 6546304 Mb that is 4p161 to4p163 (Figure 3(a)) The deletion affects at least 70 genesincluding the 200 kb critical region for the typical WHSphenotype [11] and the candidate genes LETM1 FGFRL1andWHSC1 which have been associated with seizures somefacial findings distinctive facial features and growth delayrespectively [4 12] The genes ATP5I FGFR3 HTT MSX1and PPP2R2C are likely haploinsufficient (Decipher databasehttpdeciphersangeracuk) and could also be relevant tothe WHS phenotype

Different types of chromosomal rearrangements are asso-ciated with WHS among these inherited unbalanced trans-locations are frequently maternal while de novo unbalancedtranslocations are usually paternal with the exception of thet(48) [2 5 13] In our patients we identified an isolated 4p

deletion due to a paternal balanced insertion (Figure 4) Toour knowledge this rearrangement has not been previouslyreported in WHS

Recently it has been suggested that chromosomal inser-tions are more frequent (1 500) [14ndash16] than previouslyreported (1 80000) [17] These rearrangements involve threechromosome breakage events that can be intra- or interchro-mosomalThe use of FISH to confirm deletions andor dupli-cations detected by microarrays showed that these genomicimbalances resulted from the segregation of a parentallybalanced insertion [14 15] Interestingly the short arms ofacrocentric chromosomes are frequently involved in theserearrangements especially the NOR of chromosomes 15 and22 and they are often cryptic when present in an unbalancedform [14] Genomic studies have demonstrated that differentgene families and certain satellite repeats like the olfactory


4p161

15p12

4

4

15

15der(4)

der(15)

Altern Adjacent I Adjacent II

(a) (b) (c) (d) (e) (f)

Figure 4 Chromosomes 4 and 15 ideograms showing the paternal insertion and itsmeiotic segregationThe affected siblings were the productof an adjacent I segregation

receptor gene family and the terminal 4p repeats constitutenucleolus-associated chromatin domains that interact withthe satellite repeats and rDNA of acrocentric chromosomes[18 19] This could explain the high frequency of acrocen-tric chromosomal rearrangements with different partnersRecently some WHS rearrangements have been recognizedto involve a translocation between the NOR of an acrocentricchromosome and chromosome 4 producing a satellited 4pchromosome Some of these cases are sporadic and otherfamilial [2 7 10 20] Our patients are the product of anadjacent I segregation from the paternal insertion and thenonaffected girl received both derivative chromosomes byalternate segregation (Figure 4) Wu et al [10] reported afamily with coexisting sibs which are the products of both

types of gametes from an adjacent I segregation one with a4p deletion of 5 Mb and classical WHS and the other with apure duplication of the same region of 4p

Only few cases of familiar recurrence of WHS have beendescribed and they are usually associated with a balancedchromosomal translocation in one parent Neverthelessthe WHS phenotype is modified by the trisomy of otherchromosomal region [5 13 21 22] One instance of a familialrecurrence of a 4p pure deletion was due to a meioticamplification of a maternal 15 Mb deletion The mother hadmild WHS while her two affected sons displayed a typicalphenotype One of the sons was studied and revealed a 28Mb deletion [23] Another case of two sibs showing a mildform of WHS were reported to have a pure 4p deletion of 28


Mb from amother with a karyotype 46XXt(414)(p163p12)[20] Our patients also have a pure 4p terminal deletion of 65Mb associated with classical WHS phenotype due to a fatherins(154)(p12p161p163) however only minor phenotypedifferences were observed between sibs in both families Thedifferences in the severity of the phenotypes in these twofamiliar cases could be result of the size of the chromosomaldeleted region as has been suggested [5]

The small difference in the size of the deleted material25 Kb among our propositus and his affected sister could beattributed to amaternal polymorphism recombination aneu-somy or microarray data normalization The most strikingclinical differences between sibs were the type of cardiacdefect the presence of downslanting palpebral fissures andptosis only in the boy and kidneymalrotation present only inthe girl Comparing the clinical data of our patients with thedata reported by Zollino et al [5] in patients with classicalWHSphenotype and deletions between 5 and 18Mb (Table 1)the only major differences were the absence of ocularcoloboma andhypospadias Until now fewWHSpatients hadbeen studied by genomic high-resolution methods [1 2 410 14 20] As the number of these studies increases a betterdetermination of the exact size of deletions will be achievedimproving the definition of the regions and genes implicatedin each phenotypic trait associated with the classical WHS

