down syndrome and chromosomes

Down Syndrome and Down Syndrome and ChromosomesChromosomes

Yujen “Ted” HsiaYujen “Ted” HsiaEmeritus Professor Emeritus Professor

Cell & Molecular Biology and PediatricsCell & Molecular Biology and Pediatrics

WCCC Total Life Recovery ProgramWCCC Total Life Recovery Program

Tuesday 30 June 2009Tuesday 30 June 2009

Let Us Pray• Almighty God: • We thank You for Your mercy, Your grace, and for

every generous and perfect gift You have given us.• Please provide for our physical needs, enlighten our

minds, give us wisdom, and help our spiritual growth.• Be our strong defense against all harm and danger.• Help those who are ill, hungry, cold, or sad in their hearts.• We pray for Your church, for those who know Your love,

and for those You love who have not yet known You. • Bless us, our loved ones, and those who seek to help us.• Help us to understand Your ways, learn from You, and

praise your wondrous works.

AmenAmen..

What Did We Learn Last Time?• Rods are for dim vision. Cones are for color vision.• Light stimulates a retinal derivative of vitamin A.

This alters the Opsin light sensitive photoreceptors.• The 3 cone types respond to Blue, Green, or Red.• Colorblindness affects one of the cone opsins.

One or more color pigment genes is missing or shifted.• Some inherited autosomal conditions are influenced by the

sex of the person. Some are limited by the person’s sex.• Some conditions have X-linked inheritance.• X-linked inheritance is “diagonal” via the maternal line.• X-linked lethal disorders may have high mutation rates.• One X chromosome is randomly inactivated in females.

Down Syndrome

• Chromosome structure and properties.• Chromosome banding and gene distributions.• Disorders of chromosome number.• Disorders of chromosome structure.

Basic Cytogenetics

• Description and features.

• Physical, mental and behavioral aspects.

• Different chromosomal causes.

• Detection during pregnancy.

John Langdon Down John Langdon Down 1828-18961828-1896

• He trained at the London Hospital.He trained at the London Hospital.• He was the first to recognize what he He was the first to recognize what he

called “called “Mongolian idiocyMongolian idiocy” as a ” as a syndrome, a “throwback” to a “lower” race.syndrome, a “throwback” to a “lower” race.

• The children appeared similar, like brothers and sisters.The children appeared similar, like brothers and sisters.• The disorder became known as “The disorder became known as “MongolismMongolism.”.”• It is now called It is now called DownDown syndrome. syndrome.• He opposed slavery, and argued this “ throwback” He opposed slavery, and argued this “ throwback”

disproved the “Negroid race” was inferior. disproved the “Negroid race” was inferior. • He advocated equal education for women.He advocated equal education for women.

http://www.disabilities-us.com/slaterfamily/JLD.htmhttp://www.disabilities-us.com/slaterfamily/JLD.htm

Boy with Down SyndromeBoy with Down Syndrome

http://www.sahha.gov.mt/pages.aspx?page=497http://www.sahha.gov.mt/pages.aspx?page=497

Typical Facial Features:Typical Facial Features:

• Floppiness as an infant,

• Flat head,

• Flat, round faces,

• Small midface,

• Flat, low nasal bridge,

• Small ears, folded helices,

• Iris Brushfield spots,

• Protruding tongue,

• Redundant skin nape of neck.

• Upslanting eyes,

• Epicanthal folds,

The Eye in Down SyndromeThe Eye in Down Syndrome• Epicanthal folds are prominent.Epicanthal folds are prominent.

• Which eyes belong to a child with Down syndrome?Which eyes belong to a child with Down syndrome?

• The iris has the light smudgy The iris has the light smudgy

opacities of Brushfield spots.opacities of Brushfield spots.

Simian Crease in Down SyndromeSimian Crease in Down Syndrome

http://medgen.genetics.utah.edu/photographs/diseases/high/peri005.jpghttp://medgen.genetics.utah.edu/photographs/diseases/high/peri005.jpg

• The The triradial angletriradial angle is between is between

the triradius at the base the triradius at the base

of the palm with those at of the palm with those at

the index and fifth fingers.the index and fifth fingers.

• This angle tends to be more This angle tends to be more

obtuse in obtuse in DownDown syndrome. syndrome.

