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ChromosomChromosomesesIIDr Pupak Derakhshandeh, PhD

Ass Prof Medical Science of Tehran University

Email: derakhshandeh@tums.ac.irWebsite: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984

(English)http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889 (Persian)

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What are chromosomes?What are chromosomes?

Chromosomes are the structures that hold Chromosomes are the structures that hold our our genesgenes Genes are the individual instructions that Genes are the individual instructions that tell our bodies how to tell our bodies how to developdevelop and and functionfunctionTheThey govern our physical and medical y govern our physical and medical characteristics, such as hair color, blood characteristics, such as hair color, blood type and susceptability to disease.type and susceptability to disease. Each chromosome has a p and q arm; p is Each chromosome has a p and q arm; p is the shorter arm and q is the longer arm.the shorter arm and q is the longer arm. The arms are separated by a pinched The arms are separated by a pinched region known as the region known as the centromerecentromere

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How many chromosomes do How many chromosomes do humans have?humans have?

The typical number of The typical number of chromosomes in a human cell is 46 chromosomes in a human cell is 46 - two pairs of 2- two pairs of 22 + XX/XY2 + XX/XY

HHolding an estimated 30,000 to olding an estimated 30,000 to 35,000 genes.35,000 genes.

One set of 23 chromosomes is One set of 23 chromosomes is inherited from the biological inherited from the biological mother (from the egg), and the mother (from the egg), and the other set is inherited from the other set is inherited from the biological father (from the sperm).biological father (from the sperm).

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study of the study of the chromosomeschromosomes

with a microscope with a microscope , then , then StainStainningning TThe chromosomes look like strings he chromosomes look like strings

with light and dark "bands" with light and dark "bands" A picture, or chromosome map, of A picture, or chromosome map, of

all 46 chromosomes is called a all 46 chromosomes is called a karyotypekaryotype

The karyotype The karyotype :: identify chromosome identify chromosome abnormalitiesabnormalities:: that are evident that are evident in in either the structure or the number of either the structure or the number of chromosomes.chromosomes.

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study of the study of the chromosomeschromosomes

The pairs have been numbered from 1 The pairs have been numbered from 1 to 22, with the 23rd pair labeled "X" to 22, with the 23rd pair labeled "X" and "Y." and "Y."

In addition, each chromosome arm is In addition, each chromosome arm is defined further by numbering the bands defined further by numbering the bands that appear after stainingthat appear after staining

TThe higher the number, the further that he higher the number, the further that area is from the centromere.area is from the centromere.

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Study of the Study of the chromosomeschromosomes

The first 22 pairs of chromosomes are The first 22 pairs of chromosomes are called "called "autosomesautosomes" "

FFinal pair is called the "inal pair is called the "sex chromosomessex chromosomes." ."

The sex chromosomes an individual has The sex chromosomes an individual has determines that person's gender; determines that person's gender; females have two X chromosomes (XX), females have two X chromosomes (XX), and males have an X and a Y and males have an X and a Y chromosome (XY)chromosome (XY)

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Karyotype Karyotype 4646)), Xy), Xy)

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How Chromosome How Chromosome Abnormalities Abnormalities

Happen?Happen?MeiosisMeiosis

MitosisMitosis

Maternal AgeMaternal Age

EnvironmentEnvironment

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MeiosisMeiosis

Chromosome abnormalities :Chromosome abnormalities : happen as a result of an error in happen as a result of an error in cell cell

divisiondivision. . ““Meiosis” Meiosis” :: the cell division that the egg the cell division that the egg

and sperm go through when they are and sperm go through when they are developing. developing.

Normally, meiosis causes a halving of Normally, meiosis causes a halving of chromosome material, so that each chromosome material, so that each parent gives 23 chromosomes to a parent gives 23 chromosomes to a pregnancypregnancy

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MeiosisMeiosis

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MeiosisMeiosis

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Chromosome Chromosome abnormalitiesabnormalities

AAbnormality of bnormality of chromosome number or chromosome number or structure:structure:

Numerical AbnormalitiesNumerical Abnormalities Structural AbnormalitiesStructural Abnormalities

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Numerical AbnormalitiesNumerical Abnormalities When an individual is missing either a When an individual is missing either a

chromosome from a pair (chromosome from a pair (monosomymonosomy) or ) or has more than two chromosomes of a pair has more than two chromosomes of a pair ((trisomytrisomy).).