5 Conclusions

The clinical variability in our classical WHS patients couldbe explained by polymorphisms in the 4p alleles present plusmultifactorial inheritance patterns

Our results reinforce the importance of thorough clinicaldiagnosis as well as conventional andmolecular karyotypingof patients and their parents for proper genetic diagnosis andcounseling Particularly the use of high-density SNP arraysfor CNV analysis in the patients enables the determinationof the size of the deletion with higher precision and candetect cryptic partial trisomies In order to give an adequategenetic counseling the parents of a child with a 4p deletionshould always be studied by FISH with subtelomeric 4pand WHSCR1 specific probes to corroborate if they arecarriers of a cryptic balanced rearrangement In conclusionwe identified a novel type of chromosome rearrangementinvolved in sibs recurrent classical WHS and its mecha-nism is apparently more frequent than previously thoughtThis case demonstrates the importance of the combinedapplication of classical and molecular techniques to clarifychromosomal structural rearrangements

Conflict of Interest

The authors declare no conflict of interests and state thatnone of them have any financial relation with the commercialidentities mentioned in this work

Acknowledgment

The authors thank the family for their participation in thestudy and CONACyT (2006-C01-13947)

References

[1] A Battaglia T Filippi and J C Carey ldquoUpdate on theclinical features and natural history of Wolf-Hirschhorn (4p-)syndrome experience with 87 patients and recommendationsfor routine health supervisionrdquo American Journal of MedicalGenetics C vol 148 no 4 pp 246ndash251 2008

[2] S T South H Whitby A Battaglia J C Carey and AR Brothman ldquoComprehensive analysis of Wolf-Hirschhornsyndrome using array CGH indicates a high prevalence oftranslocationsrdquoEuropean Journal ofHumanGenetics vol 16 no1 pp 45ndash52 2008

[3] A Battaglia J C Carey S T South and T J Wright ldquoWolfHirschhorn syndromerdquo inGeneReviews [Internet] R A PagonT D Bird C R Dolan and K Stephens Eds Seattle Universityof Washington Seattle Wash USA 2007

[4] NMCMaasGVanBuggenhout FHannes et al ldquoGenotypendashphenotype correlation in 21 patients with WolfndashHirschhornsyndrome using high resolution array comparative genomehybridisation (CGH)rdquo Journal of Medical Genetics vol 45 no2 pp 71ndash80 2008

[5] M Zollino M Murdolo G Marangi et al ldquoOn the nosologyand pathogenesis of Wolf-Hirschhorn syndrome genotype-phenotype correlation analysis of 80 patients and literaturereviewrdquo American Journal of Medical Genetics C vol 148 no4 pp 257ndash269 2008

[6] D Wieczorek M Krause F Majewski et al ldquoUnexpected highfrequency of de novo unbalanced translocations in patientswithWolf-Hirschhorn syndrome (WHS) [7]rdquo Journal of MedicalGenetics vol 37 no 10 pp 798ndash804 2000

[7] J B Ravnan J H Tepperberg P Papenhausen et al ldquoSubtelom-ere FISH analysis of 11 688 cases an evaluation of the frequencyand pattern of subtelomere rearrangements in individuals withdevelopmental disabilitiesrdquo Journal of Medical Genetics vol 43no 6 pp 478ndash489 2006

[8] S T South H Whitby T Maxwell E Aston A R Brothmanand J C Carey ldquoCo-occurrence of 4p163 deletions with bothpaternal andmaternal duplications of 11p15 modification of theWolf-Hirschhorn syndrome phenotype by genetic alterationspredicted to result in either a Beckwith-Wiedemann or Russell-Silver phenotyperdquo American Journal of Medical Genetics A vol146 no 20 pp 2691ndash2697 2008

[9] Z Ou P Stankiewicz Z Xia et al ldquoObservation and predictionof recurrent human translocationsmediated byNAHR betweennonhomologous chromosomesrdquoGenomeResearch vol 21 no 1pp 33ndash46 2011