• Short hand bones.Short hand bones.

• Single “simian” palmar Single “simian” palmar

crease.crease.(Common in normal people.)(Common in normal people.)

• Bent “pinkies.”Bent “pinkies.”

Down Syndrome, Trisomy 21• This child has This child has

star-likestar-like

creases on creases on

the soles. the soles.

• The first inter-toe cleft has a wide “sandal gap.”The first inter-toe cleft has a wide “sandal gap.”

Redundant Skin at the Nape of the

Neck in Down Syndrome

• All newborn infants have this to some degree.

• It is marked in this infant with Down syndrome.

Down Syndrome: Complications in Childhood

http://www.path.cam.ac.uk/~part1/lectures/gd4/gd4c.htmlhttp://www.path.cam.ac.uk/~part1/lectures/gd4/gd4c.html

• Developmental delay after age 1 year.Developmental delay after age 1 year.• Poor growth, delayed puberty.Poor growth, delayed puberty.• Noisy breathing, ear infections.Noisy breathing, ear infections.• 15% have unstable neck vertebrae.15% have unstable neck vertebrae.

only 1% to 2% have symptoms.only 1% to 2% have symptoms.• Increased susceptibility to Increased susceptibility to

infections.infections.• 20-fold rise in risk for leukemia.

Down Syndrome: Intellectual Development

• Early motor milestones are often delayed by floppiness, Early motor milestones are often delayed by floppiness, but may be within normal limits for up to a year.but may be within normal limits for up to a year.

• Progressive developmental lag is seen by 12 months.Progressive developmental lag is seen by 12 months.• Most learn to talk, have bowel and bladder control, Most learn to talk, have bowel and bladder control,

acquire simple self-help skills, but intellect is weak.acquire simple self-help skills, but intellect is weak.• Learning to speak is greatly helped by sign language.Learning to speak is greatly helped by sign language.• Expressive language is better than receptive language.Expressive language is better than receptive language.• They do much better with special education classes.They do much better with special education classes.• Educational achievements range from a first- to a sixth- Educational achievements range from a first- to a sixth-

grade level, but at much slower rate. IQ ~40-75. grade level, but at much slower rate. IQ ~40-75. • Institutionalized or neglected children do more poorly.Institutionalized or neglected children do more poorly.

• Developmental skills may seem normal at first,Developmental skills may seem normal at first,

but become progressively delayed with age. but become progressively delayed with age.

Developmental MilestonesDevelopmental MilestonesIn Down SyndromeIn Down Syndrome

Behavior in Down Syndrome


• Most have very friendly, happy, Most have very friendly, happy,

talkative, agreeable personalities.talkative, agreeable personalities.• Most have excellent memories.Most have excellent memories.• Most enjoy rhythm and music.Most enjoy rhythm and music.• Psychiatric problems occur in Psychiatric problems occur in

~ 17% of children, ~27% of adults.~ 17% of children, ~27% of adults.

Attention-deficit-hyperactivity complex.Attention-deficit-hyperactivity complex.

Autism.Autism.

Obsessive-compulsive behavior.Obsessive-compulsive behavior.

Depression as adolescents.Depression as adolescents.

Special Olympics

• 9 y.o. Sara Rosati celebrates her gold medal victory in the Special Olympics 25-meter run.

http://njmonthly.com/articles/towns_and_schools/steve-adubato-only-in-nj/steve-adubato-atypical-inspiration-.html

• People with Down syndromeenjoy friendly competition,

not aggressive competition.• The Special Olympics are an

ideal facility for them.Everyone wins a medal.

Health Issues in Later Life• Adult height is short.• Females have ~50/50 risk for

a child with Down syndrome.• Males are very rarely fertile.• All have very accelerated aging.• Adults have increased risk for:

Obesity.Diabetes mellitus.Cancers.Heart disease.Psychiatric disturbances.Alzheimer disease by age 40.

Down Syndrome: Epidemiology


• It affected 1 in 800 births world-wide.It affected 1 in 800 births world-wide.[Incidence is declining due to antenatal detection.][Incidence is declining due to antenatal detection.]

