Genetics

Short essays

1. Genetic counselling
 Definition: A process of communication and education that addresses concerns relating to the
development and/or transmission of a hereditary disorder.
 Goal: To help a patient learn more about the causes of genetic conditions and how they affect
them.
 Indications:
o Personal or family history of a genetic condition, birth defect, chromosomal disorder,
or hereditary cancer.
o Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
o A child with a known inherited disorder, a birth defect, mental retardation, or
developmental delay.
o A woman who is pregnant or plans to become pregnant at or after age 35.
o Abnormal test results that suggest a genetic or chromosomal condition.
o An increased risk of developing or passing on a particular genetic disorder on the
basis of a person’s ethnic background.
o People related by blood (for example, cousins) who plan to have children together.
 Steps of genetic counselling:
o Diagnosis—based on accurate family history, medical history, examination, and
investigations
o Assessment of risk
o Communication
o Discussion of options
o Long-term contact and support
 What happens during a genetic consultation?
o When a person is diagnosed with a genetic condition, the genetics professional
provides information about the diagnosis, how the condition is inherited, the chance
of passing the condition to future generations, and the options for testing and
treatment.
o During a consultation, a genetics professional will:
 Interpret and communicate complex medical information.
  Help each person make informed, independent decisions about their health
care and reproductive options.
 Respect each person’s individual beliefs, traditions, and feelings.
o A genetics professional will NOT:
 Tell a person which decision to make.
 Advise a couple not to have children.
 Recommend that a woman continue or end a pregnancy.
 Tell someone whether to undergo testing for a genetic disorder.
2. Aneuploidy
 Aneuploidy : Refers to loss or gain of one or more chromosomes
o Monosomy: The absence of a single chromosome is referred to as monosomy.
Monosomy for an autosome is almost always incompatible with survival to term.
Lack of contribution of an X or a Y chromosome results in a 45,X karyotype which
causes Turner syndrome
o Trisomy: presence of an extra chromosome is referred to as trisomy. (eg: Down
syndrome-trisomy 21;Edward syndrome-trisomy 18. Patau syndrome-trisomy 13)
o Tetrasomy: presence of 2 extra chromosome is referred to as tetrasomy.
o Cause for aneuploidy: Results because of Non-Disjunction in meiosis
o Normally the bivalent pair of homologous chromosomes separate during anaphase of
cell division. Failure of separation of one of the pairs of homologous
chromosomes during anaphase is called non-disjunction.
o Non disjunction in meiosis: usually results in trisomy/monosomy/tetrasomy

o
3. X chromosome
 The X chromosome is one of the two sex chromosomes in humans (the other is the Y
chromosome).
 The sex chromosomes form one of the 23 pairs of human chromosomes in each cell.
 The X chromosome spans about 155 million DNA building blocks (base pairs) and represents
approximately 5 percent of the total DNA in cells.
 The X chromosome contains 800 to 900 genes that provide instructions for making proteins.
These proteins perform a variety of different roles in the body.
 Each person normally has one pair of sex chromosomes in each cell.
 Females have two X chromosomes, while males have one X and one Y chromosome. Early in
embryonic development in females, one of the two X chromosomes is randomly and
permanently inactivated in cells other than egg cells. This phenomenon is called X-
inactivation or Lyonization. X-inactivation ensures that females, like males, have one
functional copy of the X chromosome in each body cell. Because X-inactivation is random, in
normal females the X chromosome inherited from the mother is active in some cells, and the
X chromosome inherited from the father is active in other cells.
 The following chromosomal conditions are associated with changes in the structure or
number of copies of X chromosome.
o Klinefelter syndrome
o Turner syndrome
o 48,XXYY syndrome
o intestinal pseudo-obstruction
o microphthalmia with linear skin defects syndrome
o triple X syndrome
4. Y chromosome

