UNIT 1: HUMAN GENETICS

MILESTONES IN HUMAN GENETICS

 Arnold: First observed chromosomes:1879

 Hansemann & Flemming Counted the chromosomes: 1891
 Winiwarter: Isolated X chromosome • Painter: Isolated Y chromosome
 Tijio and Albert Levan: 1956: Described correct chromosome number as 22 pair of autosomes and 2 sex
chromosomes.
 Levan introduced the use of Colchicine to arrest mitosis at metaphase.
 Hsu,Makino & Nishimura and Hughes: Hypotonic technique: In 1952 in karyotyping.
 Gall and Prudue described in situ hybridization techniques.

CHROMOSOME
It is a packaged and organized structure containing the DNA of a living organism.

• Chromosome arms divided into regions on the basis of landmarks The region adjacent to centromere of short
arm and long arm are given number 1 as p1, q1 respectively,. the next distal region is given 2 and so on

• The regions are subdivided into bands and the bands are subdivided into sub bands as the resolution increases
and the numbering done sequentially.

SHAPES OF CHROMOSOMES
The shapes of chromosomes are :

Metacentric chromosomes have

centromeres that lie near the centers of
the chromosomes.

Submetacentric chromosomes
contain centromeres in off-center
locations on the chromosomes. The
short arm of the chromosome is called p
(for petit) arm, whereas the long arm is
called the q arm

Acrocentric chromosomes have very short p arms. These chromosomes usually end in structures called
satellites, which are connected to the main structure of the chromosome by stalks.

Telocentrics are chromosomes that lack short arms. These chromosomes do not exist in humans.

International system for Human Cytogenetic Nomenclature.

CHROMOSOME BANDING
• Each human chromosome has a short arm ("p" for "petit")
and long arm ("q" for "queue"), separated by a centromere.

• Each chromosome arm is divided into regions, or

cytogenetic bands, that can be seen using a microscope and
special stains.• The cytogenetic bands are labeled p1, p2, q1,
q2, etc., counting from the centromere out toward the
telomeres.

• At higher resolutions, sub-bands can be seen within the bands. The sub-bands are also numbered from the
centromere out toward the telomere.
• Example 1: The cytogenetic map location of a gene is 7q31.2. This indicates that the gene is on chromosome 7, q
arm, band 3, sub-band 1, and sub-subband 2.

• The ends of the chromosomes are labeled ptel and qtel.

• Example 2: The notation 7qtel refers to the end of the long arm of chromosome

Chromosome Regions and Band Designations

The recommendations of “Paris Conference (1971): Standardization in Human Cytogenetics’’ provided a
diagrammatic representation of banding patterns, elucidating the typical band morphology for each
chromosome, which came to be known as an ideogram. The Paris Conference (1971) introduced a numbering
system helpful in designating specific bands and regions while describing a structural abnormality.

Why to study Banding pattern?

Always metaphase chromosomes whose size has condensed and whose diameter is increased are used for
chromosome banding studies after fixing the stage.

Banding is used to identify individual chromosomes unambiguously. It is especially critical for distinguishing
chromosomes of similar sizes and shapes

This allows you to see smaller pieces of the chromosome, so that you could identify smaller structural
chromosome abnormalities not visible on a routine analysis.

Classification of Banding Techniques

Based on GC and AT rich regions. Constitutive Heterochromatin Region.

1. Q banding:

The first banding method developed

• Uses quinacrine mustard or quinacrine dihydrochloride,

• creates a flourescent transfers band on exposure to UV light,

• Q­ bands fade over time not routinely used .

Q Banding Techniques Advantages

• Simple and Versatile. • Used where G band is not accepted.

• Used in study of chromosome heteromorphism.

Disadvantages

• Tendency to fade during examination, Photo-degradation,

Chromopore- absorb light of a particular wavelength due to a
chemical bond formed between dye and light, UV light breaks
the chemical bond.

2. G banding
 Uses Giemsa dye to produce
 transverse bands light (GC
 rich DNA) dark band (A­T rich DNA)
 G­bands are identical to Qbands, Around 400 bands
per haploid
 Advantages

 • Used in identification of bands rich in Sulphur content.

 • Used in the identification of chromosomal abnormalities
 • Gene Mapping.

Disadvantages • Not used in plants.

G banding not used in Plants. Why????

• Human mitotic metaphase chromosome is 2.3 times shorter.

• Plant mitotic metaphase chromosome is 10 times shorter than human chromosome.

• Hence difficult to demonstrate the arrangement of bands at this level of saturation with G banding
technique

3. Rbanding
• Treating chromosomes with a hot alkaline solution before Giemsa staining
• Produces bands that are the reverse of G­bands, called R­ bands.
• In R banding telomeres should appear as dark bands and their absence as the result of deletion is more
obvious.

4. C‐ Banding
• selectively stains constitutive
heterochromatin, and are located at all
centromeres and distal long arm of Y
chromosome.
• Staining with giemsa followed by heat
denaturation results in darkly staining
heterochromatic regions at centromere with
light staining chromosome arms.
C Banding Techniques Advantages
• Identification of chromosomes particularly
in insects and plants.
• Identification of bivalents at diakinesis
using both centromere position.
• Paternity testing. • Gene mapping.

