Practical 7

Numerical chromosomal abnormalities –

conclusion

Nondisjunction of sex chromosomes during spermatogenesis – 1st meiotic

division

XY

XY

XY XY

XXY XXY X X+X

nondisjunction

fertilization

Nondisjunction of sex chromosomes during spermatogenesis – 2nd meiotic

division – X chromosome

XY

YX

XX Y Y

XXX X XY XY+X

nondisjunction

fertilization

Nondisjunction of sex chromosomes during spermatogenesis – 2nd meiotic

division – Y chromosome

XY

YX

X X YY

XX XX XYY X+X

nondisjunction

fertilization

Barr body

• = sex-chromatin

• Inactivated X chromosome

• Female XX

– 1 Barr body

• Male XY

– no Barr hody

• Klinefelter syndrome XXY

– 1 Barr body

Murray L. Barr

Task 1: Describe following karyotype according to ISCN1995. How much Barr bodies are present in

somatic cells of this individual?

• 49,XXXXY

• Rare form of

Klinefelter

syndrome

• 3 Barr bodies

Number of Barr bodies = X chromosome number – 1

Practical 7

Structural chromosomal abnormalities

Task 2: The photo 1 shows multiple structural abnormalities after irradiation of an individual with

high dosage of X-rays. Describe structural chromosomal aberrations on the photo.

gap

breakage

triradial

quadriradial

chromatid breakage

chromosomal (double-chromatid) breakage

Photo 1

Origin of structural chromosomal abnormalities

• Incorrect repair of chromosomal

breakages – mainly interchromosomal

rearrangements

• Non-reciprocal crossing-over during

meiosis I. – intrachromosomal

rearrangements – microdeletion

syndromes, X;Y translocation

Task 3

• A boy (see photo) with severe mental retardation had been cytogenetically examined – see karyotype.

• Describe corresponding chromosomal abnormality and determine the cytogenetic finding.

Karyotype 3

Terminal deletion of short arms of the chromosome 5

46,XY,del(5)(p15.2)

Simplified finding: 46,XY,del(5p)

Cat cry syndrome Cri du chat syndrome

• A disorder caused by the loss of part of the short (p) arm from chromosome 5. Also called the cri du chat (or cri-du-chat) syndrome.

• incidence varies between 1 in 20,000 to 1 in 50,000 births. • The frequency of the syndrome among profoundly retarded patients

(with an IQ less than 20) is approximately 1 in 100.

• severe developmental and mental retardation (IQ below 20)

• characteristic constellation of congenital malformations:– microcephaly (small head)

– round face

– hypertelorism (wide-spread eyes)

– micrognathia (small chin)

– epicanthal folds (inner eye folds)

– low-set ears

– hypotonia (poor muscle tone)

– some patients survive into adulthood

Task 4• A child with the Down

syndrome had been cytogenetically examined. The mother and the father are healthy.

• Describe the chromosomal abnormality in the child and put down the cytogenetic finding.

• Calculate the risk for further offspring of the mother.

Photo – karyotype 4

Robertsonic translocation of chromosomes 14 and 21

Down syndrome – translocation form

der(14;21)

Robertsonic translocation

= robertsonic fusion

= centric fusion

Translocation of two acrocentric chromosomes, centromeric fusion.

derivative chromosome

46,XY,der(14;21)(q10;q10),+21older description: 46,XY,t(14;21)

For calculation of the risk for further offspring karyotyping of

parents is necessary.

Karyotype of the mother

balanced robertsonic translocation of chromosomes 14 and 21

Photo – karyotype 5

45,XX,der(14;21)(q10;q10)older description: 45,XX,t(14;21)

The mother is carrier of balanced robertsonic translocation of

chromosomes 14 and 21. She is healthy but her offspring has increased risk of the Down

syndrome.

Risk for further offspring

Normal karyotype

Carrier M. Down Trisomy 14

Monosomy 21

Monosomy 14

Lethal during prenatal development

Theoretical risk 1/3 … 33%

Empiric risk 8 – 10%

Chromosomal constitution of mother carrier:

Task 5Photo 6 – karyotype of the child

• A child with the Down syndrome had been cytogenetically examined. The mother and the father are healthy.

• Describe the chromosomal abnormality in the child and put down the cytogenetic finding.

• Calculate the risk for further offspring of the mother.

Robersonic translocation of two 21 chromosomes

Translocation form of the Down syndrome

der(21;21)

46,XY,der(21;21)(q10;q10),+21

older description: 46,XY,t(21;21)

der(21;21)

Karyotype of the mother

balanced robertsonic translocation of two 21 chromosomes

Photo (karyotype) 7

der(21;21)

45,XX,der(21;21)(q10;q10)older description: 45,XX,t(21;21)

der(21;21)

Risk for further offspring

+21fertilization

der(21;21) nulisomic gamete

der(21;21)

m. Downmonosomy 21 – lethal during early prenatal development

Risk: 100%

Task 6A girl with a Turner syndrome features had been

examined in the genetic counselling clinic. Describe her karyotype and determine the

chromosomal finding.

Isochromosome of long arm of chromosome X46,X,i(X)(q10)

older description: 46,X,iso(Xq)

Origin of isochromosomes

i(Xp)

i(Xq)

Normal separation in anaphase Abnormal division – origin

of isochromosomes Xp and Xq

Chromosomal abnormalities in Turner syndrome:

• Numerical aberrations:

– X monosomy : 45,X

– X monosomy in mosaic: 45,X/46,XX

• Structural aberrations:

– Isochromosome Xq, isochromosome Xp

– Deletion forms: „46,X,del(Xp)“, „46,Xdel(Xq)“

– Ring chromosomes: 46,X,r(X)

Origin of ring chromosome

reparationdeletion of terminal

segments

ring chromosome

r(X)

Task 7

• A boy (see photo) with mental retardation, long narrow face, large ears, a high arched palate, flat feet and overly flexible joints (especially the fingers) had been cytogenetically examined. The karyotype contained abnormality on chromosome X – see partial karyotype.

• Describe X-chromosomal abnormality and determine the cytogenetic finding.

Photo 2 – partial karyotype of chromosome X

Fragile site on band Xq27.3• 46,Y,fra(Xq27.3)

• Gene responsible for fragile X syndrome is called FMR1

(fragile X mental retardation 1).

• The gene appears in three forms that are defined by the

number of repeats of a pattern of DNA called CGG

repeats:

– Individuals with less than 60 CGG repeats have a normal

gene.

– Individuals with 60 – 200 CGG repeats have a premutation

(they carry an unstable mutation which can expand in

future generations).

– Individuals with over 200 repeats have a full mutation

which causes fragile X syndrome. The full mutation causes

the gene to shut down or methylate a region of the FMR-1

gene.

• Normally, the FMR-1 gene produces an important

protein called FMRP. When the gene is turned off, the

individual does not make fragile X mental retardation

protein (FMRP).  The lack of this specific protein causes

fragile X syndrome.

Fragile X syndrome• the most common inherited cause

of mental impairment.

• The syndrome occurs in approximately 1 in 3600 males.

• the most common cause of inherited mental impairment. This impairment can range from learning disabilities to more severe cognitive or intellectual disabilities.

• the most common known cause of autism or "autistic-like" behaviors.

See you at the end of the summer term!