 The Y chromosome is one of the two sex chromosomes in humans (the other is the X
chromosome).
 The sex chromosomes form one of the 23 pairs of human chromosomes in each cell.
 The Y chromosome spans more than 59 million building blocks of DNA (base pairs) and
represents almost 2 percent of the total DNA in cells.
 Each person normally has one pair of sex chromosomes in each cell. The Y chromosome is
present in males, who have one X and one Y chromosome, while females have two X
chromosomes.
 The Y chromosome likely contains 50 to 60 genes that provide instructions for making proteins.
 Because only males have the Y chromosome, the genes on this chromosome tend to be involved
in male sex determination and development. Sex is determined by the SRY gene, which is
responsible for the development of a fetus into a male. Other genes on the Y chromosome are
important for male fertility.
 The following chromosomal conditions are associated with changes in the structure or number of
copies of Y chromosome.
o 46,XX testicular disorder of sex development
o 47,XYY syndrome
o 48,XXYY syndrome
o Y chromosome infertility
 5. Sex linked inheritance
 Sex-linked inheritance refers to the pattern of inheritance shown by genes that are located on
either of the sex chromosomes.
 Types:
a. X linked
i. X linked recessive
ii. X linked dominant
b. Y linked

X linked recessive inheritance: An X-linked recessive trait is one determined by a gene carried on the
X chromosome and usually manifests only in males.

Rules:

o The incidence of disease is very much higher in males than in females.

o The mutant allele is passed from an affected man to all of his daughters, but they do not express
it.
o A heterozygous ‘carrier’ woman passes the allele to half of her sons, who express it, and half
her daughters who do not.
o The mutant allele is NEVER passed from father to son.

Risk calculation

XH : normal

Xh : hemophilic gene

o Examples:
o Haemophilia A (Factor VIII)
 o Haemophilia B (Factor IX)
o G6PD deficiency
o Red and green colour blindness
o Duchenne muscular dystrophy (dystrophin)
o Fragile X syndrome
o Becker muscular dystrophy (dystrophin)
o Agammaglobulinaemia (X-linked)
o Ocular albinism
o Hunter syndrome

X linked dominant inheritance: Disorders that are manifest in the heterozygous female as well as in the
male.

Rules:

o The condition is expressed and transmitted by BOTH sexes.

o The condition occurs twice as frequently in females as in males.
o An affected man passes the condition to every daughter, but never to a son.
o An affected woman passes the condition to half her sons and half her daughters.
o Females are usually less seriously affected than males.

Risk calculation:

XP: Phosphatemia gene

Examples:

o Hypophosphataemia (vitamin D resistant rickets)

 o Hereditary motor and sensory neuropathy
o Incontinentia pigmenti (lethal in males)
o Rett syndrome (can be lethal in males)
o Oro-facio-digital syndrome

Y linked inheritance: Y linked inheritance or holandric inheritance implies that only males are affected.

Rules:

o Y-linked genes are expressed in and transmitted only by males, to all their sons.