5. Nuclear organizing region (NOR) banding

• Specific chromosomal region that forms and
maintain the nucleoli are called NOR.
• NOR located on stalk of acrocentric
chromosomes and contain gene for 18S and
28S rRNA.
• Stained by Geimsa (N­ banding) or silver
impregnation ( Ag­NOR)
N Banding Techniques Advantages
• Used in the identification of Nucleolar
organizer region.
• Superior banding pattern for plants.
 UNIT 2 : CYTOGENETICS
INDICATIONS FOR CYTOGENETIC ANALYSIS
• Prenatal – pregnancies involving older (>35yrs) women.

• Confirmation or exclusion of diagnosis known chromosomal syndromes.

• Unexplained psychomotor retardation with or without dysmorphic features.

• Abnormalities of sexual differentiation and development ­ ambiguous genitalia.

• Recurrent miscarriage, stillbirth or spontaneous abortions.

• Females with proportionate short stature and primary amenorrhea.

• Parents and children of persons with chromosomal translocations, deletions and duplications.

• Pregnancies at risk of aneuploidy from results of fetal ultrasound.

• Neoplastic conditions­ soft tissues and hematological.

Cytogenetic examination

 Clinical cytogenetics → determination of karyotype of patients with inborn defects

 Prenatal diagnostics → examination of chromosomal complement of embryos, in vitro fertilization
 Oncocytogenetics → specification of diagnosis and prognosis of malignant diseases
 Services of hygiene laboratories - testing of mutagenicity of chemicals on human organism on
chromosomal level, radiation cytogenetics etc.

Limitations of classical cytogenetics

 Sensitivity of chromosomal banding techniques is limited these techniques require a high rate of
dividing cells with good chromosomal morphology (resolution limit of 10 Mb)
 In some leukemias malignant cells are not proliferating in the cell culture (only the normal cells are
dividing) → the results of cytogenetic examination is not representative for malignant process
 chromosomal changes in leukemic cells are often complex or could be cryptic under the limit of light
microscopy chromosomal changes

APPROACH TO THE DIAGNOSIS OF CYTOGENETIC DISORDERS

1. Karyotyping 2. Insitu hybridization 3. Fluorescence insitu hybridization

4. Spectral karyotyping 5. Comparative genomic hybridization

KARYOTYPE

Particular chromosome complements of an individual or a related group of individuals, as defined by the

chromosome size, morphology and number is known as a “Karyotype”. Karyotype is a test to identify and
evaluate the size, shape, and number of chromosomes in a sample of body cells. Extra or missing chromosomes,
or abnormal positions of chromosome pieces, can cause problems with a person's growth, development, and
body functions.
Derived from Greek word “karyon”, which means "nucleus”, karyotype is represented as Idiogram.

• When the haploid set of chromosomes of an organism are ordered in a series of decreasing size, it is said to be
an idiogram.

• In other sense diagrammatic representation of a karyotype is an Idiogram.

• Standard display of stained and photographed chromosomes in metaphase spread, arranged in pairs, in order
of decreasing length.

Grygorii Levitsky (1931) seems to have been the first person to define the karyotype as the “phenotypic
appearance of the somatic chromosomes, in contrast to their genic contents”.

Size of chromosome Position of centromere Presence of secondary constriction Size of satellite

Types of Karyotypes:
Asymmetric Karyotype • Show larger difference between smaller and larger chromosome in a set.

• Have more acrocentric chromosomes.

• Have relatively advanced feature

Symmetric Karyotype • Show lesser difference between smaller and larger chromosome in a set.

• Have more metacentric chromosomes.

• Have no relatively advanced feature

Procedure for karyotyping:

1. Tissue sample

• Prenatal -Amniotic fluid ­ 20ml, Chorionic villi­ 25mg of

vascularized and budding villi from chorion frondosum, PUBS
(percutaneous umbilical blood sampling)

• Postnatal – Peripheral venous blood –4 ml of heparinized, Skin

fibroblasts­ 4mm diameter, Bone marrow­ 1 ml of heparinised
bone marrow, Lymph node­ 0.5 to 1 cm, Solid tumors­ Part of
specimen submitted for histopathological examination. Ideally
0.5­1 gm

2. Culture

• Culture medium – Preservative free sodium heparin, (RPMI 1640 ), mitotic stimulant (phytohemagglutinin) and
antibiotics( penicillin, streptomycin ).

• Short term culture: 1­3 days – blood, bone marrow, chorionic villi

• Long term culture: 1­3 wks ­ other tissue types

3. Arrest of cell division: at metaphase, by Colchicine [Deacetyl methyl colchicine] for 20 min.

4. Cells harvested – centrifugation, Incubated for 10min in hypotonic solution (dilute solution of KCl 0.075 mol)

5. Cell fixation­ 3:1 methanol/ glacial acetic acid mixture (carnoy’s) for 30min.

6. Staining : Trypsinization of the chromosomes prior to staining, weakens the DNA­Protein interactions, add
buffer (Na2HPO4 and NaH2PO4), banding techniques done with the dyes.