• It is the most common chromosomal cause of It is the most common chromosomal cause of mental retardation, affecting about 1 in 3 mental retardation, affecting about 1 in 3 moderately retarded school-age children. moderately retarded school-age children.

[[Fragile XFragile X is the most common single gene cause.] is the most common single gene cause.]• Many risk factors have been proposed.Many risk factors have been proposed.

The major risk factor is increased The major risk factor is increased maternal agematernal age..• 1959: Lejeune and Jacobs independently discovered 1959: Lejeune and Jacobs independently discovered

DownDown syndrome patients had 3 chromosomes syndrome patients had 3 chromosomes 21 21..

Normal Human ChromosomesNormal Human Chromosomes• Chromosomes are in pairs, one from each parent.Chromosomes are in pairs, one from each parent.• The chromosomes are in the cell’s nucleus.The chromosomes are in the cell’s nucleus.• They contain about 30,000 loci (addresses) for genes.They contain about 30,000 loci (addresses) for genes.• Most human cells have 23 pairs: 46,Most human cells have 23 pairs: 46,XX XX or 46,or 46,XYXY..• Whenever a cell divides, its chromosomes are duplicated, Whenever a cell divides, its chromosomes are duplicated,

so both daughter cells receive the same chromosomes. so both daughter cells receive the same chromosomes.

This is called This is called MitosisMitosis. . • Except for when germ cells are made, when theExcept for when germ cells are made, when the

chromosomes become unpaired.chromosomes become unpaired.

This is called This is called MeiosisMeiosis..• The egg has 23,The egg has 23,XX, the sperm has 23,, the sperm has 23,XX or 23, or 23,YY..

Human Cells• A human A human diploiddiploid cell has: cell has:

26 chromosome pairs.26 chromosome pairs.6,000,000,000 bases DNA.6,000,000,000 bases DNA.~30,000 genes.~30,000 genes.

• Germ cell chromosome Germ cell chromosome number is number is haploidhaploid [23]. [23].

• After fertilization, the sperm andAfter fertilization, the sperm andovum pronuclei fuse, restoring ovum pronuclei fuse, restoring the the diploiddiploid number [46]. number [46].

• Only the egg has DNA from Only the egg has DNA from the mitochondria.the mitochondria.

sperm

Egg with sperm drawn to scale

Human ChromosomesHuman Chromosomes• A chromosome is much more than

just a container for holding DNA.• Like a space shuttle, it has very Like a space shuttle, it has very

complex structure and function.complex structure and function.• Genes control its construction.Genes control its construction.

• Its gene passengers are usually Its gene passengers are usually arranged in no apparent order, but arranged in no apparent order, but each has its own specific locus.each has its own specific locus.

• Certain genes control how other genes Certain genes control how other genes in chromosomes become activated.in chromosomes become activated.

• Most genes remain mostly inactive.Most genes remain mostly inactive.They may be activated only at They may be activated only at certain times, or in certain cells. certain times, or in certain cells.

Electron Microscopy of Cell NucleusElectron Microscopy of Cell Nucleus

http://www.geocities.com/Colosseum/Arena/7982/1.htmlhttp://www.geocities.com/Colosseum/Arena/7982/1.html

Nuclear Nuclear membranemembrane

EuchromatinEuchromatin

HeterochromatiHeterochromatinn

NucleolusNucleolus • Chromosomes are not Chromosomes are not visible in visible in interphaseinterphase..

• The The nucleusnucleus contains contains all the nuclear DNA.all the nuclear DNA.

• The The nucleolusnucleolus is an is an organizing center organizing center [[NORNOR] for ribosomal ] for ribosomal RNA genes.RNA genes.

• Dense Dense heterochromatinheterochromatin is information poor.is information poor.

• LooseLoose euchromatineuchromatin is isinformation rich.information rich.

The Chromatin in Chromosomes The Chromatin in Chromosomes has Complex Structure.has Complex Structure.

• It is 50% DNA, 1% RNA, 50% protein.It is 50% DNA, 1% RNA, 50% protein.• Half the proteins are structural histones.Half the proteins are structural histones.