Example: Hypertrichosis (hairiness) of ear rims

6. Cri du chat syndrome
o Cri-du-chat syndrome is also called as Lejeune syndrome caused by micro deletions in short arm
of chromosome 5
o Frequency: 1/20 000–1/50 000
o Karyotype: 46,XX,del(5)(p15.2)
o Clinical Features:
o The newborn baby has a low birth weight and makes a distinctive cry similar to that of a
kitten due to under-development of the larynx (French: ‘cri du chat’: ‘cry of the cat’).
o Facial features: microcephaly, hypertelorism, epicanthic folds, divergent strabismus,
low-set ears, hypotonia, severe breathing problems and often failure to thrive.
o Patent ductus arteriosus is present in 30%.
o Severe intellectual handicap (IQ ∼35).
o Management: A structured exercise regime is recommended, plus verbal stimulation and
correction of squints.
o Lifespan: Survival into adulthood sometimes occurs.
7. Autosomal dominant inheritance
 A trait or disorder that is determined by a gene on an autosome is said to show autosomal
inheritance
 An autosomal dominant trait is one that manifests in the heterozygous state, that is, in a person
possessing both an abnormal or mutant allele and the normal allele.
 Rules:
o Both males and females express the allele and can transmit it equally to sons and
daughters.
o Every affected person has an affected parent (‘vertical’ pattern of expression in the
pedigree). Direct transmission through three generations is practically diagnostic of a
dominant.
o Any child born to a person affected with a dominant trait or disorder has a 1 in 2 (50%)
chance of inheriting it and being similarly affected.
o If both parents are unaffected, all the children are unaffected.
o Pleiotropy; Autosomal dominant traits may give rise to two or more apparently unrelated
effects. For ex. in tuberous sclerosis affected individuals can present with a range of
problems including learning difficulties, epilepsy, a facial rash known as adenoma
sebaceum.
o Variable Expressivity: The clinical features in autosomal dominant disorders can show
striking variation from person to person, even in the same family. This difference
between individuals is referred to as variable expressivity.
 Examples:
o Marfan syndrome
o EHLERS-DANLOS SYNDROMES (some)
o Osteogenesis imperfecta
o Achondroplasia
o Familial hypercholesterolemia
o Acute intermittent porphyria
o Huntington disease
o Neurofibromatosis
o Myotonic dystrophy
o Tuberous sclerosis
o Polycystic kidney
o Hereditary spherocytosis
o Von willebrand disease
8. Autosomal recessive inheritance

Answer:

 A trait or disorder that is determined by a gene on an autosome is said to show autosomal

