Genetics Ch. 6 Clinical Cytogenesis: The Chromosomal Basis of Human Disease
Cytogenetics – study of chromosomes and their abnormalities
Chromosome abnormalities – responsible for a significant fraction of genetic
diseases (1 of every 150 live births); leading cause of mental retardation and
pregnancy loss
Karyotype (karyogram) – ordered display of chromosomes according to length
Normal female karyotype: 46, XX
Normal male karyotype: 46, XY
Chromosomes classified by size and position of centromere
- Metacentric – centromere occurs near midline of chromosome
- Acrocentric – centromere near the tip
- Submetacentric – centromere between the middle and the tip
Telomere – tip of each chromosome
p – short arm of each chromosome (petite)
q – long arm of each chromosome
Chromosome banding – helps greatly in detection of deletions, duplications,
structural abnormalities, helps to identify individual chromosomes
- Includes quinacrine, Geimsa, reverse, C and NOR banding
Fluorescence in situ Hybridization (FISH) – labeled probe is hybridized to
metaphase, prophase, or interphase chromosomes
- Can be used to test for missing/additional chromosome material and
chromosome rearrangements
- Probe undergoes complementary base pairing only with the
complementary base DNA sequence at a specific location on one of
denatured chromosomes
- Normal Patient: probe hybridizes in 2 places, reflecting the presence of
2 homologous chromosomes in somatic cell nucleus
- Not Normal Patient: hybridizes to only one of the patients
chromosomes  indicates deletion on copy of chromosome to which
probe fails to hybridize
Comparative Genomic Hybridization (CGH) – differentially labeled DNA from
test and control sources is hybridized to normal metaphase chromosomes or
probes in microarrays, allows the detection of chromosome duplications and
deletions, but not balanced rearrangements.
- Array CGH  can detect deletions/duplications shorter than 100kb and
requires only small amounts of DNA
Abnormalities of Chromosome Number
 Polyploidy
o Presence of a complete set of extra chromosomes in a cell
o Polyploidy conditions that have been observed in humans:
 Triploidy (69 chromosomes in nucleus of each cell)
 Estimated 15% chromosome abnormalities
 Common causes: fertilization of an egg by 2
sperm (dispermy), or meiotic failure (diploid
sperm or egg is produced)
 Tetraploidy (92 chromosomes in each cell nucleus)
 Much rarer
 Common causes: mitotic failure (all of the
duplicated chromosomes migrate to one of the 2
daughter cells), or from fusion of 2 diploid zygotes
 Because the number of chromosomes present in each of
these conditions is a multiple of 23, the cells are euploid
(Greek – “good set”), however surplus gene product
causes multiple anomolies such as defects of heart and
CNS

Autosomal Aneuploidy
o Cells that contain additional or missing individual chromosomes
(not a multiple of 23)
o Usually only one chromosome is affected
o Common cause: nondisjunction (failure of chromosomes to
disjoin normally during meiosis)
o Most clinically important of chromosome abnormalities
o Monosomy – only one copy of a chromosome in an otherwise
diploid cell
o Trisomy – three copies of a chromosome; produce less severe
consequences than monosomies – proves the body can tolerate
excess genetic material more readily than it can tolerate a deficit
of genetic material
 Trisomy 21
 Karyotype: 47, XY, +21 or 47, XX, +21
 Low nasal root, palpebral fissures, small
overfolded ears, flattened maxillary region, short
neck, broad/short hands, deep flexion crease
across palms (“Simian crease”), decreased
muscle tone
 Increased frequency of medical problems:
obstruction of duodenum or atresia, respiratory
infections, structural heart defects, mental
retardation
 95% cases caused by nondisjunction
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Extra chromosome donated by mother in 90-95%
cases
Mosaicism – seen in 2-4% (have some normal
somatic cells, some trisomy 21 cell), milder clinical
expression of the phenotype
There is a maternal age effect (risk increases to 1/400 at age 35,
1/100 at age 40, 1/25 at age 45); mother contributes the extra
chromosome in 90% of cases

Trisomy 18
 Karyotype: 47, XY, +18, also known as Edwards
syndrome
 Second most common autosomal trisomy
 Small ears, small mouth, short sternum, short
halluces, congential heart defects, diaphragmatic
hernia, radial aplasia
 95% have complete trisomy 18, only a small
percentage have mosaicism
 90% of cases result of extra chromosome of
mother

Trisomy 13
 Karyotype: 47, XY, +13, also termed Patau
syndrome
 Oral-facial clefts, microphthalmia (small
abnormally formed eyes), malformations of CNS,
significant mental retardation
 80% have full trisomy 13
 Most are spontaneously lost during pregnancy
Sex Chromosome Aneuploidy
o Primarily due to X inactivation
o Less severe than those of autosomal aneuploidy
 Monosomy of X Chromosome (Turner Syndrome)
 Karyotype: (50%) 45, X, (30-40%) mosaicism 45,
X / 46, XX, and less commonly 45, X / 46, XY
 Short stature, sexual infantilism, triangle shaped
face, posteriorly rotated ears, broad “webbed”
neck, congenital heart defects, structural kidney
defects, most lack ovaries and do not develop
secondary sexual characteristics
 60-80% derived from absence of paternally
derived sex chromosome
 Specific gene involved: SHOX gene