7. Microscopic analysis and photography

8. Karyotype production (manual/automated)

9. Interpretation

Representation of a karyotype
• By arranging chromosomes of somatic complement in a descending order of size keeping their centromeres in a
straight line.

Longest chromosome –on extreme left. Shortest chromosome –on extreme right Sex chromosomes
–allosomes–extreme right

The nomenclature for a karyotype follows certain basic rules. When designating a karyotype, the first item
specified is the total number of chromosomes, including the sex chromosomes present in that cell, followed by a
comma (,) and the sex chromosomes, in that order. Thus a normal female karyotype is written as 46,XX and a
normal male karyotype as 46,XY. The format is a continuous string of characters, without a space between
characters. A chromosome abnormality, when present, follows the sex chromosome designation along with an
abbreviation or symbol denoting the abnormality.

Advantages of Karyotyping
• Reveals structural features of each chromosomes.

• Helps in studying chromosome banding pattern.

• Helps in the identification of chromosomal aberrations.

• Diagnosis of prenatal genetic defects. • Aids in studying evolutionary changes .

Extra: Species showing a greater asymmetry is more advanced. HOW???

1. Degree of asymmetry

• Proportion of metacentric, acrocentric chromosomes in a set.

• Ratio between size of largest and smallest chromosomes in a set.

2. Interpretation

• Higher the proportion of acrocentric chromosomes, Greater the value of size ratio, more asymmetrical is a
karyotype

Successful cytogenetic analysis depends on –

­ Chromosomes must be identified & characterized normal/abnormal, Chromosomes must be separated from
one another, Arranged according to the length in a decreasing order, Cells must be in adequate numbers Analysis
must be performed on viable Chromosomes

CHROMOSOME PAINTING
Chromosome 'painting' refers to the hybridization of fluorescently labeled chromosome-specific, composite
probe pools to cytological preparations.

• First termed by Pinkel et.al in 1988. • Chromosome painting coupled with Fluorescence in situ hybridization
(FISH) is used routinely for identification of chromosomes.

Helps in the identification of Chromosomal rearrangements.

Helps in the identification of Chromosomal breakpoints.

Procedures Sample preparation and hybridization

• Prepare slides with metaphase chromosomes . • Dehydrate in ethanol. • Denature DNA at 70ᵒC. • Denature
labeled probe. • Incubate at 37ᵒC for 4-16 hours for hybridization.

Helps in determination of extra chromosomal material.

In situ hybridization
• Main purpose – detection of specific nucleic acid sequences in chromosomes.

• In early studies, radio isotopes were used as labels for nucleic acids, and detection of hybridized sequence were
done with autoradiography.• As technology advanced, detection by enzymatic and fluorescent means become
available for quick and safe analysis.

• Uses Detection of missing,additional chromosomes,chromosome rearrangements and microdeletions.

Fluorescence in situ hybridization (FISH)

Permits detection of selected acquired genetic changes in dividing (metaphase) and nondividing (interphase
nuclei) cells

Is useful in establishing the percentage of neoplastic cells at the time of diagnosis and after therapy

FISH studies are used to investigate the origin and progression of hematologic malignancies and to establish
which hematopoietic compartments are involved in neoplastic processes

PROCEDURE:

The probe and metaphase target are denatured by a high temperature and formamide.

Probe is hybridized to the chromosomal target.

Unbound probe is removed by post hybridization washes.

Bound probe is detected by fluorescence Microscopy

TYPES OF PROBES USED

1] Centromere enumerating probe (CEP)

Bind to highly repitative sequence alpha satellite sequences of centromere and produce strong signals. Similar
sequences in pericentric region results in cross hybridization artifact.

2] Locus specific identifier(LSI) probe

Target distinct chromosomal region of interest and utilize single copy rather than repetitive DNA.

3] Whole chromosomes probes

Also known as chromosome painting probes or chromosomes libraries, consists of thousands of overlapping
probes that recognize unique and moderately repetitive sequences along the entire length of individual
chromosomes

Advantages –

­ Many more cells can be examined at a single time.

­ Metaphases are not essential, so abnormalities can be detected in non dividing cells.

­ Can be performed in a shorter period of time.

­ Abnormalities that cannot be detected by conventional cytogenetic analysis may be detected.

Main disadvantage –

­ Only those abnormalities that are specifically sought will be found whereas conventional analysis permits all
chromosomes to be evaluated

Permeabilization problems Uneven cell penetration

High amount of background autofluorescene

Conclusion

. Studies structural features of each chromosomes.

Helps in studying Ideograms, chromosome banding pattern and Chromosomal painting techniques.

Helps in the identification of chromosomal aberrations. Helps in studying evolutionary changes.