[10] L Wu D Meng Z Zhou J Du Z Long and D Liang ldquoAfamily with partial duplicationdeletion 4p due to a balanced t(4 15) (p162 p112) translocationrdquo American Journal of MedicalGenetics A vol 155 no 3 pp 656ndash659 2011

[11] M Zollino R Lecce R Fischetto et al ldquoMapping theWolf-Hirschhorn syndrome phenotype outside the currentlyacceptedWHS critical region and defining a new critical regionWHSCR-2rdquoAmerican Journal of Human Genetics vol 72 no 3pp 590ndash597 2003

[12] H Engbers J J van der Smagt R vanrsquot Slot J R VermeeschR Hochstenbach and M Poot ldquoWolf-Hirschhorn syndromefacial dysmorphic features in a patient with a terminal 4p163deletion telomeric to the WHSCR and WHSCR 2 regionsrdquoEuropean Journal of Human Genetics vol 17 no 1 pp 129ndash1322009


[13] M Zollino R Lecce A Selicorni et al ldquoA double cryptic chro-mosome imbalance is an important factor to explain phenotypicvariability in Wolf-Hirschhorn syndromerdquo European Journal ofHuman Genetics vol 12 no 10 pp 797ndash804 2004

[14] S H L Kang C Shaw Z Ou et al ldquoInsertional transloca-tion detected using FISH confirmation of array-comparativegenomic hybridization (aCGH) resultsrdquo American Journal ofMedical Genetics A vol 152 no 5 pp 1111ndash1126 2010

[15] N J Neill B C Ballif A N Lamb et al ldquoRecurrencesubmicroscopic complexity and potential clinical relevanceof copy gains detected by array CGH that are shown to beunbalanced insertions by FISHrdquo Genome Research vol 21 no4 pp 535ndash544 2011

[16] B A Nowakowska N de Leeuw C A Ruivenkamp et alldquoParental insertional balanced translocations are an importantcause of apparently de novoCNVs in patientswith developmen-tal anomaliesrdquo European Journal of Human Genetics vol 20 no2 pp 166ndash170 2012

[17] J O Van Hemel and H J Eussen ldquoInterchromosomal inser-tions identification of five cases and a reviewrdquoHuman Geneticsvol 107 no 5 pp 415ndash432 2000

[18] A Nmeth A Conesa J Santoyo-Lopez et al ldquoInitial genomicsof the human nucleolusrdquo PloS Genetics vol 6 no 3 articlee1000899 2010

[19] S VanKoningsbruggenM Gierlinski P Schofield et al ldquoHigh-resolution whole-genome sequencing reveals that specific chro-matin domains frommost human chromosomes associate withnucleolirdquoMolecular Biology of the Cell vol 21 no 21 pp 3735ndash3748 2010

[20] D Liang Z Zhou D Meng et al ldquoThree patients with Wolf-Hirschhorn syndrome carrying a satellited chromosome 4prdquoBirth Defects Research A vol 94 no 7 pp 549ndash552 2012

[21] J Goodship A Curtis I Cross et al ldquoA submicroscopic translo-cation t(410) responsible for recurrent Wolf-Hirschhorn syn-drome identified by allele loss and fluorescent in situ hybridi-sationrdquo Journal of Medical Genetics vol 29 no 7 pp 451ndash4541992

[22] E Reid N Morrison L Barron et al ldquoFamilial Wolf-Hirschhorn syndrome resulting from a cryptic translocation aclinical and molecular studyrdquo Journal of Medical Genetics vol33 no 3 pp 197ndash202 1996

[23] F Faravelli M Murdolo G Marangi F D Bricarelli M DRocco and M Zollino ldquoMother to son amplification of a smallsubtelomeric deletion a new mechanism of familial recurrencein microdeletion syndromesrdquo American Journal of MedicalGenetics A vol 143 no 11 pp 1169ndash1173 2007

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Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Table 1 Phenotype traits of our patients with a 4p deletion of sim65Mb compared with the frequencies of the main clinical features associatedwith 4p deletions of an average size between 5 and 18Mb from Zollino et al [5]

II-2 II-4 Sex Male FemaleAge at examination (years Months) 99 75Preterm delivery (lt38 weeks) + +Hypotonia + + 91Mildmoderate mental retardation minus minus 24Severe mental retardation + + 80Seizures + + 80Prenatal growth delay + + 84Postnatal growth delay + + 91Microcephaly + + 95Typical facial dysmorphisms + + 100

