Chromosomal errors

 Types
 Mechanisms of production
 Consequences
 Diagnostic
 Prophylaxis
 Adaptive modifications in limits of
norm of reaction
Ontogenetic modifications
Phenotypic
Spontaneous anomalies under
environmental conditions

Phenocopies
Variability
Genomic recombination
Combinative Inter-chromosomal recombination
Intra-chromosomal recombination
Genotypic
Genomic mutations
Mutational Chromosomal mutations
Gene mutations
 Tetraploidy (4n)
Polyploidy
Triploidy (3n)

Numeric
Monosomy (45,X)
Aneuploidy
Trisomy (47,XXY, 47,XX, 21..)

Chromosomal Inversion (inv)

abnormalities
Equilibrated Translocation (t)

Robertson’s translocation (rob)

Structural Deletion (del)

Non- Duplication (dup)

equilibrated
Isochromosome (i, iso)

Ring chromosome (r)

 Chromosomal abnormalities

• Constitutional (~0,83% nb; >8% pregnancies)

– Non-equilibrated (0,4%) – abnormal
phenotype:
– Equilibrated (0,43% nb) – normal phenotype
+ reproduction disorders;
• Acquired → cancers

!!! Non-equilibrated disorders – polyploidy, aneuploidy,

structural non-equilibrated aberrations (del, dup, i, r)
 Non-equilibrated constitutional
chromosomal disorders (0,4% nb – 1:250nb)
• May be :
– numeric / structural
– Full trisomy / partial (dup)
– Full monosomy / partial (del)
– homogenous / mosaic
• Represent dosage abnormalities
• Determine abnormal phenotypes:
– Growth retardation;
– Mental retardation;
– Sexual / reproduction disorders
• Changes are determined by:
– The length of chromosome / fragment
– Type of chromosomal disorder
– Affected chromosome
– Number of affected cells
 Mental and physic
retardation 47,XX (XY), +13
♀>♂
Microcephaly
Microophthalmy
Skull deffects
Deafness
Cleft leap
Transverse crease, single
flexion crease
Polydactily

Heart disorders

Polycystic kidney

Double uterus
Double ureters

Abnormal nuclear
segmentation in leucocytes
Mental and physic 47,XX (XY), +18
♀>> ♂
retardation

Short neck
Abnormal ears

Transverse crease
Flexion abnormalities

Heart abnormalities

Abnormal kidneys
Intestine abnormalities

Muscular hypertony Multiple abnormalities of

genitals
 Transverse crease,
single flexion crease
 Equilibrated chromosomal abnormalities
(0,43% - 1:232nb)

 May be:
– Reciprocal translocations;
– Robertson’s translocations;
– Inversions;
 Rearrangements in chromosomal structure;
 The phenotype may be normal or abnormal, depending on
involved genes;  abnormal gametes;
 Induce reproduction disorders:
– Sterility;
– Spontaneous miscarries (abortions);
– Dead newborns;
– Newborns with malformations.
 An abnormal chromosome 22 (Philadelphia chromosome)
 Found in the malignant cells ~ 90% of patients with chronic
myeloid leukemia (CML).
 It is the product of a balanced reciprocal translocation involving
chromosomes 9 and 22  t(9;22) (q34;q11)
 A proto-oncogene is activated
 Polyploidy

• Errors in meiosis – non-separation of IInd cytes

• Errors during fertilization
– Diginy (♀2n + ♂1n)
– Dispermy (♀1n + ♂1n + ♂1n)
– Diandry (♀1n + ♂2n)
– Endo-mitosis
 Aneuploidy

Errors during:
 Gametogenesis
– Chromosomal non-disjunction during AI or AII
– Anaphase lag during AI or AII

 First zygotic divisions

• Chromatidian non-disjunction
• Anaphase lag
 Non-disjunction during meiosis

• Maternal  92% of trisomies 21

• Paternal  70% 45,X or 47,XXY
• Causes ???
– Environmental factors have a minimal role !!!
– Mother’s age – partial !!!
Structural chromosomal aberrations

• Mechanisms:
– Physical, chemical or biological (viruses)
factors may induce errors during replication
 cleavage in both strands and abnormal
linkage;
– Presence of fragile sites in chromosomes;
– Unequal crossing-over.
 Deletion (del)

Terminal Interstitial
 Inversion (inv)

Paracentric Pericentric
 Translocations (t)