SPECTRAL KARYOTYPING (multicolor fluorescence in situ hybridization)

24 colour multi chromosomal painting assay that allows visualization of all human chromosomes in 1
experiment.

• Uses –

1. Ability to detect complex chromosomal rearrangements.

2. Identifies marker chromosomes– makes this highly sensitive and valuable tool for identifying recurrent
chromosomal abnormalities.

chromosomes of a single cell…Pepsin treatment ( at 37 degree C for 3­5 min)…labeled with a different
combination of fluorescent dyes and allowed to hybridize, specific for each chromosome… Imaged immediately
and Spectral karyotype done using SPK View softwareSP

Comparative genomic hybridization

2 genomes Test DNA Normal DNA Labeled with 2 different fluorescence(green and red)

Dyes….Allowed to hybridize… 2 samples are equal or Produce yellow fluorescence OR focal deletion

Duplication fluorescence skewed towards green or red

• Uses ­ Has higher sensitivity ­ Can be performed using DNA extracted from fixed as well as tumor sample

­ Technique makes it possible to perform a genome wide scan for structural alteration even on those cases for
which other cytological analysis is not feasible or successful.

Cancer cells
High genome instability - one of the most important events in the malignant process

Gene mutations and numerical chromosomal aberrations

Nonrandom chromosomal aberrations are associated with specific disease subtypes and have a clear prognostic
implications.
Method for diagnosiss: Conventional cytogenetic analysis, I-FISH, WCP-FISH, mFISH, mBAND, CGH, Array CGH

Multicolor FISH ‐ mFISH

allows in one hybridization experiment distinguish according to different color every pair of autosomes and sex
chromosomes and then it is possible to make analyses of the whole genome and every structural and numerical
rearrangement

analyses of complex chromosomal rearrangements in bone marrow cells of patients with hematological
malignancies will bring us detailed informations about involvement of specific chromosomes or their regions into
rearrangements

Multicolor banding with high resolution ‐ mBAND

enables determination of exact breakpoints of chromosomal aberrations with much higher resolution than
classical banding

Array-based comparative genomic hybridization (aCGH)

new tool to search for recurrent gains or loss of chromosomal regions throughout the genome according to
detection with very high resolution of copy number changes at DNA level

only recently is aCGH successfully utilised in diagnostics of leukemias and the results revealed a large spectrum of
genomic imbalancies, including novel recurrent deletions and amplifications

The impact of conventional and molecular cytogenetic analysis in oncohematology

Is part of the work up at diagnosis Provides comprehensive information on the karyotype

 help to specify diagnosis  help to determine the prognosis  help monitor effectiveness of treatment
 UNIT 3: SYNDROMES
Chromosomal aberrations are broadly classified as numerical or structural aberrations.

Numerical Aberrations
Numerical aberrations are those that cause a change (addition or deletion) in the number of chromosomes.
They are further classified as euploidy changes or aneuploidy changes. • Euploidy is the condition when an
organism gains or losses one or more complete set of chromosomes, thus causing change in the ploidy
number. For example, triploid (3n), tetraploid (4n) etc. (Table 2.1).

• Aneuploidy is the condition when an organism gains or losses one or more chromosomes and not the entire
set. For example, trisomy (2n + 1), monosomy (2n – 1) (Table 2.1).

In humans, euploidy conditions do not exist

because the extent of abnormality is too large to
sustain life. Aneuploidy conditions, however, are
more common and are manifested in disorders
such as Down syndrome, Klinefelter syndrome
and Turner syndrome.

Structural Aberrations
Structural aberrations are those that involve a
change in the chromosome structure. These
include deletions, duplications and
rearrangements (inversions and translocations).
Structural changes occur when chromosomes
break and later rejoin in combinations that are
different from the original. When there is a net loss or gain or chromosomal segments, the change is called an
unbalanced structural change. When there is no net loss or gain of chromosomal segments, instead there is
only a rearrangement; it is called a balanced structural change (Figure 2.2). Thus, balanced changes usually do
not show any abnormal phenotypes, which unbalanced changes do. You should keep in mind that these
changes are not mutations in genes; they only cause the number and order of genes to be changed.

As with aneuploidy changes, structural changes are also seen in humans, and manifest in disorders such as Cri-
du-chat syndrome, Wolf-Hirschhorn syndrome, Prader-Willi syndrome and Angelman syndrome.

DOWN SYNDROME
Down syndrome was one of the first reported chromosomal abnormalities in humans. It was described as
Mongolian Idiocy by John Langdon Down in 1866. It wasn’t until 1959 that it was shown to be caused by the
presence of an extra chromosome 21, resulting in an increase of number of chromosomes to 47 (karyotype 47,
XX / XY, +21). Thus, this disorder is also known as trisomy 21 or Down syndrome. Figure 2.3 shows the
karyotype of an individual with 3 copies of chromosome 21, or trisomy 21. With an incidence of 1 in 800 live
births, this is one of the common trisomy seen in humans. This incidence increases to 1 in 350 when the
woman conceives beyond 35 years of age and to 1 in 25 when she conceives beyond 45 years. Down syndrome
is caused by trisomy 21 in almost 90% of the cases. 6% of the cases are also shown to be caused by a
translocation rather than a numerical change (see Section 2.5.2) and the other 4 % are known to be caused by
mosaicism.