The rest have important gene regulatory roles.The rest have important gene regulatory roles.• Chromatin is long invisible strands of DNA, Chromatin is long invisible strands of DNA,

usually wound around nucleosomes.usually wound around nucleosomes.• When cells are to divide, DNA strands double,When cells are to divide, DNA strands double,

condense as “beads on a string,”condense as “beads on a string,”then pack tightly into chromatin supercoils.then pack tightly into chromatin supercoils.

• A chromosome then becomes visible, as A chromosome then becomes visible, as chromatidchromatid arms in an arms in an XX-shaped structure.-shaped structure.

Chromatin PackagingChromatin Packaging

http://www.accessexcellence.org/AB/GG/chroma_packg.htmlhttp://www.accessexcellence.org/AB/GG/chroma_packg.html

DNADNA double helixdouble helix

““Beads on a string”Beads on a string”

Packed nucleosomesPacked nucleosomes

ExtendedExtended chromatinchromatin

Condensed chromatinCondensed chromatin

Chromatid armsChromatid arms

DNA can be DNA can be packed packed x x 50,000.50,000.

nmnm22

1111

3030

300300

14001400

700700

It becomes It becomes condensed for condensed for cell division.cell division.The genes in The genes in DNA can only DNA can only be active when be active when not condensed.not condensed.XX-shaped -shaped chromosomeschromosomesare formed are formed before cell before cell division.division.

The Parts of a ChromosomeThe Parts of a Chromosome

• In cell division, chromosomes have In cell division, chromosomes have sister sister chromatidchromatid arms. arms.

CentromereCentromerepp (short arm) (short arm)

qq (long arm) (long arm)

SatellitesSatellites

TelomereTelomere

ChromatidsChromatids

chromatidchromatid arms are short ( arms are short (pp))

• The sister The sister chromatidchromatid arms are joined at the arms are joined at the centromerecentromere..

or long (or long (qq).).

• Small Small acrocentricacrocentric chromosomes have variable chromosomes have variable satellitessatellites..

SatellitesSatellites contain multiple copies of RNA genes. contain multiple copies of RNA genes.

• The The chromatidchromatid arms are capped with arms are capped with telomerestelomeres..

TelomereTelomere

These have key functions.

pp

qq

G-Banded Metaphase Chromosomes

faculty.mwsu.edu/biology/jon.scales/Courses/.../aberrations.faculty.mwsu.edu/biology/jon.scales/Courses/.../aberrations.pptppt Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or displayCopyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Centromere

• They are numbered according to their sizes.• Dark bands are Q or G stained and information poor.• Light bands are R stained and information rich.

Satellites

Variable Regions

Q Banded Chromosomes• Sex?

• Number?• Any missing?

• Any extra?

• Structurally altered?

• Karyotype?

FemaleFemale..

NoneNone..

NoneNone..

46.46.

Probably Normal FemaleProbably Normal Female.. 46,46,XXXX..Diagnosis?Diagnosis?

NoNo..

XXXX..

SKY BandsSKY Bands• Specific probes can Specific probes can

label specific label specific regions on a regions on a chromosome.chromosome.

• These need not be These need not be related to histologicrelated to histologicbanding patterns.banding patterns.

• These stained bands These stained bands help to detect thehelp to detect theparts of a chromo-parts of a chromo-some even if they some even if they become rearranged.become rearranged.

http://www.chroma.com/image-1.htmlhttp://www.chroma.com/image-1.html

“Painted” Chromosomes Spectral Karyotype [SKY]

• Sex?

• Number?• Missing?• Extra?• Structurally Structurally

alteredaltered?• Karyotype?

XYXY,, MaleMale..

0.0.

0.0.

46.46.

Probably Normal MaleProbably Normal Male..46,46,XYXY..

Diagnosis?Diagnosis?

NoneNone..

MitosisMitosis• SS phase: phase: DNA DNA synthesis synthesis

precedes precedes mitosismitosis,,((and and meiosis Imeiosis I.).)

Prophase

MetaphaseAnaphase

TelophaseTelophase

• MetaMetaphase: a spindle phase: a spindle forms, chromosomes forms, chromosomes line up at the equator.line up at the equator.

• AnaAnaphase: the sister phase: the sister chromatidschromatids separate. separate.

• TeloTelophase: two daughter phase: two daughter

nuclei and cells form.nuclei and cells form.

