Chromosomal Abnormalities ISDK

October 21, 2013

Chromosomes are tiny string-like structures in cells of the body that contain the genes

Each person normally has 23 pairs of chromosomes, or 46 in all.

We inherit one chromosome per pair from our mother and one from our father.

Chromosomes

• However, When a baby is born with too many or too few chromosomes, or with one or more chromosomes that are missing a piece or are rearranged, is suffering from chromosomal abnormalities.

Chromosomal Abnormalities

About 1 in 150 babies is born with a chromosomal abnormality.

A change in the number or structure of chromosomes can cause problems with growth, development, and function of the body’s systems.

Children with a chromosomal abnormality have mental and/or physical birth defects.

95% of chromosomally abnormal conceptus are aborted spontaneously

Abortion mostly occurs in 1st trimester

Chromosomal Abnormalities

The majority of human chromosomal abnormalities occur in the Autosomes. 

Most of these abnormalities are monosomies or trisomies.  In the case of a monosomy, there is only one copy of each kind of

chromosome instead of the usual pair of homologous chromosomes.  With trisomy, there are three of each type of chromosome. 

All fetuses with autosomal monosomies spontaneously abort early in pregnancy. 

Likewise, almost all fetuses with trisomies die before birth.  Those that survive usually have multiple physical

malformations, mental retardation, and relatively short lives.

Chromosomal Abnormalities

Chromosomal Disorders

50% of 1st trimester miscarriages(Before 24 week)

5% of stillbirths(from 24 week to) 0.5% of live borns

Down syndrome—trisomy 21Fragile X syndrome

Somatic cell abnormalities in cancers

A chromosome abnormality reflects an abnormality of chromosome number or structure. We can classify them into:

I- NUMERICAL ABNORMALITIES

II- STRUCTURAL ABNORMALITIES

What are chromosome abnormalities?Chromosomal Abnormalities

I. NUMERICAL ABNORMALITIES

Chromosomal abnormalities in the number of chormosomes.

1. Euploidy2. Aneuploidy

NUMERICAL ABNORMALITIESHOW DOES IT HAPPEN

1.Euploidy: Cells has chromosomes multiple of 23 such as

– 23, 46. 69, and 92

These may be normal or AbnormalNormal– Haploid cells : Gametes has 1 copy each 23 cells– Diploid cells: Somatic cells has 2 copy each 23 x2= 46

NUMERICAL ABNORMALITIESHOW DOES IT HAPPEN

Abnormal Tripoloidy 3 copies of each chromosome 23 x 3= 69

1 egg fertilized by 2 sperms

Tetra ploidy. 4 copies of each chromosome 23 x 4= 69

1 egg fertilized by 3 sperms

Deviation from normal number of chromosomes due to loss or gain of specific chromosomes.

Generally caused by “non-disjunction” of chromosome during meiosis.

It is a major cause of human reproductive failure. Most human miscarriages are aneuploids.

All autosomal monosomies are lethel Most of all Trisomies are also lethel But some Trisomies[ three copies of a particular chromosomes] are

compatible with survival to term with chromosomes 13, 18, and 21.

2.Aneuploidy

Types of AneuploidyThe different conditions of aneuploidy are: Nullisomy - the loss of both pairs of homologous chromosomes;

individuals are called nullisomics and their chromosomal composition is 2N-2. Humans with this condition will not survive.

Monosomy - the loss of a single chromosome; individuals are called monosomics and their chromosomal composition is 2N-1

Trisomy - the gain of an extra copy of a chromosome; individuals are called trisomics and their chromosomal composition is 2N+1

Tetrasomic - the gain of an extra pair of homologous chromosomes; individuals are called tetrasomics and their chromosomal composition is 2N+2

Cause of Aneuploidy The development of aneuploids may have arisen by a

process called non-disjunction. Non-disjunction occurs when paired chromosomes do

not separate either during meiosis I or meiosis II. The direct result of this event is that gametes develop

that have too few or too many chromosomes. If this occurs during meiosis I normal gametes are not

developed, If it occurs during meiosis II half of the gametes will be

normal and the other half will be abnormal.

Meiosis(Normal)

Non Disjunction at Meiosis I

Non Disjunction at Meiosis II

Non Disjunction (Quick Review)

Autosomal Chromosome Problems

• First identified by Dr. John Langdon Down in 1866

• Trisomy 21• Associated with increased maternal age• The result of an extra copy of chromosome 21.

People with Down syndrome are 47, 21+.

Down Syndrome (Trisomy 21)

Down syndrome affects 1:700 children and alters the child's phenotype either moderately or severely:

Characteristic facial features, short stature; heart defects

Susceptibility to respiratory disease, shorter lifespan

Often sexually underdeveloped and sterile, usually some degree of mental retardation.