There are many phenotypic manifestations that are typical in patients of this syndrome. However, as in other
syndromes, not all affected individuals show all the symptoms. Any single individual usually expresses only a
subset of the manifestations. Some of the most common are:

• Flat face, round head, and typical epicanthic fold of the eyes • Short, broad hands • Mental retardation •
Hypotonia – poor muscle tone • Short stature• Protruding furrowed tongue • Mild to moderate
developmental disabilities • Typical dermatoglyphic patterns (palm and fingerprint patterns)

The most common cause of this trisomy is the non-disjunction (see Section 2.5.1) or the failure of separation of
the chromosomes during meiotic division. Due to this one of the gametes undergoing fertilization contains two
copies of chromosome 21 instead of the normal one copy (gametes are haploid containing one copy of each
chromosome). This non-disjunction can occur at either meiosis I or II. Chromosomal analysis has shown that
75% of the cases are due to nondisjunction occurring at meiosis I. When such a gamete is fertilized by a normal
gamete, it results in trisomy 21.

Cri‐du‐chat Syndrome
This syndrome results from a deletion on the short arm of chromosome 5. It is also known by other names
such as 5p deletion syndrome and Lejeune’s syndrome. The disorder gets its name from the characteristic cat-
like cry of affected infants.

Described first by Jérôme Lejeune in 1963, this disorder has an incidence of 1 in 25,000 live births. This
disorder, being autosomal, should affect males and females in equal frequencies; but incidence is seen to be
more in females by a ratio of 4:3 of females: males affected.

The deletion occurring on the short (p arm) arm of chromosome 5 varies in different affected individuals. The
phenotypic effects are also shown to vary between individuals. Most cases show deletion of 30 to 60% of the
terminal region of the short arm. Studies show that larger deletions tend to result in more severe intellectual
disability and developmental delay than smaller deletions. Figure 2.7 shows the chromosome 5 pair from a
karyotype of an individual with this syndrome. You can see that one of the chromosomes (left) has the normal
length of the short arm while the other (right) has significantly reduced short arm. More specifically, a dark
band is prominently seen in the normal chromosome, which is missing in the deletion chromosome.

Affected individuals characteristically show a distinctive, high-pitched, catlike cry in infancy with growth
failure, microcephaly, facial abnormalities, and mental retardation throughout life. Some common clinical
manifestations are: • Cry that is high-pitched and sounds like a cat • Downward slant to the eyes • Low birth
weight and slow growth • Low-set or abnormally shaped ears • Mental retardation (intellectual disability) •
Partial webbing or fusing of fingers or toes • Slow or incomplete development of motor skills • Small head
(microcephaly) • Small jaw (micrognathia) • Wide-set eyes

Edward Syndrome
Trisomy 18 is a chromosomal abnormality. It's also called Edwards syndrome, after the doctor who first
described it. In the case of trisomy 18, the baby has three copies of chromosome 18. This causes many of the
baby's organs to develop in an abnormal way.

There are three types of trisomy 18:

 Full trisomy 18. Theextra chromosome is in every cell in the baby's body. This is by far the most
common type of trisomy 18.
  Partial trisomy 18.The child has only part of an extra chromosome 18. That extra part may be
attached to another chromosome in the egg or sperm (called a translocation). This type of trisomy 18
is very rare.

 Mosaic trisomy 18. The extra chromosome 18 is only in some of the baby's cells. This form of trisomy
18 is also rare.

 Trisomy 18 is the second most common type of trisomy syndrome, after trisomy 21 (Down
syndrome). About 1 in every 5,000 babies is born with trisomy 18, and most are female.

 The condition is even more common than that, but many babies with trisomy 18 don't survive past
the second or third trimester of pregnancy.

What Are The Symptoms of Trisomy 18?

Babies with trisomy 18 are often born very small and frail. They typically have many serious health problems
and physical defects, including:

 Cleft palate

 Clenched fists with overlapping fingers that are hard to straighten

 Defects of the lungs, kidneys, and stomach/intestines

 Deformed feet (called "rocker-bottom feet" because they're shaped like the bottom of a rocking
chair)

 Feeding problems

 Heart defects, including a hole between the heart's upper (atrial septal defect) or lower (ventricular
septal defect) chambers

 Low-set ears

 Severe developmental delays

 Chest deformity

 A doctor may suspect trisomy 18 during a pregnancy ultrasound, although this isn't an accurate way
to diagnose the condition. More precise methods take cells from the amniotic fluid (amniocentesis) or
placenta (chorionic villus sampling) and analyze their chromosomes.