inheritance
 Recessive traits and disorders are manifest only when the mutant allele is present in a double
dose (i.e., homozygosity).
 Individuals heterozygous for such mutant alleles show no features of the disorder and are
perfectly healthy; they are described as carriers.
 Rules:
o Both males and females are affected.
o There are breaks in the pedigree and typically the pattern of expression is ‘horizontal’
(i.e. sibs are affected but parents are not).
o Affected children can be born to normal parents, usually in the approximate ratio of one
affected to three unaffected. (25 % chance of affected offspring with each pregnancy )
o When both parents are affected all the children are affected, unless mimic genes are
involved
o Affected individuals with normal partners usually have only normal children.
o There will be a positive history of consanguinity. (marriage within relatives)
 Examples:
o Cystic fibrosis
o Phenylketonuria
o Galactosemia
o Homocystinuria
o Lysosomal storage disorders
o Α-1 antitrypsin deficiency
o Wilson disease
o Hemochromatosis
o Glycogen storage diseases
o Thalassemias
o Sickle cell anemia
9. Prenatal diagnosis
o The term ‘prenatal diagnosis’ refers to the diagnosis of genetic (and other) disorders in
established pregnancies.
o Non-invasive procedures:
1. Ultrasound scanning:
 In ultrasound scanning, echoes reflected from organ boundaries are
converted to images on a monitor.
 Indications for ultrasonography include confirmation of viable or multiple
pregnancy, assessment of fetal age and growth, location of the placenta and
assessment of amniotic fluid volume.
 Ultrasonography can be used as a component of screening for fetal trisomy
(see below) and is an integral aspect of invasive techniques such as
amniocentesis, chorionic villus and fetal blood sampling.
2. Magnetic resonance imaging (MRI0 New, fast MRI techniques permit prenatal
imaging, useful in the diagnosis of internal anomalies such as brain malformation.
3. Screening of maternal blood: Maternal serum can provide useful indicators, for
example of α-fetoprotein (AFP), chorionic gonadotrophin (hCG) and unconjugated
oestriol (UE3), pregnancy associated plasma protein A (PAPP-A) and inhibin A in
relation to trisomies 21 and 18. Elevated levels of AFP are associated especially with
NTDs and other body wall defects such as gastroschisis.
4. Triple test: Down syndrome, can be screened for in pregnancy by taking into
account risk factors such as maternal age and the levels of three biochemical
markers in maternal serum,
 α-Fetoprotein
 Unconjugated estriol
 Human chorionic gonadotrophin
5. Quadruple test: Down syndrome, can be screened for in pregnancy by taking into
account risk factors such as maternal age and the levels of four biochemical markers
in maternal serum,
 α-Fetoprotein
 Unconjugated estriol
 Human chorionic gonadotrophin
 Inhibin A
o Invasive procedures:
1. Indications for invasive procedures
 increased risk of trisomy based on maternal serum/ ultrasound screening;
 previous child with de novo chromosome abnormality;
 presence of a balanced chromosome rearrangement in a parent that
predisposes to an unbalanced karyotype in the fetus;
 family history of a detectable genetic defect;
 elevated serum AFP or family history of NTD;
 parental consanguinity in families with testable recessive disease;
 maternal illness, medication or teratogen exposure;
 abnormal amniotic fluid volume;
 parents known to be carriers of certain disorders.
2. Amniocentesis:
 Amniocentesis involves the aspiration of 10 to 20 ml of amniotic fluid
through the abdominal wall under ultrasonographic guidance.
 This is usually performed around the 16th week of gestation.
 The sample is spun down to yield a pellet of cells and supernatant fluid. The
fluid can be used in the prenatal diagnosis of neural tube defects by assay of
α-fetoprotein The cell pellet is resuspended in culture medium with fetal calf
serum, which stimulates cell growth. After approximately 14 days, there are
usually sufficient cells for chromosome and DNA analysis,
 There is 0.5% to 1% risk of miscarriage associated with the procedure.
3. Chorionic villous sampling:
 In contrast to amniocentesis, chorionic villus sampling (CVS), can be
undertaken during the first trimester.
 This procedure is usually carried out at 11 to 12 weeks’ gestation under
ultrasonographic guidance by either transcervical or, more usually,
transabdominal aspiration of chorionic villus (CV) tissue
 This tissue is fetal in origin, being derived from the trophoblast. Maternal
decidua, normally present in the biopsy sample, must be removed before the
sample is analyzed.
 Placental biopsy is the term used when the procedure is carried out at later
stages of pregnancy.
 Chromosome analysis can be undertaken on CV tissue either directly,
looking at metaphase spreads from actively dividing cells, or after culture.
  Major advantage : it offers first-trimester prenatal diagnosis
 Disadvantage: 1% to 2% risk of causing miscarriage, can cause limb abnor
malities in the embryo if carried out before 9 to 10 weeks’ gestation; for this
reason is not performed before 11 weeks’gestation.
4. Cordocentesis:
 Procedure to obtain a small sample of fetal blood from one of the umbilical
cord vessels is known as cordocentesis.
 Fetal blood sampling is used routinely in the management of rhesus iso-
immunization and can be used to obtain samples for chromosome analysis to
resolve problems associated with possible chromosomal mosaicism in CV or
amniocentesis samples.
10. Trisomy 18
 Also called as Edward syndrome
 Incidence :1:5000 and prognosis is very poor, with most infants dying during the first days or
weeks of life, though most cases are detected prenatally, often leading to termination
 Karyotype: 47,XX,+18 or 47,XY,+18
 Clinical features:
o Head and face; Microcephaly, fine features, elongated skull with prominent occiput,
small, low-set ears with large lobes, small mouth, micrognathia
o Hands and feet: Rocker bottom’ feet with prominent heels; a distinctive way of
clenching the fists with index and little fingers overlapping the middle ones; often a
single palmar crease.
o General features: Prenatal growth deficiency; abnormal muscle tone; major
malformations of the renal and CN systems. Severe learning difficulty; most require
complete care and can never walk or feed themselves.
 Life expectancy : 50% die in the first few weeks, 95% in the first year

