De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay:

Case report 

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Case Report

De novo reciprocal translocation t(4;20) (q28;q11)associated in a child with developmental delay:Case report

Kavitha Eppa a,*, Iravathy Goud Kalal b, Pranathi Reddy Guttala c,Sakina Aneeb d

a Consultant, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad,

Andhra Pradesh 500033, Indiab HOD, Consultant, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad,

Andhra Pradesh 500033, Indiac Consultant, Department of Internal Medicine, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh

500033, Indiad Technologist, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad,

Andhra Pradesh 500033, India

a r t i c l e i n f o

Article history:

Received 25 January 2014

Accepted 18 July 2014

Available online xxx

Keywords:

Developmental delay

Translocation

Cytogenetic analysis

Karyotype

* Corresponding author. Tel.: þ91 9491226E-mail addresses: matamkavitha@gmail.

Please cite this article in press as: Eppadevelopmental delay: Case report, Apollo

http://dx.doi.org/10.1016/j.apme.2014.07.0040976-0016/Copyright © 2014, Indraprastha M

a b s t r a c t

The common cause of mental impairment and the wide range of physical abnormalities is

balanced chromosome rearrangement. As such, it is difficult to interpret, posing as a

diagnostic challenge in human development. We present a unique case report with a

denovo autosomal-balanced reciprocal translocation involving chromosomal regions 4q

and 20q.The etiology of the translocation, i.e. 46,XX,t (4;20)(q28;q11) was detected by con-

ventional high-resolution Giemsa-Trypsin-Giemsabanding technique. Parents non-

consanguineous, with 2 healthy children. To the best of our knowledge this is the first

case reported so far with the balanced reciprocal translocation involving 4q and 20q

associated with the delayed milestone development.

Conclusion: The reason likely may be due to the rearrangement of genetic material at these

breakpoints having a crucial relationship and thus manifesting developmental delay in the

proband.

Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.

1. Introduction

In humans the incidence of balanced chromosomal trans-

locations is approximately 1 in 500.1 In cytogenetic evaluation,

119, þ91 040 23607777x40com, kavitha_e@apolloho

K, et al., De novo reciprMedicine (2014), http://

edical Corporation Ltd. A

balanced chromosome translocations are defined as those

rearrangements where no loss or gain of genetic material is

observed. Most of the balanced chromosome rearrangements

(BCRs) are not considered to be associated with the clinical

12; fax: þ91 040 23608050.spitals.com (K. Eppa).

ocal translocation t(4;20) (q28;q11) associated in a child withdx.doi.org/10.1016/j.apme.2014.07.004

ll rights reserved.

a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1e32

(phenotype) abnormalities. But, they are of concern, as the

carriers of BCRs offer a greater risk to their descendants with

congenital anomalies or recurrent miscarriages. On the basis

of a few evaluation procedures, it is estimated that 6.7% of the

carriers of de novo BCRs have the risk of phenotypic abnor-

malities.2 In the present paper, we describe de novo

autosomal-balanced reciprocal translocation involving chro-

mosomes 4 and 20 in a child associated with delayed mile-

stone development.

2. Case report

The proband is a 7 months boy, the third male child of a

healthy, young, non-consanguineous couple with 2 other

healthy children. No family history. Pregnancy and delivery at

38 weeks were normal. Birth weight was 3.2 kgs. Length was

44 cm and head circumference (HC) was 34 cm. The child was

neither focusing nor following the object at 3 months did not

attain social smile and has delayed mile stones. At 7 months

there was no head control, and was not recognizing the

parents.

Examination revealed hypotonia (frog posture) with facial

asymmetry and microcephaly, HC below 3rd centile. There

was no plagiocephaly with closed anterior fontanel. Some

dysmorphic features (low set ears, high arched palate, single

palmer crease and hypoplastic toe nails) were seen. He was

not following and there was no startle. He had horizontal

nystagmus. There was axial hypotonia with limbs spasticity

and brisk deep tendon reflexes. There was no clonus. He had

no organomeghaly.

2.1. Materials & methods

Tandem mass: Normal, elevated liver enzymes: ALT-55IU/

L(0e41), AST:86 U/L(0e38). CT brain: smooth brain surface

with thick cortex, absent corpus callosum and asymmetry in

the lateral ventricles. MRI brain: polymicrogyria and double

Fig. 1 e Karyotype showing reciprocal tra

Please cite this article in press as: Eppa K, et al., De novo reciprdevelopmental delay: Case report, Apollo Medicine (2014), http:/

cortex. Ophthalmology: Impression was visual impairment.

The proband was referred for cytogenetic evaluation to the

Department of Cytogenetics & Molecular biology, Apollo

Hospitals, Jubilee Hills, Hyderabad.

3. Cytogenetic analysis

Peripheral blood from the patient and his parents was

cultured with phytohemagglutinin (PHA) stimulation for

72 hours before harvest with their informed written consent.

Stimulated cultureswere set by standardmethod3 followed by

GTG-banded chromosome study.4 About 50 metaphases were

scored for all individuals under light transmissionmicroscope

and spectral karyotyping software was used for cytogenetic

analysis. Metaphases were karyotyped according to Interna-

tional System for Human Cytogenetic Nomenclature (ISCN)

criteria, Mitelman (2005).5 All metaphases in proband showed

balanced reciprocal translocation between chromosome

number 4 and long arm (q11) of chromosome number 20, [46,

XY, t(4;20)(q28;q11)] [Fig. 1]. Chromosomal studies on the

parents showed normal results.

3.1. Results & discussion

Cytogenetic evaluation of the GTG-bandedmetaphases from a

lymphocyte culture showed a balanced reciprocal trans-

location involving long arm (q28) of chromosome 4 and long

arm (q11) of chromosome 20 in all the cells of the proband

with a karyotype of 46,XY t(4;20)(q28;q11) [Fig. 1]. Chromo-

somal studies on the parents showed normal results.

