Chromosomal Errors Engl

8/7/2019 Chromosomal Errors Engl

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Types

Mechanisms of production Consequences

Diagnostic

Prophylaxis

Chromosomal errorsChromosomal errors


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Variability

Phenotypic

Genotypic

Combinative

Mutational

Adaptive modifications in limits of

norm of reaction

Ontogenetic modifications

Spontaneous anomalies under

environmental conditions

Phenocopies

Genomic recombination

Inter-chromosomal recombination

Intra-chromosomal recombination

Genomic mutations

Chromosomal mutations

Gene mutations


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ChromosomalChromosomalabnormalitiesabnormalities

Numeric

Structural

Polyploidy

Aneuploidy

Tetraploidy (4n)

Triploidy (3n)

Monosomy (45,X)

Trisomy (47,XXY, 47,XX, 21..)

Equilibrated

Non-equilibrated

Inversion (inv)

Translocation (t)

Robertsons translocation (rob)

Deletion (del)

Duplication (dup)

Isochromosome (i, iso)

Ring chromosome (r)


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Chromosomal abnormalitiesChromosomal 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)


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NonNon--equilibrated constitutionalequilibrated constitutionalchromosomal disorders (chromosomal disorders (00,,44%% nbnb 11::250250nb)nb)

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


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Mental and physicretardation

Microophthalmy

Deafness

Transverse crease, singleflexion crease

Heart disorders

Polycystic kidney

Abnormal nuclearsegmentation in leucocytes

Skull deffects

>

Microcephaly

Cleft leap

Polydactily

Double uterus

47,XX (XY), +13

Double ureters


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Mental and physicretardation

>>

Short neck

Transverse crease

Abnormal kidneys

Muscular hypertony

Abnormal ears

Flexion abnormalities

Heart abnormalities

47,XX (XY), +18

Intestine abnormalities

Multiple abnormalities ofgenitals


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Transverse crease,

single flexion crease


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Equilibrated chromosomal abnormalitiesEquilibrated chromosomal abnormalities((00,,4343%% -- 11::232232nb)nb)

May be:

Reciprocal translocations;

Robertsons translocations;

Inversions;

Rearrangements in chromosomal structure;

The phenotype may be normal or abnormal, depending oninvolved genes; s abnormal gametes;

Induce reproduction disorders: terility;

Spontaneous miscarries (abortions);

Dead newborns;

Newborns with malformations.


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An abnormal chromosome 22 (Philadelphia chromosome)

Found in the malignant cells ~ 90% of patients with chronicmyeloid leukemia (CML).

It is the product of a balanced reciprocal translocation involvingchromosomes 9 and 22 t(9;22) (q34;q11)

A proto-oncogene is activated


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PolyploidyPolyploidy

Errors in meiosis non-separation of IInd cytes

Errors during fertilization

Diginy (2n + 1n) Dispermy (1n + 1n + 1n)

Diandry (1n + 2n)

Endo-mitosis


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AneuploidyAneuploidy

Gametogenesis

Chromosomal non-disjunction during AI or AII Anaphase lag during AI or AII

Errors during:

First zygotic divisions

Chromatidian non-disjunction Anaphase lag


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NonNon--disjunction during meiosisdisjunction during meiosis

Maternal 92% oftrisomies 21

Paternal 70% 45,X or47,XXY

Causes ??? Environmental factors havea minimalrole !!!

Mothersage partial !!!


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Structural chromosomal aberrationsStructural 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.


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Deletion (del)Deletion (del)

Terminal Interstitial


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InversionInversion (inv)(inv)

Paracentric Pericentric


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Translocations (t)Translocations (t)

Reciprocal With insertion Robertsonian

(rob)


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Other chromosomalOther chromosomal

aberrationsaberrations

Unequal crossing over duplication (dup)

Ring chromosome(r)

Isochromosome(i, iso)


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The consequences of robertsonian

translocation t(13q21q)


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Down syndromeDown syndrome

TrisomyTrisomy 2121

Frequencyp 1:700 nb;

Symptomsp characteristic phenotype

Muscular hypotony

Cranial and facial disorders

Transversal crease

Visceral malformations Mental and physical retardation (IQ: 20 85)


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Down syndromeDown syndrome

TrisomyTrisomy 2121


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Cytogenetic analysis in DownCytogenetic analysis in Down

syndromesyndrome Free, homogenous trisomy (92-95%); Free trisomy 21 in mosaic (47/46) (2-3%); trisomy 21 trough Robertsons translocation:

Between 21

st

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 isrequired


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Identification of number ofchromosomes 21 using FISH

46,XX 47,XX,+21

Karyotype of G-bandedchromosome from a female

Down syndrome


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PossiblePossible karyotypeskaryotypes in Downin Down

syndromesyndrome

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


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Genes involved in production of Down

syndrome

Down syndrome is produced in trisomy 21

Down syndrome is produced in trisomy ofregion 21q22 (DSCR Down Syndrome CriticalRegion), which contains important genes

DSCAM - axonsgrowth

CRYA1 - alphaprotein from crystallinelens

ETS2 - oncogeneets-2 (leukemia),

APP - betaamyloidalprecursorprotein(Alzheimerdisease).

SOD1 - responsible for folicacid metabolism


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Sex chromosomes syndromesSex 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,

A

bnormality in gonads (primary amenorrhea;azoospermy)

Sterility (infertility).


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Turner syndromeTurner syndrome

Abnormal gonadsnmonosomy 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.


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Symptoms in Turner syndromeSymptoms 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 secondarysexual characters.


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Cytogenetic analysis in TurnerCytogenetic analysis in Turner

syndromesyndrome

Barr body test

Karyotyping

Homogenous monosomy X (50-60%)n paternalND (70%);

Mosaics 45,X/46,XX (25%);

Structural anomalies of X: isochromosomes,deletions, ring chromosmes.


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KlinefelterKlinefelter syndrome (syndrome (4747,XXY),XXY)

Frequency " 1 : 1000 in male nb (up to1/600)

Clinical diagnostic is possible only atpuberty.

Difficulties in diagnostics.

Normal penis, normal sexual functions. Minimal testicular development (less than

3 cm x 1.5 cm), no sperm cells.


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KlinefelterKlinefelter syndrome (syndrome (4747,XXY),XXY)

Absence ofspermatogenesis primarysterility; Absence oftestosteronep weakdevelopedsecondary

sexualtraits. In 30% individualsshow somedegree ofgynecomastia

IQupto normal

Cytogeneticanalysis:positive Barrbodytest 47,XXY (85%), Mosaics 46,XY/47,XXY orpolysomies XY (48, XXXY,

49,XXXXY) 13%; Thephenotypelooksalotlike man XX.


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Prader-Willy syndrome Angelman syndrome

46,XX, 15q-46,XY, 15q-


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Identification ofchromosomal aberrationusing FISH on metaphase

chromosome

Identification of

chromosomalaberration using

SKY


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Indications forIndications for karyotypingkaryotyping

(1) Children with multiple congenitaldisorders;

(2) Mental and physical retardation;

(3) If in (1),(2) a non-equilibrated

chromosomal disorder is established, isnecessary to make a karyotype of:

parents;

Ist degree relatives

(4) Inter-sexual statements;

(5) Abnormalities at puberty

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Chromosomal Errors Engl