S phase

• ProProphase: Chromosomes phase: Chromosomes become visible.become visible.

Breakage-ReunionBreakage-Reunion• BreakageBreakage--reunions reunions can can

occur anywhere; some occur anywhere; some regions have marked regions have marked susceptibility to breaks.susceptibility to breaks.

• CrossingsCrossings--overover form form chiasmatachiasmata between between chromatidchromatid arms of homologous chromosomes. arms of homologous chromosomes.

• In meiosis a cell normally has ~50 In meiosis a cell normally has ~50 crosscross--over over events.events.• More More crosscross--oversovers occur during occur during oogenesisoogenesis than than

spermatogenesisspermatogenesis..• BreakageBreakage--reunion reunion errorserrors can cause can cause unequalunequal

crossingscrossings--over over and chromosomeand chromosome rearrangements rearrangements..

chiasmachiasma

chiasmachiasma

centromerecentromere

centromerecentromerechromatidchromatid

Chromosome Number (N) in Chromosome Number (N) in Meiosis and MitosisMeiosis and Mitosis

http://www.dac.neu.edu/biology/d.scheirer/mitosis_meiosis.gifhttp://www.dac.neu.edu/biology/d.scheirer/mitosis_meiosis.gif

• MitosisMitosis conserves conserves didiploidy in ploidy in daughter cells.daughter cells.

• MeiosisMeiosis reduces reduces

didiploidy to ploidy to hahaploidy.ploidy.

Meiosis Meiosis II

NNNN

2 N2 N2 N2 N

2 N2 N 2 N2 N

NNNNNNNN

Mitosis Mitosis

Meiosis Meiosis IIII

Chromosomal ErrorsChromosomal Errors

Abnormal segregation in Abnormal segregation in meiosismeiosis or or mitosismitosis..• Non-Non-disjunctiondisjunction.. (Failure to separate normally.)• Common, most are lethal.Common, most are lethal.

Errors in NumberErrors in Number

Errors in StructureErrors in StructureAbnormal Abnormal breakagebreakage--reunionreunion..• Common, mostly silent.Common, mostly silent.• Quantitative: Reduced gene expressionQuantitative: Reduced gene expression

Increased gene expression.Increased gene expression.• Qualitative: Altered gene function.Qualitative: Altered gene function.

, to the cell or the organism., to the cell or the organism.

Meiotic Non-Disjunction

http://www.erin.utoronto.ca/~w3bio380/Lectsked/Lect04/Egg2.htmhttp://www.erin.utoronto.ca/~w3bio380/Lectsked/Lect04/Egg2.htm

Meiosis

I

II

24 22

Non-disjunctionNormal

Non-disjunction Normal Normal Normal

Maternal 21 Paternal 21

23 23 24 24 22 22

Chromosomes in Spontaneous AbortionChromosomes in Spontaneous Abortion

46,46,NN

++161645,45,XX

triploidytriploidy

otherother

other other autosomal autosomal trisomiestrisomies

At least 15% of first trimester pregnancies are lost.At least 15% of first trimester pregnancies are lost.

50% Normal

50% Abnormal

A G Banded Karyotype• Sex?

• Number?• Missing?• Extra?• Structurally Structurally

alteredaltered? • Karyotype?

XYXY..

0.0.

1616..

47.47.

• In the early fetus, trisomyIn the early fetus, trisomy 16 16 is very common.is very common.• All are miscarried before the 16th gestational week.All are miscarried before the 16th gestational week.

47,47,XYXY,+,+1616..

NoNo..

http://www.pathology.washington.edu/Cytogallery/cytogallery.htmlhttp://www.pathology.washington.edu/Cytogallery/cytogallery.html

MaleMale..

Trisomy 21 in Down Syndrome

24,X,24,X,+21+21 23,Y23,Y

47,XY,+2147,XY,+21

Egg,Egg,extra extra 2121

Sperm, Sperm, normalnormal

Zygote

Extra 21Trisomy 21

Down Syndrome: Genetic Basis


• AboutAbout 94% have trisomy94% have trisomy 21 21..• About 4% to 5% have a About 4% to 5% have a Robertsonian translocationRobertsonian translocation..

