Cytogenetics I

Numerical chromosomal abnormalitiesRNDr Z.Polívková

Lecture No 430 – course: Heredity

Frequencies of chromosomal abnormalities (CHA)

30 % of all spontaneous abortion (SA) > 50% of early abortions 0.6% liveborn babies 5% of all recognised pregnancies

Estimate: > 50% of all human zygotes with CHA

Most of them are lost before recognition of pregnancy

Occurence of CHA in:

stillbirth, neonathal death mentally retarded congenital malformations with/without

mental retardation disorders of sexual development dysfertile couples (with spontaneous abortions,

sterility…)

infertile males

Review of chromosomal abnormalities

congenital

acquired

numerical

aneuploidy

polyploidy

trisomy 2n+1

monosomy 2n-1

triploidy 3n

tetraploidy 4n

structuralbalanced

unbalanced

Robertsonian translocationreciprocal translocation inversioninsertion

deletionduplicationring chromosomedicentric chromosomeisochromosome

mosaic = 2 or more cell lines

origin from 1 zygote

chimaera = karyotype 46,XX/46,XY

2 cell lines - origin from 2 zygotes

Acquired CHA : chromatid and chromosome breaks, chromatid exchanges, chromosome exchanges: dicetrics, rings, translocations

caused by mutagens – clastogens

- mutagenesis - genotoxicology

23

23

23

69

46 23

69

23 46

69

+

+

+

Dispermy

Diploid ovum + haploid sperm

Haploid ovum + diploid sperm

Partial mole (hyperplasia of trophoblast, reduced embryonal tissues)

Partial mole

Origin of triploidy

nonmolar product (small placenta)

Triploidy – lethal genetic constitution

46

92

Origin of tetraploidy

endoreduplication in mitotic division of zygote

Tetraploidy = lethal genetic constitution

23,X

23,X

46,XX 46,XY

23,Y

23,X

Origin of chimaera

+

ovum

polar body

Fertilization of egg and polar body each by sperm with different gonosome

Human partenogenesis

ovarial teratoma = duplication of chromosomes and division of unfertilized ovum (diploid)

Hydatiforme mole (complete = without embryonal tissues) = dispermy or duplication of sperm in enucleated ovum

Nondisjunction in meiosis

= failure of homologs (in M I) or sister chromatids (in M II) to disjoin to daughter cells

Consequence: disomic, nullisomic gametes -trisomy, monosomy after fertilization

Nondisjunction in mitosis= failure of chromatids to disjoin to daughter cells

Consequence: mosaics

Meiotic nondisjunction

+ +

trisomic zygote 47,XXorXY,+21

MI

MII

in II.meiotic division in I.meiotic division

nullisomic gamete disomic gamete

23,X 23,Y

46,XY

46,XY46,XY

47,XY,+21

45,XY -21

46,XY46,XY

47,XY,+21

46,XY46,XY46,XY46,XY 47,XY,+21

Mitotic nondisjunction – origin of mosaic

mosaic - 2 or more cell lines with different karyotypes– origin from 1 zygote

normal zygote

trisomic cell line

47

47 47

2324

47 47 47

46 46 47 47 47 47 47 47

46

Origin of mosaic from trisomic zygote – by chromosomal loss during mitotic division

loss of chromosomeby anaphase lag

47,XXorXY,+21/46XXorXY

normal cell

trisomic zygote

normal cell line

46,XX

46,XX 45,X

46,XX 45,X 45,X46,XX

loss of X chromosome during mitotic division of normal zygote

Origin of monosomy X - postzygotic

45,X/46,XX

monosomic cell line

Numerical CHA – origin

Triploidy 3n – dispermy = fertilization of ovum by 2 sperms

- fusion of haploid and diploid gametes (nondisjunction of all chromosome in M I or MII)

Tetraploidy 4n – endoreduplication in mitotic division of zygote (= division of chromosomes without division of cell)

Trisomy 2n+1 – nondisjunction of homologs in M I or chromatids in M II

and fertilization of disomic gamete

Mosaic trisomy – nondisjunction in mitotic division of normal zygote or loss of chromosome from trisomic zygote

mosaic – 2 (or more)cell lines with different karyotypes – origin from one cell during mitotic division of zygote

Monosomy – nondisjunction and fertilization of nullisomic gamete

- loss of one chromosome (lagging in anaphase)

– in meiosis,in mitosis

Chimaera – 2 cell lines with different karyotypes – origin from 2 zygotes

fertilization of egg and polar body each by sperm with different gonosome

46,XX/46,XY

monosomy X = only X monosomy is compatible with life but 99% of X monosomies are aborted autosomal monosomies –lethal – very early abortion or

failure of implantation

autosomal trisomies = only some are compatible with life (+21, +18, +13, mos +8)

other autosomal trisomies are only in abortions (+16….)