Down Syndrome is correlated with age of mother but can also be the result of nondisjunction of the father's chromosome 21 in 1% cases.

Down Syndrome (Trisomy 21)

Clinical findings Newborn – hypotonia , increased sleepiness , excess nuchal skin Mental retardation The average IQ of children with Down syndrome is around 50,

compared to normal children with an IQ of 100. Small stature Craniofacial findings – brachycephaly ( flat occiput ) , epicanthic

folds , upward slanting eyes , protruding tongue, low set ears , flat nose , low nasal bridge , high arched palate .

Short broad hands Clinodactyly ( incurving ) little finger ASD,VSD , PDA Anal duodenal atresia Happy & affectionate

Clinical Features

Patau syndrome (Trisomy 13) Patau Sundrome, also known as Trisomy 13 and Trisomy D. Is a chromosomal abnormality, a syndrome in which a patient

had an additional chromosome 13 due to non-disjunction of chromosomes during meiosis.

Some are caused by Robertsonian Translocations. The extra chromosome 13 disrupts the normal course of

development, causing serious eye, brain, circulatory defects as well as cleft palate, heart and kidney defects.

. 1:5000 live births. Children rarely live more than a few months.

PolydactylCleft PalateCutis Aplasia(Congenital absence of skin). is a

congenital focal absence of epidermis.Kidney Failures

Clinical Features

Patau syndrome (Trisomy 13)

Edwards Syndrome (Trisomy 18)Edward’s Syndrome also kwnon as Trisomy 18 (T18) or Trisome

E.It is a genetic disorder caused by the presence of all of an extra

18th chromosome (Trisomy 18).It is named after John H. Edwards, who first described the

syndrome in 1960. It is the second most common autosomal trisomy, after Down

Syndrome, that carries to term.Edward’s Syndrome occurs in around one in 6,000 live births and

around 80 % of those affected are female.Children with full Trisomy 18 generally do not live more than a

few months

Edwards Syndrome (Trisomy 18)

Almost every organ system affected Upturned Nose Kidney Malformations Omphalocele.

An omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall.

ArthrogryposisArthrogryposis, is characterized by multiple joint contractures

and can include muscle weakness and fibrosis. Microcephaly Underdeveloped Phalanges

Clinical Features

DiGeorge syndrome(Monosomy 22)22q11.2 deletion syndrome

• Congenital thymic aplasia, and thymic hypoplasia

• Is a syndrome caused by the deletion of a small piece of chromosome 22.

• The deletion occurs near the middle of the chromosome at a location designated q11.2

• Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems

DiGeorge syndrome

Precursor T cell differentiation defect Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and

T regulatory (Treg) cells B cells are present but T-dependent B cell responses are

defective Anti-viral and anti-fungal immunity impaired Developmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease Treated with thymic transplant Autosomal dominant trait

Pallister-Killian Syndrome also known as Tetrasomy 12p Mosaicism or Pallister Mosaic Aneuplody Syndrome.

Is a genetic disorder occurring in humans. Pallister-Killian occurs due to the presence of the anomalous

extra isochromosome 12p, the short arm of the twelfth chromosome.

An isochromosome is a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm

This leads to the development of Tetrasomy 12p. Because not all cells have the extra isochromosome, Pallister-Killian is a mosaic condition.

TETRASOMY in the smaller arm of chromosome 12. 2n+2 or 48 chromosomes

Pallister-Killian Syndrome

Clinical findings

Hypo/Hyper PigmentationEpilepsyHigh ForeheadsFlat noseSupernumerary NipplesPsychomotor Retardation

Isodicentric 15, also called idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15).

Isodicentric chromosome 15 is the scientific name for a specific type of chromosome abnormality.

Individuals with isodicentric chromosome 15, or "idic(15)", have 47 chromosomes instead of the typical 46 chromosomes.

The extra chromosome is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image.

Individuals with idic(15) have a total of four copies of this chromosome 15.

With extra genetic material in chromosome 15. 47 chromosomes

IDIC 15 (Isodicentric 15)

IDIC 15 (Isodicentric 15)

Clinical Features

Epicanthal Folds in the EyeShort StatureDelayed Language DevelopmentSeizuresSome are Mentally Retarded

Which of the following is an example of monosomy?

A. 46,XXB. 47,XXXC. 69,XYYD. 45,X

Sex Chromosome(X Y) Abnormalities Male Sex Female Sex

X Chromosome

Y Chromosome

The majority of known types of chromosomal abnormalities involve Sex chromosomes.

In frequency of occurrence, they are only slightly less common than autosomal abnormalities. 

However, they are usually much less severe in their effects. 