Reciprocal With insertion Robertsonian

(rob)
 Other chromosomal
aberrations

Unequal crossing over – Ring chromosome Isochromosome

duplication (dup) (r) (i, iso)
The consequences of robertsonian
translocation t(13q21q)
 Down syndrome
Trisomy 21
• Frequency  1:700 nb;
• Symptoms  characteristic phenotype
– Muscular hypotony
– Cranial and facial disorders
– Transversal crease
– Visceral malformations
– Mental and physical retardation (IQ: 20 – 85)
Down syndrome
Trisomy 21
 Cytogenetic analysis in Down
syndrome
• Free, homogenous trisomy (92-95%);
• Free trisomy 21 in mosaic (47/46) (2-3%);
• trisomy 21 trough Robertson’s translocation:
– Between 21st and other acrocentric chromosome
(4-5%);
– t(21q;14q), t(21q;22q) t(21q;21q);
• t(21q;Dq) are inherited in 50%, usually from mother;
• t(21q;Gq) usually are de novo.

!!! In these cases a karyotype of both parents is

required
 Identification of number of
chromosomes 21 using FISH

46,XX 47,XX,+21

Karyotype of G-banded
chromosome from a female
Down syndrome
 Possible karyotypes in Down
syndrome

• 47,XX,+21
• 47,XY,+21
• 46,XX / 47,XX,+21
• 46,XY / 47,XY,+21
• 46,XX,rob(21;21)
• 46,XY,rob(21;14)
• 46,XY, i (21q)
• etc
 Genes involved in production of Down
syndrome
• Down syndrome is produced in trisomy 21
• Down syndrome is produced in trisomy of
region 21q22 (DSCR – Down Syndrome Critical
Region), which contains important genes
– DSCAM - axons growth
– CRYA1 - alpha protein from crystalline lens
– ETS2 - oncogene ets-2 (leukemia),
– APP - beta amyloidal precursor protein
(Alzheimer disease).
– SOD1 - responsible for folic acid metabolism
Sex chromosomes’ syndromes

• Frequency:
– 1 : 400 nb males (47,XXY; 47,XYY)
– 1 : 650 nb females (45,X; 47,XXX)
• Less sever phenotypes:
– Puberty development retardation,
– Abnormality in gonads (primary amenorrhea;
azoospermy)
– Sterility (infertility).
 Turner syndrome

• Abnormal gonads  monosomy X, full or

partial; homogenous or in mosaic:
45,X; 46,XX/45,X; 46,X,i(Xp); 46,X,i(Xq);
46,X,Xp-; 46,X,Xq-; 46,X,rX...
• 2% of zygotes, 95% is lethal,
• 1/2500-1/3000 of female newborns.
 Symptoms in Turner syndrome
• 1/3 of diagnostics in neonatal period:
– Female child,
– Short stature,
– Short neck, pterygium coli.

• 1/3 of diagnostics at puberty:

– Growth retardation,
– Short neck, a broad back of the neck.

• 1/3 of diagnostics after puberty:

– Hypo-stature, primary amenorrhea, deficient secondary
sexual characters.
 Cytogenetic analysis in Turner
syndrome

• Barr body test

• Karyotyping

 Homogenous monosomy X (50-60%)  paternal

ND (70%);
 Mosaics 45,X/46,XX… (25%);
 Structural anomalies of X: isochromosomes,
deletions, ring chromosmes.
 Klinefelter syndrome (47,XXY)

• Frequency  1 : 1000 in male nb (up to

1/600)
• Clinical diagnostic is possible only at
puberty.
• Difficulties in diagnostics.
• Normal penis, normal sexual functions.
• Minimal testicular development (less than
3 cm x 1.5 cm), no sperm cells.
 Klinefelter syndrome (47,XXY)
 Absence of spermatogenesis – primary sterility;
 Absence of testosterone  weak developed secondary
sexual traits.
 In 30% individuals show some degree of gynecomastia
 IQ up to normal

 Cytogenetic analysis: positive Barr body test

 47,XXY (85%),
 Mosaics 46,XY/47,XXY or polysomies XY (48, XXXY,
49,XXXXY) – 13%;
 The phenotype looks a lot like „man XX”.
 46,XY, 15q- 46,XX, 15q-

Prader-Willy syndrome Angelman syndrome

 Identification of
chromosomal
aberration using
SKY

Identification of
chromosomal aberration
using FISH on metaphase
chromosome
 Indications for karyotyping
• (1) Children with multiple congenital
disorders;
• (2) Mental and physical retardation;
• (3) If in (1),(2) a non-equilibrated
chromosomal disorder is established, is
necessary to make a karyotype of:
– parents;
– Ist degree relatives
• (4) Inter-sexual statements;
• (5) Abnormalities at puberty