 After birth, the doctor may suspect trisomy 18 based on the child's face and body. A blood sample can
be taken to look for the chromosome abnormality. The chromosome blood test can also help
determine how likely the mother is to have another baby with trisomy 18

Patau Syndrome
Trisomy 13, also called Patau syndrome, is a chromosomal condition associated with severe intellectual
disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart
defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers
or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate),
and weak muscle tone (hypotonia). Due to the presence of several life-threatening medical problems, many
infants with trisomy 13 die within their first days or weeks of life. Only five percent to 10 percent of children
with this condition live past their first year.
Trisomy 13 occurs in about 1 in 16,000 newborns. Although women of any age can have a child with trisomy
13, the chance of having a child with this condition increases as a woman gets older.

Cause: Most cases of trisomy 13 result from having three copies of chromosome 13 in each cell in the body
instead of the usual two copies. The extra genetic material disrupts the normal course of development, causing
the characteristic features of trisomy 13.
Trisomy 13 can also occur when part of chromosome 13 becomes attached (translocated) to another
chromosome during the formation of reproductive cells (eggs and sperm) or very early in fetal development.
Affected people have two normal copies of chromosome 13, plus an extra copy of chromosome 13 attached to
another chromosome. In rare cases, only part of chromosome 13 is present in three copies. The physical signs
and symptoms in these cases may be different than those found in full trisomy 13.

A small percentage of people with trisomy 13 have an extra copy of chromosome 13 in only some of the body's
cells. In these people, the condition is called mosaic trisomy 13. The severity of mosaic trisomy 13 depends on
the type and number of cells that have the extra chromosome. The physical features of mosaic trisomy 13 are
often milder than those of full trisomy 13.

Most cases of trisomy 13 are not inherited and result from random events during the formation of eggs and
sperm in healthy parents. An error in cell division called nondisjunction results in a reproductive cell with an
abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of chromosome
13. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have
an extra chromosome 13 in each cell of the body.

Translocation trisomy 13 can be inherited. An unaffected person can carry a rearrangement of genetic material
between chromosome 13 and another chromosome. These rearrangements are called balanced translocations
because there is no extra material from chromosome 13. A person with a balanced translocation involving
chromosome 13 has an increased chance of passing extra material from chromosome 13 to their children.

SEX CHROMOSOME SYNDROMES

Turner Syndrome
This syndrome is characterized by the partial or complete absence of one of the X chromosomes in females.
This results in a reduction of the total number of chromosomes to 45 (karyotype – 45, X). Thus, this syndrome
is also called Monosomy X. Its first description as a syndrome was by Henry Turner in 1938. Later, in 1954, the
absence of barr body (inactivated X-chromosome seen in buccal cells) and presence of only one X chromosome
was noted. As we saw in Down syndrome, monosomy of X is not the only cause of this syndrome. Mosaicism,
deletions and isochromosome (see Sections 2.3.4 and 2.4.6) have also been shown to cause this condition.

It is well known that, of the two X chromosomes in females, one is inactivated throughout her lifetime. If
normal females have only one active X chromosome, then why should the loss of one X chromosome cause
abnormal phenotype? The answer lies in the fact that although we speak of inactivated X chromosome, not all
genes on that chromosome are being inactivated. There is a small subset of genes on the X chromosomes that
are required to be expressed by both chromosomes for normal female development. Thus, individuals who
lack one X chromosome fail to develop normal female character.

Some of the commonly seen manifestations of Turner syndrome are: • Primary hypogonadism – poor ovary
development • Short stature • Minimal breast development • Broad shield-like chest with widely spaced
nipples • Absence of menstrual periods• Absence of secondary sexual characteristics • Horseshoe-shaped
kidney • Inability to produce gametes – sterility
Klinefelter Syndrome
The presence of an additional X chromosome in males causes abnormal sexual development and is described
as Klinefelter syndrome. This set of characteristics was first described by Harry Klinefelter in 1942. In 1959 it
was shown to be due to the presence of an additional X chromosome in males by the presence of barr bodies
in these males (normal males do not show barr body). The additional X chromosome results in an increase in
the total number of chromosomes to 47 (karyotype 47, XXY). It has an overall incidence of 1 in 1000 live male
births. While most patients show the XXY condition, individuals showing variations like XXXY or XXYY have also
been reported.

The additional X chromosome arises due to non-disjunction (see Section 2.5.1) during meiosis. Due to this, the
gamete contains two X chromosomes rather than one. When such an egg containing XX is fertilized by sperm
containing Y, an XXY zygote is formed that develops into a Klinefelter male. The extra X chromosome may be
either of maternal or paternal origin, but it is more often to be of maternal origin.