Up to half of these may be inherited.Up to half of these may be inherited.• In at least 2%, In at least 2%, mosaicismmosaicism may arise from somatic may arise from somatic

nonnon--disjunctiondisjunction, with unpredictable severity., with unpredictable severity.

Undoubtedly many milder Undoubtedly many milder mosaicsmosaics are missed. are missed.• Partial Partial 2121qq trisomy can cause trisomy can cause DownDown syndrome. syndrome.

The critical region is The critical region is 21q21q22.1 to 22.1 to 21q21q22.2.22.2.

http://upload.wikimedia.org/wikipedia/en/d/d6/Human_chromosome_21.png

A G Banded Karyotype• Sex?• Number?• Missing?• Extra?• Structurally Structurally

alteredaltered? • Karyotype?

FemaleFemale..

0.0.2121..

47.47.

TrisomyTrisomy 21 21, Down syndrome., Down syndrome.

47,47,XXXX,+,+2121..


NoNo..

http://www.pathology.washington.edu/Cytogallery/cytogallery.htmlhttp://www.pathology.washington.edu/Cytogallery/cytogallery.html

Origin of the Extra 21

http://prx.hml.org:2055/das/book/11709583/view/873

• Right: the child has one copy of both maternal chromosomes.

(Meiosis I error.)

• Left: the child has two copies of one paternal chromosome.

Father

Mother

Child

(Meiosis II error.)

A Finite Number of Eggs in a WomanA Finite Number of Eggs in a Woman

• In oogenesis In oogenesis meiosis I meiosis I stops at prophase by stops at prophase by fetal age 25 weeks.fetal age 25 weeks.

• At puberty, a woman At puberty, a woman has ~400,000 oocytes.has ~400,000 oocytes.

• Every menstrual cycle,Every menstrual cycle,a few oocytesa few oocytescomplete complete meiosis Imeiosis Ito form a ripe ovum.to form a ripe ovum.

• At fertilization, one egg At fertilization, one egg completes completes meiosis IImeiosis II..

http://www.erin.utoronto.ca/~w3bio380/Lectsked/Lect04/Egg2.htmhttp://www.erin.utoronto.ca/~w3bio380/Lectsked/Lect04/Egg2.htm

Ger

ms

cell

s M

illio

nsG

erm

s ce

lls

Mil

lions

1.01.0

Months post Months post conceptionconception

Years post birthYears post birthBir

th0 3 6 9 10 30 500 3 6 9 10 30 50

0.50.5

3.03.0

6.06.0

9.09.0

Number of Eggs in a Human Ovary by

Maternal Age

• Delayed oogenesis Delayed oogenesis may raise risks formay raise risks fornonnon--disjunctiondisjunction..

• This applies to any This applies to any chromosome.chromosome.

• Prolonged suspension Prolonged suspension in in meiosis Imeiosis I may be may bewhy why meioticmeiotic nonnon- - disjunctiondisjunction risk rises risk rises with maternal age.with maternal age.

• Most Most nonnon--disjunctiondisjunction of of 2121 is in maternal is in maternal meiosis Imeiosis I..• Some Some nonnon--disjunctiondisjunction occurs in maternal occurs in maternal meiosis II meiosis II

and in paternal and in paternal meiosis I meiosis I or or IIII. .

Inci

denc

e pe

r 1,

000

birt

hs

20 25 30 35 40 45Maternal Age

Maternal Age and Trisomy 21Maternal Age and Trisomy 21

20

15

10

5

http://www.kumc.edu/instruction/medicine/pathology/ed/ch_6/Persons%20Chromosome%20abnormalities.ppthttp://www.kumc.edu/instruction/medicine/pathology/ed/ch_6/Persons%20Chromosome%20abnormalities.ppt

Chromosome Testing by FISH

• ““Painting” of any cell can reveal a specific target.Painting” of any cell can reveal a specific target.• This can detect chromosome aneuploidies.This can detect chromosome aneuploidies.• On the right, one On the right, one XX, one , one YY, and two , and two 1818’s are seen.’s are seen.

• On the left, two On the left, two 1313’s but three ’s but three 2121’s are seen. ’s are seen. • This test can diagnose aneuploidy for a targeted This test can diagnose aneuploidy for a targeted

chromosome, but not structural changes.chromosome, but not structural changes.