Consequences of chromosomal abnormalities

nondisjunction: in oogenesis > in spermatogenesis

liveborn +21 - 80% mat : 20 pat

in M I > in M II

+21 mat - 80% in M I : 20 in M II

Parental origin of nondisjunction –detected by tracing of variants on acrocentrics or by molecular genetics methods

Nondisjunction - most frequently maternal

and in the 1st meiOtic division

Causes of nondisjunction

Internal – individual risk of chromosomes to nondisjunction

main factor = age of mother > 35 let - age of father > 50 let

External – environmental factors –chemicals, radiation

are not main factors of nondisjunction

Maternal age :

Error in M I : agging of ovum

failure in function of mitotic spindle

changes in intracellular condition caused

by hormonal insufficiency

accumulation of mutagenic events during life

Error in M II: delayed fertilization –

overripness of ovulated egg

agging of sperms

(low frequent sexual intercourses in older couples)

M.Down (DS)- trisomy 21Frequeny in liveborn: 1/800

3/4 of DS are aborted

95% of DS = 47,XX or XY, +21= free trisomy

5% of DS = translocation form of trisomy

t(14/21, 13/21, 21/22, 21/21)

in 1/2 of cases with translocation form of trisomy -1 parent = carrier of balanced Robertsonian translocation !!!

empiric risk for carriers of balanced nonhomologous Robertsonian translocation = 15% for women carriers

< 2% for men carriers

Risk for carriers of balanced homologous Robertsonian translocation

21/21 = 100%

1% of DS – mosaic form of trisomy

Risk of trisomy 21 and maternal age

Mother´s age risk +21 35 1/350 37 1/225 40 1/100 45 1/25

Reccurence risk (after previous pregnancy with free trisomy 21) 1% ??

47,XX,+21 – free trisomy 21

46,XX,der(14;21)(q10;q10),+21 translocation form of trisomy

45,XX,der(14;21)(q10;q10) - balanced Robertsonian translocation

Phenotype of DS

dysmorphic features of the face:

round face

flat nasal bridge

mongoloid slant of palpebral fissures big tongue short fingers, clinodactyly simian creases on hands short stature organ malformations mental retardation

Down syndrome

Simian crease in DS

Downův syndrome

Edwards syndrome (ES) - trisomy 18

frequency: 1/5000 of liveborn

karyotype: 47,XX or XY,+18

Clinical signs:• dysmorphic features of face• low set malformed ears• prominent occiput• short sternum• abnormal overlapping of fingers• severe malformations of heart or other organs• severe retardation of development

47,XX +18

Edwards syndrome

Overlapping of fingers in ES

Patau syndrome

frequency: 1/10000 of liveborn karyotype: 47,XX or XY,+13 20% translocation form - t 13/13, t 13/14

Clinical signs: - dysmorfic features (hypertelorismus, microphthalmia)

- microcephaly

- polydactyly- cleft lip and palate- severe organ malformations (heart defect, malf.CNS)- severe retardation of development

47,XX +13

Patau syndrome (PS)

Polydactyly in PS

Turner syndrome

Frequency: 1/5000 liveborn girls

99% of monosomy X - abortions karyotypes: 45,X 53% 45,X/46,XX 15% 46,X,i(Xq) 10% 45,X/46,X,i(Xq) 8% 46,XXq- nebo p- 6% others (with Y chrom., dic X...) 8%

45,X - in 77% of monosomies X - paternal gonosome is lost (X or Y)

45,X

Clinical signs of TS small stature sterility (degeneration of gonads) - except i(Xq), Xp- underdevelopment of secondary sexual characteristics amenorrhea neck webbing, low hair line (posterior) mostly normal inteligency

in newborns often edema on foot dorsum !!!

(lymphedema in fetal life – cystic hygroma) Xp- phenotype of TS, but fertility

Xq- gonadal dysgenesis

Karyotype with Y chromosome = risk of malignity of gonade

Turner syndrome (TS)

Klinefelter syndrome

frequency: 1/1000 liveborn boys

karyotypes: 47,XXY 46,XY/47,XXY 48,XXYYor 48,XXXY 49,XXXXY – phenotype similar to DS

but patients are tall 1/3 of cases-nondisjunction in paternal M I 47% nondisjunction in maternal M I –

efect of mother´s age 22% nondisjunction in maternal M II

Clinical signs in KS

sterility hypogonadism – atrophy of testes gynecomastia – secondary sexual characteristics of female

type (is not constant feature) tall stature inteligence may be slightly reduced or normal

47,XXY

Klinefelter syndrome

Syndrome 47,XXX frequency: 1/1000 of women

phenotype normal, only in some patients psychiatric problems

fertile – mostly chromosomally normal progeny

Syndrome 47,XYYfrequency : 1/1000 of men

phenotype normal, tall stature

supposed connection with agresivity was not proved

47,XXX

47,XYY

http://dl1.cuni.cz/course/view.php?id=324 presentation

http://dl1.cuni.cz/course/view.php?id=324 supplementary text to cytogenetics

Thompson &Thompson: Genetics in medicine, 7th ed. Chapter 5: Principles of clinical cytogeneticsChapter 6: Clinical cytogenetics: Disorders of the autosomes and the sex chromosomes