Klinefelter Syndrome
 Karyotype: 47, XXY
 Patients are taller than average, disproportionately
long arms and legs, small testes, low testosterone
levels, gynecomastia, sparse body hair,
predisposition for learning disabilities
 Extra X chromosome derived maternally in about
50% of Klinefelter cases, increases in advanced
maternal age, mosaicism seen in 15% cases
 Degree of mental deficiency / physical abnormality
increases with each additional X chromosome

Trisomy X
 Karyotype: 47, XXX
 Females suffer from sterility, menstrual irregularity,
mild mental retardation
 90% cases due to nondisjunction in mother,
incidence increases in older mothers

47, XYY Syndrome
 Karyotype: 47, XYY
 Males tend to be taller than average, reduced IQ,
redisposition to violent criminal behavior
Chromosome Abnormalities and Pregnancy Lost
- 1/3 of pregnancies lost after implantation
- Chromosome abnormalites leading cause of pregnancy loss
- 50% chromosome abnormalities = trisomies; 20% = monosomies, 15%
= triploids; remainder tetraploids / structural abnormalities
Abnormalities of Chromosome Structure
- Unbalanced  rearrangement causes a gain or loss of chromosome
material
- Balanced  rearrangement does not produce a loss or gain of
chromosome material
-
Translocations – interchange of genetic material between
nonhomologous chromosomes, 2 basic types:
o Reciprocal translocations – caused by 2 breaks on different
chromosomes, subsequent exchange of material
o Robertsonian translocations – occur when the long arms of 2
acrocentric chromosomes fuse at the centromere; carrier can
produce conceptions with monosomy or trisomy of the long
arms of acrocentric chromosomes
 Common example – chromosomes 14 and 21
-
Deletions – caused by a chromosome break, subsequent loss of
genetic material
o Example: Cri-du-chat syndrome – deletion of distal short arm of
chromosome 5
o Example: Wolf-Hirschhorn syndrome – deletion of distal short
arm of chromosome 4
-
Microdeletion Syndromes
o Example: Prader-Willi syndrome  due to imprinting,
inheritance of a microdeletion of the paternal chromosome 15
material produces Prader-Willi syndrome; microdeletion of the
maternally derived chromosome 15 produces Angelman’s
syndrome
-
Subtelomeric Rearrangements – involve deletions or duplication of
DNA in the gene-rich regions near telomeres
-
Uniparental Disomy – a condition in which one parent has contributed
2 copies of a chromosome, and the other parent has contributed no
copies
-
Duplications – arise from unequal crossover, or they can occur
among the offspring of reciprocal translocation carriers; produce less
serious consequences than do deletions of the same region
-
Ring chromosomes – when deletions occur at both tips of a
chromosome, chromosome ends can then fuse, form a ring
-
Inversions – result of 2 breaks on a chromosome followed by
reinsertion of the intervening fragment at its original site, but in inverted
order
-
Isochromosomes – chromosome that has 2 copies of one arm but no
copies of the other
Chromosome abnormalities and Clinical Phenotypes
 Most chromosome abnormalities are associated with developmental
delay in children and mental retardation in older persons  reflects
large number of genes involved in CNS development
 Most chromosome syndromes involve alterations of facial
morophogenesis  patient resembles other patients with same
disorder
 Growth delay seen in autosomal syndromes
 Congenital malformations occur with increased frequency in most
autosomal chromosome disorders
Cancer Cytogenetics
- Chronic Myelogenous Leukemia (CML) – caused by reciprocal
translocation between chromosome 22 and the long arm of
chromosome 9 (Philadelphia chromsome)
o Proto-oncogene ABL moved from normal position on 9q to 22q
o Alters ABL gene product, causes increased tyrosine kinase
activity  leads to malignancy in hematopoietic cells
- Burkitt Lymphoma – reciprocal translocation involving chromosomes
8 and 14, moves the MYC proto-oncogene from 8q24 to 14q32
Clinical Commentaries
1. Health Supervision in Children with Down Syndrome
a. Most common congenital heart defect: AV canals, surgical
correction appropriate before 1 year
b. Strabismus = deviation of eye from normal visual axis and other
eye problems  should be examined by physician regularly
c. Hypothyroidism is common  thyroid levels measured regularly
d. Sensorineural and conductive hearning loss  routine hearing tests
e. Instability of 1st and 2nd vertebrae  can lead to spinal cord injuries
f. Referral to preschool programs to provide intervention for
developmental disabilities
2. Genetic Basis of Sex Determination
a. SRY = sex determining region on the Y
b. By bending DNA, protein is thought to promote DNA-DNA
interactions; this trigger events leaving to male differentiation; also
protein of SRY acts antagonistically with DAX1 (which represses
differentiation into male)
c. In absence of SRY, DAX1 continues to repress these genes,
female embryo is created
3. DiGeorge Sequence, Velocardiofacial Syndrome, and Microdeletions of
Chromosome 22
- DiGeorge sequence – characterized by structural or functional
defects of thymus, conotruncal heart defects, hypoparathyroidism,
and secondary hypocalcemia
- Children with this sequence were found to have deletion of long
arm of chromosome 22
- Velocardiofacial Syndrome (VCF) – palatal abnormalities,
characteristic facial appearance, heart malformations, learning
disabilites
- Some persons with VCF have all features of DiGeorge sequence
- Suggests the two are related, caused by abnormalities on
chromosome 22