XX 1818YY 1313 2121

Down Syndrome Mosaicism• Trisomy Trisomy 2121 may be limited may be limited

to only some tissues.to only some tissues.• Severity depends on the Severity depends on the

degree of tissue involvement.degree of tissue involvement.• Phenotype is variable.Phenotype is variable.• May be detected in ~ 2% of May be detected in ~ 2% of

apparent Down syndrome.apparent Down syndrome.• Cannot predict severity.Cannot predict severity.• May be due to May be due to nonnon--disjunctiondisjunction

in a +in a +2121 zygote to produce a zygote to produce a normal cell line, or in a normal cell line, or in a normal somatic cell to normal somatic cell to produce a +produce a +2121 cell line. cell line.

47,XY+21/46,XY

MosaicismWhat is it?

• Mosaic artMosaic art::picture is made from picture is made from different colored tiles.different colored tiles.

• Genetic MosaicismGenetic Mosaicism::when some of a person’s when some of a person’s cells differ in chromosomes cells differ in chromosomes or in genetic alleles.or in genetic alleles.

• Mosaic Down syndromeMosaic Down syndrome: : body cells may contain 46, body cells may contain 46, or 47+or 47+2121 chromosomes. chromosomes.

Robertsonian TranslocationsRobertsonian TranslocationsTwo Two

acrocentricsacrocentricsBreaks occur at the Breaks occur at the centromerecentromere

of both acrocentrics.of both acrocentrics.

The The qq arms fusearms fuse

(Acrocentric (Acrocentric pp satellites have satellites have similar similar repetitive repetitive genes, loss of genes, loss of some satellites some satellites has no clinical has no clinical importance). importance).

The The pp arms fusearms fuse

21 2121 21

14 1414 14

rbtrbt((14q14q//21q21q))

rbtrbt((14p14p//21p21p))

The fusedThe fused p p arms are lost.arms are lost.

In effect, a In effect, a 2121 has fused has fused with a with a 1414..

Risk for Down Syndrome if a Parent is a Translocation Carrier

Non-viable

Normal Parent “Carrier” Parent

Normal Carrier +21 -14 -21 +14

What Do These Chromosomes Show?• Sex?Sex?• Number?Number?• Missing?Missing?• Extra?Extra?• Structurally Structurally

altered?altered?• Karyotype? Karyotype?

XYXY,, Male Male..

1414, , 2121..

14p14p+.+.

45.45.

Normal Male with balancedNormal Male with balanced

45,45,XYXY, -, -1414, -, -2121,,rbt(rbt(14q14q//21q)21q)..


http://medgen.genetics.utah.edu/photographs/diseases/high/69b.gifhttp://medgen.genetics.utah.edu/photographs/diseases/high/69b.gif

14q14q//21q21q..

Robertsonian Robertsonian 1414//2121 “carrier.” “carrier.”



XYXY,, Male Male..

1414..14p14p+.+.

46.46.

Down syndrome male with imbalanced Down syndrome male with imbalanced

46,46,XYXY, -, -1414, , +rbt(+rbt(14q14q//21q21q).).



14q14q//21q21q..

Robertsonian (Robertsonian (14q14q//21q21q), equivalent to extra ), equivalent to extra 2121. .

A Q Banded Karyotype• Sex?• Number?• Any missing?

• Any extra?

• Karyotype?

• Diagnosis?

This almost always arises This almost always arises de novode novo..

XXXX,, Female Female..

2121..

rbt(rbt(21q21q//21q21q).).

46.46.

Down syndromeDown syndrome..

46,46,XX,XX,--2121,+,+21q21q//21q21q..

• Sex?• Number?• Any missing?

• Any extra?

• Phenotype?

• Diagnosis?

A Q Banded Karyotype

45,45,XXXX, -, -2121--2121, +rbt(, +rbt(21q21q//21q21q).).She cannot have a normal baby.

FemaleFemale..

2121,, 2121..

rbtrbt((21q21q//21q21q).).

45.45.

NormalNormal..

21q21q//21q21q “Carrier.”“Carrier.”

What Do These Chromosomes Show?What Do These Chromosomes Show?• Sex?Sex?