An exampleAn example: : Down Syndrome, also known Down Syndrome, also known as Trisomy 21 (an individual with Down as Trisomy 21 (an individual with Down Syndrome has three copies of Syndrome has three copies of chromosome 21, rather than two).chromosome 21, rather than two).

Turner Syndrome is an example of Turner Syndrome is an example of monosomy the individual is born with only monosomy the individual is born with only one sex chromosome, an X.one sex chromosome, an X.

Kleinfelter Kleinfelter Syndrome is an example ofSyndrome is an example of tritrisomy the individual is born with somy the individual is born with threethree sex chromosome,sex chromosome, XXY XXY..

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Down Syndrome Down Syndrome ((Trisomy 21(Trisomy 21(

Trisomy 2(Trisomy 2(

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Down Down Syndrome Syndrome ((Trisomy Trisomy 21(21(

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Down syndrom) Down syndrom) Trisomy 21, Trisomy 21, 47)47)

critical region:critical region: A region on the long (q) arm of A region on the long (q) arm of

chromosome 21chromosome 21 Down syndrome causes mental Down syndrome causes mental

retardation, a characteristic facial retardation, a characteristic facial appearance, and multiple appearance, and multiple malformationsmalformations

AAssociated with a major risk for ssociated with a major risk for heart malformations a small but still heart malformations a small but still significant risk of acute leukemia . significant risk of acute leukemia .

3 copies of chromosome number 21 3 copies of chromosome number 21

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incidence of 1 in 660 and is by far the incidence of 1 in 660 and is by far the most common chromosomal most common chromosomal abnormalitabnormalityy

SSlight flattening of the facelight flattening of the face AA low bridge of the nose (lower than low bridge of the nose (lower than

the usually flat nasal bridge of the the usually flat nasal bridge of the normal newborn)normal newborn)

AAn epicanthal fold (a fold of skin over n epicanthal fold (a fold of skin over top of the inner corner of the eye, top of the inner corner of the eye, which can also be seen less which can also be seen less frequently in normal babies)frequently in normal babies)

A A ring of tiny harmlessring of tiny harmless white spots white spots around the irisaround the iris

mental retardationmental retardation

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Down SyndromeDown Syndrome: : Prenatal Prenatal RiskRisk

The risk of trisomy 21 is The risk of trisomy 21 is directly related to maternal directly related to maternal age age

Patients who will be 35 years Patients who will be 35 years or older on their due date or older on their due date should be offered chorionic should be offered chorionic villus sampling or second-villus sampling or second-trimester amniocentesis trimester amniocentesis

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Women younger than 35 years Women younger than 35 years should be offered maternal serum should be offered maternal serum screening at 16 to 18 weeks of screening at 16 to 18 weeks of gestation gestation

The maternal serum markers The maternal serum markers used to screen for trisomy 21 are used to screen for trisomy 21 are alpha-fetoprotein, unconjugated alpha-fetoprotein, unconjugated estriol and human chorionic estriol and human chorionic gonadotropingonadotropin

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The use of ultrasound to The use of ultrasound to estimate gestational age estimate gestational age improves the sensitivity and improves the sensitivity and specificity of maternal serum specificity of maternal serum screeningscreening. .

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Etiology and Clinical Etiology and Clinical ManifestationsManifestations

Trisomy 21 is present in 95 Trisomy 21 is present in 95 percent of persons with Down percent of persons with Down syndrome.syndrome.

Mosaicism, a mixture of normal Mosaicism, a mixture of normal diploid and trisomy 21 cells, diploid and trisomy 21 cells, occurs in 2 percent. occurs in 2 percent.

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Etiology and Clinical Etiology and Clinical ManifestationsManifestations

The remaining 3 percent The remaining 3 percent have a Robertsonian have a Robertsonian translocation in which all or translocation in which all or part of an extra part of an extra chromosome 21 is fused chromosome 21 is fused with another chromosomewith another chromosome. .