Individuals with this syndrome show hypogonadism and reduced fertility. These males do no develop
masculine secondary sexual characteristics and show femaletype characteristics. Some of the clinical
manifestations include:

• Primary male hypogonadism • Reduced facial, body and pubic hair • Small and soft testes • Slight learning
difficulties • Increased breast tissue – gynacomastia • Long limb bones and lanky body • Azoospermia –
absence of sperm production leading to infertility

Multiple XXX syndrome

Triple X syndrome, also called trisomy X or 47,XXX, is a genetic disorder that affects about 1 in 1,000 females.
Females normally have two X chromosomes in all cells — one X chromosome from each parent. In triple X
syndrome, a female has three X chromosomes.
Many girls and women with triple X syndrome don't experience symptoms or have only mild symptoms. In
others, symptoms may be more apparent — possibly including developmental delays and learning disabilities.
Seizures and kidney abnormalities occur in a small number of girls and women with triple X syndrome.
Symptoms
Signs and symptoms can vary greatly among girls and women with triple X syndrome. Many experience no
noticeable effects or have only mild symptoms.
Being taller than average height is the most typical physical feature. Most females with triple X syndrome
experience normal sexual development and have the ability to become pregnant. Some girls and women with
triple X syndrome have intelligence in the normal range, but possibly slightly lower when compared with
siblings. Others may have intellectual disabilities and sometimes may have behavioral problems.
Occasionally significant symptoms may occur. If signs and symptoms are present, they are often variable. Signs
and symptoms in girls and women with triple X syndrome may include an increased risk of:

 Delayed development of speech and language skills, as well as motor skills, such as sitting up
and walking

 Learning disabilities, such as difficulty with reading (dyslexia), understanding or math

 Behavioral problems, such as attention-deficit/hyperactivity disorder (ADHD) or symptoms of

autism spectrum disorder

 Psychological problems, such as anxiety and depression

  Problems with fine and gross motor skills, memory, judgment and information processing
Sometimes triple X syndrome may be associated with these signs and symptoms:

 Vertical folds of skin that cover the inner corners of the eyes (epicanthal folds)

 Widely spaced eyes

 Abnormally curved pinky fingers

 Flat feet

 Abnormally shaped breastbone

 Weak muscle tone (hypotonia)

 Seizures

Although triple X syndrome is genetic, it's usually not inherited — it's due to a random genetic error.
Normally, people have 46 chromosomes in each cell, organized into 23 pairs, including two sex chromosomes.
One set of chromosomes is from the mother and the other set is from the father. These chromosomes contain
genes, which carry instructions that determine everything from height to eye color.
The pair of sex chromosomes — either XX or XY — determines a child's sex. A mother can give the child only an
X chromosome, but a father can pass on an X or a Y chromosome:

 If the child receives an X chromosome from the father, the XX pair makes the child genetically a
female.

 If the child receives a Y chromosome from the father, the XY pair means the child is genetically
a male.
Females with triple X syndrome have a third X chromosome from a random error in cell division. This error can
happen before conception or early in the embryo's development, resulting in one of these forms of triple X
syndrome:

 Nondisjunction. In most cases, either the mother's egg cell or the father's sperm cell divides
incorrectly, resulting in an extra X chromosome in the child. This random error is called
nondisjunction, and all the cells in the child's body will have the extra X chromosome.

 Mosaic. Occasionally, the extra chromosome results from an incorrect cell division caused by a
random event early in the embryo's development. If this is the case, the child has a mosaic
form of triple X syndrome, and only some cells have the extra X chromosome. Females with the
mosaic form may have less obvious symptoms.

Triple X syndrome is also called 47,XXX syndrome because the extra X chromosome results in 47 chromosomes
in each cell instead of the usual 46.
Complications
Although some females may have mild or no symptoms associated with triple X syndrome, other girls and
women experience developmental, psychological and behavioral problems that may lead to a variety of other
issues, including:

 Work, school, social and relationship problems

 Poor self-esteem

 Need for additional support or assistance with learning, activities of daily living, school or work

XYY syndrome

XYY syndrome is a genetic condition that occurs when a male has an extra copy of the Y chromosome in each
of their cells (XYY). Sometimes, this mutation is only present in some cells. Males with XYY syndrome have 47
chromosomes because of the extra Y chromosome.

This condition is also sometimes called Jacob’s syndrome, XYY karyotype, or YY syndrome. According to the
National Institutes of Health, XYY syndrome occurs in 1 out of every 1,000 boys.

For the most part, people with XYY syndrome live typical lives. Some may be taller than average and face
learning difficulties or speech problems. They may also grow up with minor physical differences, such as
weaker muscle tone. Besides these complications, though, males with XYY syndrome don’t usually have any
distinguishing physical features, and they have normal sexual development.

What causes XYY syndrome?

XYY syndrome is the result of a random mix-up, or mutation, during the creation of a male’s genetic code.
Most cases of XYY syndrome are not inherited. Researchers don’t believe that there’s any genetic
predisposition to it. That is, men with XYY syndrome are not more or less likely than other men to have
children with XYY syndrome. The random error can occur during the formation of sperm or at different times
during the formation of an embryo. In the latter case, a male may have some cells that are not affected. This
means that some cells may have XY genotype while others have XYY genotype.

What are the symptoms of XYY syndrome?

The signs and symptoms of XYY syndrome differ from person to person and age to age.

