Effect of Chromoso ome Imbalance in Human

Effect of Chromoso 

ome Imbalance 

in Human. 

Małgorzata J.M. Now 

waczyk 

Hamilton Health Sciences Corporation 

and McMaster Unive 

ersity, Hamilton, Canada

Chromosomes 

• A storage form of DNA 

• Each consists of a single, long molecule of DNA 

• Coiled and condensed 

d manyfold (several levels 

of packing) 

• Genes are arranges along the strand of DNA 

• Genes – books 

• Chromosomes – bookcases 

• Genome – the library

Karyotype 

• Arrangement of chrom 

mosomes in pairs. 

• Homo sapiens has 23 

pairs. 

• Two sex chromosome 

es: XX or XY. 

• In each pair there is a maternal and a paternal 

chromosome. 

• Each abnormal karyotype may have a 

characteristics physical manifestation 

(phenotype)

Normal Female Karyotype 46,XX

Normal Male Karyotype 46,XY

Chromosome Defe 

ects - Definitions 

Autosome 

The non-sex chromosomes, 

one of the 22 pairs 

Sex chromosomes 

X or Y chromosome 

Structure of chromosome 

Metacentric, acrocentric, telocentric 

Centromere, telomere

Karyotype. 

Number – number of centromeres: N = 46. 

Sex chromosomes, XX or XY. 

Other : 

t(3;5)(q23.1;q15.2) ;q ) or 

rob(13;14) 

inv(2)(q22.1;p12.1) 

1) 

der(3)t(8;17)(p11.3;q21.1)mat 

del(18)(q2.1q2.23)pat1q2 23)pat 

der(3)t(3;5)(q23.1;q15.2) 

( )(q ;q )



Balanced rearrangement 

A structural rearrangement 

that results 

in a normal complement 

of 

chromosomal material 

Unbalanced rearrangement 

A structural rearrangement 

that results 

in additional or missing 

chromosomal material, can be 

stable – capable of passi 

ing through 

h 

meiosis unchanged, or unstable



Balanced rearrangemen 

ts: 

Inversions 

Pericentric 

Paracentric 

Abnormal offspring with 

Duplications or deletions



Balanced rearrangements: 

Robertsonian translocation 

this type involved two 

acrocentric chromosomess 

with the loss of the short 

arms 

the resultant normal karyotype 

has 45 chromosomes 

there is risk of unbalanced 

offspring



Reciprocal translocationn 

results from breakage of nonhomologous 

chromosome with reciprocal exchange of the 

broken-off off segments; 

usually there is no loss of 

chromosomal material 

problems with meiosis and risk of unbalanced 

offspring

Reciprocal translocation - balanced



Reciprocal translocationn - meiosis



Unbalanced rearrangements 

Deletions 

Duplications 

Marker and ring chromo 

osomes 

Isochromosomes 

Dicentric chromosomess 

many of these are uns 

stable

Reciprocal 

translocation 

- unbalanced

Chromosome Defec 

cts - Incidence 

In newborn surveys: 

Males 47,XXY 

47,XXY 

other Y,X 

total 

Females 45,X 

47,XXX 

other X 

total X 

1/1000 

1/1000 

1/1350 

1/360 male births 

1/4000 

1/900 

1/2700 

1/580 female births




Autosomal aneuploidies 

trisomy 21 

trisomy 18 

trisomy 13 

other aneuploidy 

total 

Structural abnormal 

1/830 

1/7500 

1/22,700 

1/34,000 

1/700




Structural abnormalities 

balanced rearrangements 

Robertsonian 

other 

unbalanced 

Robertsonian 

other 

Total 

1/1100 

1/885 

1/13,600 

1/1,800 

1/1800




Total chromosomal abnormalities in live births 

1/154 

Total chromosomal abno 

ormalities in spontaneous 

abortions 

40-50%

A baby: 

hypotonic, poor feeding 

g, unusual-looking 

for his ethnic background

Down syndrome: Trisomy 21 

Clinical exam: 

hypotonia 

epicanthal folds, 

single palmar creases 

nuchal fold thickening 

squa 

ared-off ears 

flat occiput 

Brus 

schfield spots 

Other: pyloric stenosis, cardiac 

defects, dislocated hips 

Developmental delay

Down syndrome: Trisomy 21

Down syndrome - Chromosomes 

Why test chromosomes? 