Cranial asymmetry + +Round-broad face + +High-diffuse frontal hair line + +High forehead + +Prominent glabella + +Sparse eyebrows + +Long eyelashes + +Downslanting palpebral fissures + minus

Ptosis +Lminus

Exophthalmos +R +Ocular coloboma minus minus 30

Strabismus + +Hypertelorism + +Broad nasal bridge + +Beaked nose + +Short nasal wings + +Short philtrum + +Prominent philtrum columns + +Downturned corners of mouth + +

Cleft lippalate +a +a 25Oligodontia + +Micrognathia + +Prominent ears + +Low set and malformed ears + +

OthersBrain anomalies +b +b

Hearing loss + +Congenital heart defects +c +d 52Renal abnormalities minus +e 37Hypospadias minus NA 41Skeletal anomalies +f +f 37

Sacral dimple + +Clinical findings + present minus absent R right L left NA not applicableaCleft palatebCorticalsubcortical atrophy enlargement of lateral ventricles and septum pellucidum agenesiscVentricular septal defect and pulmonary stenosisdAtrial septal defecteMalrotation of left kidneyfHip dislocation








1

1

(a) (b)

2

2 3 4

I

II



3 Results



der (15)

der (15)

15 15

(a)

(b)

(c)

(d) (e)

(f)

(g) (h) (i)





4 Discussion



minus 04

0

04

Log2

R

1 25 4 55 67(Mb)

163 162 161

Position (Chr4)

Chromosome 4p bands

(a)

minus 04

0

Log2

R

6 46 85 125(Kb)

Genes

CNV

Position (Chr4)

ZNF595

ZNF718

(b)

minus 04

0

Log2

R

6528 65846556 6613(Kb)

Position (Chr4)

Genes

CNV

MAN2B2

(c)







4p161

15p12

4

4

15

15der(4)

der(15)


(a) (b) (c) (d) (e) (f)








5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








1

1

(a) (b)

2

2 3 4

I

II



3 Results



der (15)

der (15)

15 15

(a)

(b)

(c)

(d) (e)

(f)

(g) (h) (i)





4 Discussion



minus 04

0

04

Log2

R

1 25 4 55 67(Mb)

163 162 161

Position (Chr4)

Chromosome 4p bands

(a)

minus 04

0

Log2

R

6 46 85 125(Kb)

Genes

CNV

Position (Chr4)

ZNF595

ZNF718

(b)

minus 04

0

Log2

R

6528 65846556 6613(Kb)

Position (Chr4)

Genes

CNV

MAN2B2

(c)







4p161

15p12

4

4

15

15der(4)

der(15)


(a) (b) (c) (d) (e) (f)








5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


der (15)

der (15)

15 15

(a)

(b)

(c)

(d) (e)

(f)

(g) (h) (i)





4 Discussion



minus 04

0

04

Log2

R

1 25 4 55 67(Mb)

163 162 161

Position (Chr4)

Chromosome 4p bands

(a)

minus 04

0

Log2

R

6 46 85 125(Kb)

Genes

CNV

Position (Chr4)

ZNF595

ZNF718

(b)

minus 04

0

Log2

R

6528 65846556 6613(Kb)

Position (Chr4)

Genes

CNV

MAN2B2

(c)







4p161

15p12

4

4

15

15der(4)

der(15)


(a) (b) (c) (d) (e) (f)








5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


minus 04

0

04

Log2

R

1 25 4 55 67(Mb)

163 162 161

Position (Chr4)

Chromosome 4p bands

(a)

minus 04

0

Log2

R

6 46 85 125(Kb)

Genes

CNV

Position (Chr4)

ZNF595

ZNF718

(b)

minus 04

0

Log2

R

6528 65846556 6613(Kb)

Position (Chr4)

Genes

CNV

MAN2B2

(c)







4p161

15p12

4

4

15

15der(4)

der(15)


(a) (b) (c) (d) (e) (f)








5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


4p161

15p12

4

4

15

15der(4)

der(15)


(a) (b) (c) (d) (e) (f)








5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




5 Conclusions





Acknowledgment


References
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




















Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

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