Symptoms in a baby who has XYY syndrome can include:

 hypotonia (weak muscle tone)

 delayed motor skill development, such as with walking or crawling

 delayed or difficult speech

Symptoms in a young child or teenager with XYY syndrome can include:

 an autism diagnosis

 attention difficulties

 delayed motor skill development, such as with writing

 delayed or difficult speech

 emotional or behavioral issues

  hand trembling or involuntary muscle movements

 he following treatment options may help address some of the most common effects of XYY syndrome.
 Speech therapy: People with XYY syndrome may have speech or motor skill disabilities. Healthcare
professionals can help treat these issues. They can also provide plans for future improvements.
 Physical or occupational therapy: Some younger people with XYY syndrome have delayed motor skill
development. They may also have difficulty with muscle strength. Physical therapists and
occupational therapists can help people overcome these issues.
 Educational therapy: Some people with XYY syndrome have learning disabilities. If your child has this
syndrome, talk with their teacher

WHAT IS DERMATOGLYPHICS?
The word dermatoglyphics comes from two Greek words (derma = skin and
glyphe = carve) and refers to the friction ridge formations which appear on the palms of the hands and soles of
the feet. Dermatoglyphics is the scientific study of fingerprints. The term was coined by Dr. Harold Cummins,
the father of American fingerprint analysis. Personality can be traced early in the mother’s womb, and it is
reflected in fingerprints (dermatoglyphics). Since each person’s fingerprints are unique, we can understand
one’s innate potential, personality, and preferences by analyzing dermatoglyphics. The study of fingerprints
has become more common, therefore, some parents began to analyse their child’s (or baby’s) prints; with the
intention to identify their potential early, and provide guidance accordingly to help expand their potential.

FINGERPRINTAND POTENTIALS
Dermatoglyphics was first applied in the pathological studies, later
to be extended to study nymphomania and violent criminals in the FBI. Because finger prints are genetic, we
can identify the personality and potential of a person based on his/her 10 finger prints. Fingerprints are usually
formed at the 13th to 19th week of an embryo. It is revealed 6 months after birth. Since each person
fingerprints is unique, fingerprints are also used for personal identification purposes. And parents can also
understand their children innate character and learning potential.

USES OF DERMATOGLYPHICS
Dermotoglyphics is like a map that leads one to understand his
own potential and talents. Everyone inherits innate intelligence from their parents. By analyzing
dermatoglyphy, we can accurately understand the distribution and amount of cells in the left and right brain of
the cell, and predict where the potential lies. Although everyone is bored with strengths and weaknesses; if
they are identified early, we may further develop the strengths and improve our weakness, so that the left and
right brain may grow in a more balanced and blend

DERMATOGLYPHICS ANALYSIS PROCEDURE

Dermatoglyphics Analysis Procedure includes collecting fingerprints, palm prints and foot prints.
Step 1: Apply ink on the palms and stamp on paper. Step 2 : Scan prints into a computer to analyze the
patterns on the prints. Step 3 : Calculate and analyze the number of prints in order to understand genetic
sequence. Step 4: Analyze one’s potential based on data.

11 BASIC PATTERNS OF FINGERPRINT:

Simple arch, tented arch, ulnar loop, radial loop, concentric whorl, spiral whorl, press whorl, imploding whorl,
composite whorl, peacock’s eye, variant patterns

USE OF DERMATOGLYPHICS IN DIAGNOSIS OF VARIOUS PATHOLOGIES:

DERMATOGLYPHICS IN DIABETES MELLITUS
TYPE II: Dermatoglyphics plays a significant role in diagnosis of diabetes mellitus using abnormalities in
fingerprint patterns. It is a genetic disease and hence dermatoglyphics can be significant in diagnosis as it has a
genetic background which may cause variations. Diabetes patients with Type I affects people in childhood as
well as in adolescence. It shows characteristic reduction in loops and notable increase in whorls and arches.
Type II have increase in the frequency of whorls and decrease in ulnar loops and no significant changes in
radial loops in both hands irrespective of their sex. Males had significant
reduction in arches in right hand whereas
females in left.

KANNAR’S SYNDROME: It is the pathology of dermatoglyphics caused by infantile autism. Infantile autism is
caused by a wide range of neurological and psychological disorders which result in delayed speech lack of
verbal communication and other communicative functions. The onset of this syndrome is around 30 months of
age and the symptoms progress with the onset of Asperger syndrome and Ret syndrome. Severe forms of
manifestations include hearing loss, mental retardation with epilepsy, dyslexia, Martin bell’s syndrome and
rare cases of tuberous sclerosis. In Digital dermatoglyphics, patients suffering from this syndrome
have a high frequency of arches and lower loops. Arches of fourth and fifth fingers and first finger of left hand
shows higher frequency than the others. Palmer dermatoglyphic distortions were common in left palm. These
patients show prominent increase in ulnar loops.

DOWN’S SYNDROME: Down’s syndrome is a genetic disorder caused by presence of third copy of chromosome
21. It is a common disease characterized by
facial intellectual capacities. abnormalities and decreased It results in severe infections of
upper respiratory tract due to partial defects in immune systems.[6] Manifestations of down’s syndrome
include high frequency of creases, bilateral, radial loops on digits 4 and 5 and ulnar loops