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Robertsonian Robertsonian translocationtranslocation

TThe reciprocal transfer of he reciprocal transfer of the long arms of two of the the long arms of two of the acrocentric chromosomes: acrocentric chromosomes: 13, 14, 15, 21 or 2213, 14, 15, 21 or 22

On rare occasions, other On rare occasions, other non-acrocentric non-acrocentric chromosomes undergo chromosomes undergo Robertsonian translocationRobertsonian translocation

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Robertsonian Robertsonian translocationtranslocation

a reciprocal transfer of the whole a reciprocal transfer of the whole long or short arms close to the long or short arms close to the centromerecentromere

A relatively common A relatively common Robertsonian translocation is Robertsonian translocation is between chromosome 14 and between chromosome 14 and chromosome 21chromosome 21

In meiosis, a trivalent is formedIn meiosis, a trivalent is formed..

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Robertsonian translocation

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Frequency of Dysmorphic Frequency of Dysmorphic Signs in Neonates with Signs in Neonates with

Trisomy 21Trisomy 21 Dysmorphic sign Frequency (%) Dysmorphic sign Frequency (%) Flat facial profileFlat facial profile 90 90

Poor Moro reflexPoor Moro reflex 85 85

HypotoniaHypotonia 80 80

Hyperflexibility of large jointsHyperflexibility of large joints 80 80

Loose skin on back of neck 80Loose skin on back of neck 80

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Frequency of Dysmorphic Frequency of Dysmorphic Signs in Neonates with Signs in Neonates with

Trisomy 21Trisomy 21Dysmorphic sign Frequency Dysmorphic sign Frequency

(%) (%)

Dysmorphic pelvis on radiographDysmorphic pelvis on radiograph7070

Small round ears Small round ears 6060

Hypoplasia of small fingerHypoplasia of small finger 6060

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Persons with Down syndrome Persons with Down syndrome usually have mild to moderate usually have mild to moderate mental retardation mental retardation

School-aged children with Down School-aged children with Down syndrome often have difficulty syndrome often have difficulty with language, communicationwith language, communication

Adults with Down syndrome have a Adults with Down syndrome have a high prevalence of early high prevalence of early Alzheimer's disease Alzheimer's disease

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Incidence of Some Incidence of Some Associated Medical Associated Medical

Complications in Persons Complications in Persons with Down Syndromewith Down Syndrome

DisorderDisorder Incidence Incidence (%)(%)Mental retardationMental retardation >95 >95

Growth retardationGrowth retardation >95 >95

Early Alzheimer's disease Early Alzheimer's disease 75%75%

by age 60by age 60

Congenital heart defectCongenital heart defect 4 400

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DisorderDisorder Incidence Incidence (%)(%)

Hearing loss Hearing loss 40 to 75 40 to 75Ophthalmic disorders Ophthalmic disorders (congenital cataracts,(congenital cataracts, glaucoma(glaucoma( 60 60EpilepsyEpilepsy 5 to 10 5 to 10Gastrointestinal Gastrointestinal

malformations )Hirschsprung malformations )Hirschsprung disease)disease) 5 5

HypothyroidismHypothyroidism 5 5LeukemiaLeukemia 5 5

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DisorderDisorder Incidence (%)Incidence (%)

Increased susceptibility to Increased susceptibility to

infection (pneumonia, otitis infection (pneumonia, otitis media, sinusitis, pharyngitis(media, sinusitis, pharyngitis(

1-61-6

InfertilityInfertility >99% in men>99% in men

anovulation in anovulation in 30% of 30% of womenwomen

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Estimated risk of Down syndrome according to maternal

age

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The risk of having a child The risk of having a child with Down syndromewith Down syndrome

1/1,300 for a 25-year-old 1/1,300 for a 25-year-old woman;woman;

at age 35, the risk increases at age 35, the risk increases to 1/365to 1/365

At age 45, the risk of a At age 45, the risk of a having a child with Down having a child with Down syndrome increases to 1/30syndrome increases to 1/30

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Maternal Serum ScreeningMaternal Serum Screening

If all pregnant women 35 years or If all pregnant women 35 years or older chose to have amniocentesisolder chose to have amniocentesis

about 30 percent of trisomy 21 about 30 percent of trisomy 21 pregnancies would be detectedpregnancies would be detected

Women younger than 35 years Women younger than 35 years give birth to about 70 percent of give birth to about 70 percent of infants with Down syndrome infants with Down syndrome ! !