trisomy 21 – 95% 

recurrence risk 

depends on maternal age 

Robertsonian translocation t( (13;21), t(14;21) – 4% 

10-15% if mother a carrier,

Recurrent Pregnanc 

cy Losses 

I 

II 

III

Autosomal Recip 

procal Translocations 

– Familial 

Draw a three-generation family tree 

Note pregnancy losse 

es, stillbirth, neonatal 

death, and family members with 

developmental dela 

ays or congenital 

anomalies 

Confirm that the cons 

sutand does not have 

health problems or learning disabilities



– Familial 

Rough risk assessment based on the family 

history and the sizes of the chromosomal 

framents involved in 

the rearrangement (any 

family ascertained by the birth of a child with 

an unbalanced karyotype is at risk for further 

incidence, in this situation the risk is often 

>1%).



– Familial 

Determine breakpoints – risk for viability are the 

highest when the breakpoints are the closest to 

telomeres, i.e., with th 

he smallest segments. 

Determine whether the product with the smallest 

imbalance would be viable (databases, literature 

search, etc): 

monosomy less likely viable than trisomy 

monosomy for whole autosome is not viable 

trisomy for only the smallest whole chromosomes 

(21, 13, 18) is viable

Case. 

27 yo G2P1 

• Healthy, one child in previous relationship 

• Baby: 

holoprosencephaly 

bilateral cleft lip 

sacral agenesis 

ambiguous genitaliaa 

born at 37/40 and died at 20 minutes of age 

•FHx: 

neonatal death of a similarly il l affected father’s sib 

work-up (30 years ago): 

buccal smear 

negative for sex chromatin 

autopsy

Work-up. 

Cytogenetic analyses 

• Abnormal male karyotype: 

• Father: 

46,XY,der(7)t(2;7)(p2 

,de )(p 3.2;q36.1) 

trisomic for a small portion of distal 2q 

monosomic for a small portion of distal 7q 

• Mother: 46,XX 

46,XY,t(2;7)(p23.2;q36.1) 

• Paternal grandmother: 46,XX,t(2;7)(p23.2;q36.1)

Case – cont’d 

• Diagnosis known 

• Genetic counselling 

risk of recurrence 

identification of other family 

members at risk 

• Prenatal diagnosis available 

CVS or amniocen 

ntesis for cytogenetic analysis 

• Next pregnancy : CVS 11 weeks -- 

balanced karyoty 

ype 46,XX,t(2;7)(p23.2;q36.1) 

2;q36 NOT at risk for anomalies, but reproductive risks 

• Healthy baby girl born atterm 

term

Trisomy 18

Trisomy 18 

Severe IUGR, postnatal t fa 

ailure to thrive 

Prominent occiput, 

small triangular face 

widely spaced nipples 

short sternum 

rocker bottom feet 

Prenatal – choroid plexus 

cysts 

95% spontaneous abortion 

80% are female 

Multiple internal malforma 

ations

Trisomy 13

Trisomy 13 

Normal intrauterine t i growt 

th or IUGR 

Severe central nervous system malformations 

holoprosence 

phaly, arhinencephaly 

Cleft lip and palate 

Mirophthalmia, colobomas 

Polydactyly, 

Rocker bottom feet 

20% are a result of an unbalanced translocation 

Multiple internal malforma 

ations – cardiac, GU,

Chromosomal Im 

mbalances – 

Aneuploidies. 

Deletion or duplications 

Missing or extra chro 

mosomal material 

Phenotypic effects depend on the type, location 

and size of imbalan 

nce. 

Duplications tolerated 

better than deletions – 

frequently normal phenotype.