We report a male child with hypotonia and dysmorphic

features. Cytogenetic study showed a denovo translocation

between 4&20 (q28,q11). Balanced chromosomal trans-

locations may cause damage or alteration of the functional

genes at the breakpoints of the defective chromosomes

resulting in the disease phenotype.6 Linking up the associa-

tion of disease consistently with chromosome abnormalities

nslocation of 46 XY t(4;20)(q28;q11).

ocal translocation t(4;20) (q28;q11) associated in a child with/dx.doi.org/10.1016/j.apme.2014.07.004

a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1e3 3

such as deletions, duplications and translocations would be

the simple way of mapping disease genes. Molecular charac-

terization of chromosomal breakpoints in carriers of balanced

translocation would be one of the vital strategies to be

implemented. Thus, disease-associated chromosome rear-

rangements that truncate, delete or otherwise inactivate

specific genes have been instrumental in the positional clon-

ing of many disease genes.7

In thispaper,wereportan interestingcasewithapparentlyde

novo reciprocal-balanced translocation that has resulted in

delayed development of milestones. Delayed milestones or

developmental delays are defined as a lag in the child's devel-

opment compared to theestablished standardnormal ranges for

hisorherage. Frombirth to6yearsofage, 8%ofall childrenshow

delays in one or more areas of development. The present report

indicates that the proband had developmental lags in the first

year of his life. At the age of 7months hehadnohead control, no

hand regards andwas not recognizingparents. The present case

report, however, is the first report of denovo balanced trans-

location involving chromosomes 4 and 20 at their respective

breakpoint, which shows an association with delayed mile-

stones andwhichhasnot been reported previously. On the basis

of thechromosomes involvedandonthe locationofbreakpoints,

the production of normal, balanced or unbalanced gametes is

decided.8 In carriers of balanced translocation, the possible

reason for the association of malformations could be gene

inactivation or disruption at the breakpoint or a position effect.9

The gene PRSS12 that maps at 4q28 encodes a extracellular

multidomain serine protease associated with neural devel-

opment and plasticity and studies in mouse suggest that the

encoded enzyme may be involved in structural re-

organizations associated with learning and memory. Molinari

et al.,10 reviewed the molecular pathogenesis of autosomal

recessive mental retardation caused by neurotrypsin muta-

tions. Another important gene NNAT mapped to 20q11 en-

codes a proteolipid which participate in the maintenance of

segment identity in the hindbrain and pituitary development,

and maturation or maintenance of the overall structure of the

nervous system, also as a regulatory subunit of ion Channels.

Hence, disruption of the gene or group of genes at this

breakpoint might suggest a cause for delayed developmental

milestones. The possible reason leading to delayedmilestones

may be due to the consequence of the abnormality described

in the patient. Hence, further analysis of the breakpoints and

molecular characterization of these genes might help in un-

derstanding the basis of delayed development of milestones.

Moreover, it is known that the modification or inactivation of

specific disease genes at chromosomal breakpoints have been

very phenomenal in identifying genes that are associatedwith

a variety of disorders, mostly early-onset disorders.7

4. Conclusion

These findings suggest that cytogenetic analysis is useful in

the investigation of children with genetic disorders of un-

Please cite this article in press as: Eppa K, et al., De novo reciprdevelopmental delay: Case report, Apollo Medicine (2014), http://

known origin to confirm clinical diagnosis and in view of an

increased risk of having congenitally abnormal children, car-

riers of balanced reciprocal translocation should, therefore, be

advised to seek genetic counseling.

Conflicts of interest

All authors have none to declare.

Acknowledgements

The authors acknowledge the parents of the child for

accepting to give the consent and samples, technical support

of Mr. V. Ravi for cytogenetics and the Management of Apollo

Hospitals for their support.

r e f e r e n c e s

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2. Warburton D. De novo balanced chromosomerearrangements and extra marker chromosomes identifiedat prenatal diagnosis: clinical significance and distributionof breakpoints. Am J Hum Genet. 1991;49:995e1013.

3. Moorehead PS, Nowell PC, Mellman WJ, Battips DM,Hungerford DA. Chromosome preparation of leukocytescultured from human peripheral blood. Exp Cell Res.1960;20:613e616.

4. Seabright M. A rapid banding technique for humanchromosomes. Lancet. 1971;2:971e972.

5. Mitelman F. ISCN. An International System for Human CytogeneticNomenclature. Basel: Karger; 2005:1e115.

6. Fryns JP, Kleczkowska A, Kubien E, Van den Berghe H.Excess of mental retardation and/or congenitalmalformation in reciprocal translocations in man. HumGenet. 1986;72:1e8.

7. Bugge M, Bruun-Petersen G, Brondum-Nielsen K, et al.Disease associated balanced chromosome rearrangements: aresource for large-scale genotype-phenotype delineation inman. J Med Genet. 2000;37:858e865.

8. Burns JP, Koduru PR, Alonso ML, Chaganti RS. Analysis ofmeiotic segregation in a man heterozygous for two reciprocaltranslocations using the hamster in vitro penetration system.Am J Hum Genet. 1986;38:945e964.

9. Buhler EM. Unmasking of heterozygosity by inheritingbalanced translocations. Implications for prenataldiagnosis and gene mapping. Ann Genet. 1983;26:133e137.

10. Molinari F, Rio M, Meskenaite V, et al. Truncatingneurotrypsin mutation in autosomal recessivenonsyndromic mental retardation. Science.2002;298:1779e1781.

ocal translocation t(4;20) (q28;q11) associated in a child withdx.doi.org/10.1016/j.apme.2014.07.004

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