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The risk of having a child The risk of having a child with Down syndromewith Down syndrome

Maternal serum screening Maternal serum screening ((multiplemultiple--marker screeningmarker screening) ) can allow the detection of can allow the detection of trisomy 21 pregnancies in trisomy 21 pregnancies in women in this younger age women in this younger age groupgroup..

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Maternal Serum ScreeningMaternal Serum Screening"triple test" or "triple screen""triple test" or "triple screen"

"Multiples of the Median (MoM)""Multiples of the Median (MoM)"

Alpha-fetoprotein (AFP)Alpha-fetoprotein (AFP) unconjugated estriolunconjugated estriol human chorionic gonadotropin human chorionic gonadotropin

(hCG) (hCG) the serum markers most widely the serum markers most widely

used to screen for Down used to screen for Down syndromesyndrome

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""Multiples of the Median Multiples of the Median ((MoMMoM))““

& & trisomy 21trisomy 21 With trisomy 21, second-With trisomy 21, second-

trimester maternal serum levels trimester maternal serum levels of AFP and unconjugated estriol of AFP and unconjugated estriol are about are about 25 percent lower than 25 percent lower than normal levelsnormal levels

maternal serum hCG is maternal serum hCG is approximately two times higherapproximately two times higher than the normal hCG levelthan the normal hCG level

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Recurrence Risk and Family Recurrence Risk and Family HistoryHistory

If a patient has had a trisomy If a patient has had a trisomy 21 pregnancy in the past, the 21 pregnancy in the past, the risk of recurrence in a risk of recurrence in a subsequent pregnancy subsequent pregnancy increases to approximately 2increases to approximately 2-3-3

percent above the baseline risk percent above the baseline risk determined by maternal agedetermined by maternal age

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Diagnosis of a chromosome-Diagnosis of a chromosome-21 translocation in the 21 translocation in the fetus or newborn is an fetus or newborn is an indication for karyotype indication for karyotype analysis of both parentsanalysis of both parents

If both parents have normal If both parents have normal karyotypes, the recurrence karyotypes, the recurrence risk is 2 to 3 percent risk is 2 to 3 percent

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Down Syndrome & Sampling Down Syndrome & Sampling RisksRisks

MethodMethod riskrisk

Chorionic villus samplingChorionic villus sampling

10 to 12 10 to 12 weeks weeks 0.5 to 0.5 to 1.5 %1.5 %

Early amniocentesisEarly amniocentesis

12 to 15 12 to 15 weeksweeks 1.0 to 2.0 %1.0 to 2.0 %

Second-trimester amniocentesisSecond-trimester amniocentesis

15 to 20 15 to 20 weeksweeks 0.5 to 1.0 %0.5 to 1.0 %

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a woman having a woman having amniocentesisamniocentesis

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Counseling AspectsCounseling Aspects

Women who will be 35 years or Women who will be 35 years or older on their due date should be older on their due date should be offered chorionic villus sampling offered chorionic villus sampling or second-trimester or second-trimester amniocentesis.amniocentesis.

Women younger than 35 years Women younger than 35 years

should be offered maternal should be offered maternal serum screening at 15 to 18 serum screening at 15 to 18 weeks' gestation. weeks' gestation.

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UltrasoundUltrasound

During the first trimester of During the first trimester of the majority of pregnancies, it the majority of pregnancies, it is possible to measure the size is possible to measure the size of the fluid area at the back of of the fluid area at the back of the fetus’s neck, known as the the fetus’s neck, known as the nuchal translucency nuchal translucency oror NT NT The The increasing size of the NT increasing size of the NT indicates a greater risk of the indicates a greater risk of the fetus having Down’s syndrome.fetus having Down’s syndrome.

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UltrasoundUltrasound

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Fluorescent In Situ Hybridisation techniques

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female fetus with trisomy-female fetus with trisomy-2121

chromosomes chromosomes 18 (aqua), X 18 (aqua), X (green), and Y (green), and Y (red).(red).

• chromosomes chromosomes 13 (green), 13 (green), and 21 (red)and 21 (red)