Chromosomal Im 

mbalances – 

“The Chromosomal Phenotype”. 

Family history of mental 

retardation/developmental delay. 

Prenatal or postnatal growth retardation. 

microcephaly, short 

stature 

Dysmorphic features. 

Congenital malformations.

Contiguous Gene 

Syndromes: 

• disorders caused by a 

bnormal gene dosage 

(duplications, deletions) resulting from chromosomal 

abnormalities 

characteristic clinical phenotype 

Smith-Magenis s, Williams s, VCF 

• chromosomal abnorma 

ality may be visible ibl with routine 

cytogenetic methods 

• often require special te 

echniques (FISH) 

• caused by low copy DNA repeats that lead to 

rearrangements

Contiguous Gene 

Syndromes: 

Williams s. 

7q 

Miller-Dieker s. 

17p13.3 

blepharophimosis-ptosisvelocardiofacial/DiGeorgee 

s 22q11.2 

epicanthus inversus s.(BPES) 

3q22.3q23 

DMD/chronic granulomato 

ous d/glycerol gy kinase def’y/RP 

Xp21 

Prader-Willi/Angelman s 15q 

Beckwith-Wiedemann s 11p15.5

Blepharophimosis-Ptosis-Epicanthus 

Inversus s.

Miller-Dieker syndrome:

Smith-Magenis syndrome:

Smith-Magenis s. 

• Smith et al., 1983 

Am J Med Genet 24:421-32 

• 9 unrelated patients 

with characteristic facial 

appearance, short 

fingers, self-destructive 

behaviors, and developmental delay 

• growth deficiency and congenital anomalies 

• interstitial deletion of 17p11.2-12

Duplication 17(p11.2p11.2) Potocki- 

Lupski Syndrome.

A 

ngelman Syndrome 

Frequency ~1/15,000 

Severe mental handicap 

Ataxia 

Seizures 

Happy appearance 

Inap 

ppropriate outbursts of laughter

Imprinting Syndrom 

mes: 

• disorders caused by abs 

ence of genetic material from 

one of the parents in areas of the genome that require 

biparental contribution 

• may be caused by chromosomal (duplications, 

deletions) or molecular abnormalities (imprinting centre 

mutations) 

characteristic clinical phenotype 

Algelman s., Prade-W 

Willi s., Beckwith-Wiedemann s. 

• chromosomal abnormality may be visible with routine 

cytogenetic methods

Prader-Willi Syndrome 


Hyperphagia and obesity 

beginning in childhoodd 

FTT without special feeding effort 

Small hands and feet 

Hypotonia in newborn period 

Almond shaped eyes 

Mild to modrate devlopmental 

delay

PWS and AS 

• Distinct from each other - not opposites 

• Involve imprinted genes in 

not the same genes - they 

the same chromosomal region but 

are not allelic 

• Caused by deficiencies in distinct genes which happen to be 

close to each other in a chromosome region which tends to get 

deleted d as a chunk

Early Investigationss 

Chromosome deletions in the region of 15q11-13 in a certain 

proportion of patients with either PWS or AS 

How can you have one single chromosome error giving you 

two distinct disorders? 

PWS - deletion was always on the paternally contributed copy 

of chromosome 15 

Angelman - deletion always 

copy of chromosome 15 

on the maternally contributed

Beckwith-Wiedemann Syndrome 


Pre- and postnatal overgrowth 

Visceromegaly 

Macroglossia 

Ear abnormalities 

Hemiyperplasia 

Increased risk of childhood 

tumours (7-21%)

Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome: 

Molecular Mechanisms 

An imprinted cluster of gene 

es at 11p15. 

Two domains of imprinted genes; two imprinting centers 

include; at least 12 imprinted genes. 

Changes in the methylation 

of the genetic centers are 

epigenetic because they do 

not involve a change in the 

nucleotide sequence. 

Parent of origin changes ca 

an be brought about by 

microscopic chromosomal rearrangements.

Effect of Chromoso ome Imbalance in Human

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