• Number?Number?• Missing?Missing?• Extra?Extra?

• Structurally Structurally altered?altered?

• Karyotype?Karyotype?

XXYXXY..

0.0.

2323 chromosomeschromosomes..

69.69.

TriploidyTriploidy..

69,69,XXYXXY..


http://www.tokyo-med.ac.jp/genet/cki-e.htmhttp://www.tokyo-med.ac.jp/genet/cki-e.htm

• TriploidyTriploidy accounts for ~3% accounts for ~3% of all perinatal mortality.of all perinatal mortality.

NoNo..

MaleMale..


• Number?Number?• Missing?Missing?• Extra?Extra?• Structurally Structurally


FemaleFemale..No No YY..

XX or or YY..

0.0.

45.45.

Turner Turner syndrome, in a liveborn girl. syndrome, in a liveborn girl. 45,45,XX..Diagnosis?Diagnosis?

http://www.tokyo-med.ac.jp/genet/cki-e.htmhttp://www.tokyo-med.ac.jp/genet/cki-e.htm

None.

> 98% of 45,> 98% of 45,XX are lost are lost in uteroin utero..

Turner Syndrome

• These girls have the typically These girls have the typically broad, "webbed" neck. broad, "webbed" neck.

• Stature is reduced.Stature is reduced.• Their fingers and toes mayTheir fingers and toes may

be swollen at birth.be swollen at birth.

http://medgen.genetics.utah.edu/photographs/pages/turner_syndrome.htmhttp://medgen.genetics.utah.edu/photographs/pages/turner_syndrome.htm

• The nails are dystrophic.The nails are dystrophic.

• Most are infertile, Most are infertile,

with no periods and with no periods and

abnormal ovaries.abnormal ovaries.



FemaleFemale..

0.0.

1313..

47.47.

Trisomy Trisomy 1313. Few are live-born,. Few are live-born,

47,47,XXXX,, ++1313..



NoNo..

and very few survive.and very few survive.

What Do These Chromosomes Show?What Do These Chromosomes Show?

• Sex?Sex?• Number?Number?• Missing?Missing?• Extra?Extra?• Structurally Structurally

altered?altered?• Karyotype?Karyotype?

MaleMale..

0.0.

1818..

47.47.

Trisomy Trisomy 1818. Few are live-born,. Few are live-born,

47,47,XXXX, +, +1818..



NoNo..

and very few survive.and very few survive.




XXYXXY, , MaleMale..

0.0.

X X oror Y Y..

47.47.

Klinefelter Klinefelter syndrome.syndrome.47,47,XXYXXY..


None.




XYYXYY, , MaleMale..

0.0.

YY..

47.47.

This is usually benign.This is usually benign.

47,47,XYYXYY..


None.

48,XXYY48,XXYY 47,XYY47,XYY

What is the Inheritance Pattern?What is the Inheritance Pattern?

II

IIII

IIIIII

IVIV

• How can they be unaffected, and transmit this disorder?

• Who are obliged to be unaffected “carriers?”Who are obliged to be unaffected “carriers?”

?? ?? Balanced Balanced translocationtranslocation

This is an imbalanced chromosomal translocation. This is an imbalanced chromosomal translocation.

ImbalancedImbalanced fetusfetus

• Unaffected offspring must also be balanced carriers.Unaffected offspring must also be balanced carriers.

1 2 3 4 5 6 7 81 2 3 4 5 6 7 8

1 2 3 4 5 6 1 2 3 4 5 6

1 21 2

1 2 3 4 5 61 2 3 4 5 6

Could the abortions be a clue?Could the abortions be a clue?

Next Time

• Williams syndrome.

• Structural abnormalities

in chromosomes.

• What are contiguous

gene deletion

syndromes?

Maternal Serum α-Fetoprotein

http://www.obgyntoday.org/previous%20conf%20understanding%20AFP.htmhttp://www.obgyntoday.org/previous%20conf%20understanding%20AFP.htm

AFP Concentration

Pre

gnan

t wom

en

NormalDown

syndrome

down syndrome and chromosomes

Health & Medicine

x chromosome

xlinked inheritance

disorders of chromosome

chromosome banding

simian crease

flat head

lethal disorders

iris brushfield spots