Sex chromosome abnormalities are gender specific. 

Sex Chromosome Abnormalities

Klinefelter syndrome: males inherit one or more extra X chromosomes--their

genotype is XXY. 

1 in 660 live male births They characteristically have relatively high-pitched voices, asexual to feminine body

contours as well as breast enlargement, and comparatively little facial and body hair. 

They are sterile or nearly so, and their Testes and Prostat glands are small. 

As a result, they produce relatively small amounts of testosterone.

Higher risk of breast cancer, extragonadal germ cell tumor and autoimmune diseases

47,XXY-90% cases 15% cases are mosaics

Male Sex 1. Klinefelter Syndrome

Male Sex 1. Klinefelter Syndrome

Clinical features

Scarce beardPubic ,chin & axillary hair absentLonger fingers and armsSterileDelicate skinNormal lifespan

XYY syndrome males inherit an extra Y chromosome, their genotype is XYY. 

As adults, these "super-males" are usually tall (above 6 feet) and generally appear and act normal. 

However, they produce high levels of testosterone.  During adolescence, they often are slender, have

severe facial acne, and are poorly coordinated.  They are usually fertile and lead ordinary lives as

adults. 

2. XYY Syndrome

2. XYY Syndrome

Female Sex 1. Turner syndrome

Turner syndrome occurs when females inherit only one X chromosome--their genotype is X0.

  If they survive to birth, these girls have abnormal growth patterns. 

They are short in stature, averaging 4 foot 7 inches as adults, and often have distinctive webbed necks (i.e., extra folds of skin), small jaws, and high arched palates. 

They generally lack prominent female secondary sexual characteristics.  They have exceptionally small, widely spaced breasts, broad shield-shaped chests, and turned-out elbows. 

Their ovaries do not develop normally and they do not ovulate. 

Female Sex 1. Turner syndrome

Female Sex 1. Turner syndrome

Genes associated with most of the features of Turner(SHOX genes)

Researchers have not determined which genes on the X chromosome are associated with most of the features of Turner syndrome.

They have, however, identified one gene called SHOX(short stature homeo box) that is important for bone development and growth.

The loss of one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome.

Cytogenetic Location of Turner(SHOX )genes

• Cytogenetic Location: The SHOX gene is located on the short (p) arm of the X chromosome at position 22.33 ; on the short (p) arm of the Y chromosome at position 11.3.– Xp22.33;– Yp11.3

Inherit three X chromosomes--their genotype is XXX or more rarely XXXX or XXXXX.  As adults, these "super-females" are usually an inch or so taller than average with unusually long legs, but otherwise appear normal. 

They have normal development of sexual characteristics and are fertile.  They may have slight learning difficulties and are usually in the low range of normal intelligence (especially the XXXX and XXXXX individuals). 

2. Triple-X females

Sex Chromosome Abnormalities

Female Genotype Syndrome Male

Genotype Syndrome

XX normal XY normal

XO Turner  XXY Klinefelter

XXX Triple-X XYY XYY

Mosaicism and Chimerism

Mosaics and chimeras are persons that have more than one genetically-distinct population of cells.

In mosaics, the genetically different cell types all arise from a single zygote.

Mosaic: The post-fertilization occurrence of two or more cell lines with different genetic or chromosomal constitutions within a single individual or tissue.

an organism or one of its parts composed of cells of more than one genotype.

In chimeras originate from more than one zygote.

Mosaicism• Chromosomal mosaicism: When an individual has two or

more cell populations with a different chromosomal makeup, this situation is called chromosomal mosaicism.

• Germline mosaicism: Two or more genetic or cytogenetic cell lines confined to the precursor (germline) cells of the egg or sperm; formerly called gonadal mosaicism

Chimerism(cellular mosaicism )• The occurrence in an individual of two or more cell

populations of different chromosomal constitutions, derived from different zygotes.

• This contrasts with mosaicism in which the different cell populations are derived from a single zygote.

• Chimeras are formed from at least four parent cells (two fertilized eggs or early embryos fused together).

• Each population of cells keeps its own character and the resulting organism is a mixture of tissues. Chimeras are typically seen in animals; there are some reports of human chimerism

This condition is either inherited, or it is acquired through the infusion of allogeneic hematopoietic cells during transplantation or transfusion.

In nonidentical twins, chimerism occurs by means of blood-vessel anastomoses.

The likelihood of offspring being a chimera is increased if it is created via in vitro fertilization

Chimerism(cellular mosaicism )

Chromosome instability syndromes

They are a group of inherited conditions associated with chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.

The following chromosome instability syndromes are known:

- Ataxia Telagiectasia- Bloom Syndrome- Fanconi Anaemia

Thank You