11. Patau syndrome/trisomy 13

Answer

 Incidence :1:5000
 Karyotype: 47,XX,+13 or 47,XY,+13
 Clinical features:
o Head and face; Microcephaly with sloping forehead; facial features coarse; cleft lip
and palate; micrognathia
o Eyes: Microphthalmia, anophthalmia, cyclopia or hypotelorism (closely spaced
eyes)
o Hands and feet: Rocker-bottom’ feet; frequently a single palmar crease, postaxial
polydactyly (6th finger present)
o General features: Midline malformations include failure of separation of the
cerebral ventricles, and cardiac abnormalities. Seizures common. Skills limited to
those of a child of 2 years. All boys have undescended testes
 Life expectancy : 50% die within the first month, 95% by 3 year
12. Chromosome

Answer:

 In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called
chromosomes.
 Each chromosome is made up of DNA tightly coiled many times around proteins called
histones that support its structure.
 The word chromosome is derived from the Greek [chroma (= color) and soma (= body)]
 Morphology of chromosomes
o Chromosomes are not visible in the cell’s nucleus—not even under a microscope—
when the cell is not dividing. However, the DNA that makes up chromosomes becomes
more tightly packed during cell division and is then visible under a microscope.
o At this time each chromosome can be seen to consist of two identical strands known
as chromatids, or sister chromatids,
o These sister chromatids can be seen to be joined at a primary constriction known as the
centromere. Centromeres consist of several hundred kilobases of repetitive DNA and
are responsible for the movement of chromosomes at cell division.
o Each centromere divides the chromosome into short and long arms, designated p (=
petite) and q (‘g’ = grande), respectively.
o The tip of each chromosome arm is known as the telomere. Telomeres play a crucial
role in sealing the ends of chromosomes and maintaining their structural integrity.
o Telomeres consist of many tandem repeats of TTAGGG sequence.

o
 Number of chromosomes
o Tjio and Albert Levan described the total number of chromosomes in human beings.
o In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46.
Twenty-two of these pairs, called autosomes, look the same in both males and females.
The 23rd pair, the sex chromosomes, differ between males and females. Females have
two copies of the X chromosome, while males have one X and one Y chromosome.

 Classification:
o Morphological: Morphologically chromosomes are classified according to the
position of the centromere.
 Metacentric : centromere is located centrally
 Acrocentric: centromere is present terminally
 Submetacentric: centromere is in an intermediate position
o Denver classification: Based on the three parameters of length, position of the centromere,
and the presence or absence of satellites, divided into group labeled A to G on the basis of
overall morphology
o Group A : 1,2,3. Metacentric except 2 (SM)
o Group B : 4,5. SM
o Group C : 6 – 12, X. SM
o Group D : 13 – 15. AC
o Group E : 16 – 18. SM
o Group F : 19 – 20. M
o Group G : 21,22, Y. AC
13. Sex chromosome

Answer:

o The X and Y chromosomes are known as the sex chromosomes because of their crucial role
in sex determination.
o They are also called as allosomes/gonosomes
o X chromosome:
 The X chromosome is one of the two sex chromosomes in humans.
 The X chromosome spans about 155 million DNA building blocks (base
pairs) and represents approximately 5 percent of the total DNA in cells.
 The X chromosome contains 800 to 900 genes that provide instructions for
making proteins. These proteins perform a variety of different roles in the
body.
 Females have two X chromosomes, while males have one X and one Y
chromosome. Early in embryonic development in females, one of the two X
chromosomes is randomly and permanently inactivated in cells other than
egg cells. This phenomenon is called X-inactivation or Lyonization.
 The following chromosomal conditions are associated with changes in
the structure or number of copies of X chromosome.
 Klinefelter syndrome
 Turner syndrome
 48,XXYY syndrome
 intestinal pseudo-obstruction
 microphthalmia with linear skin defects syndrome
 triple X syndrome

o Y chromosome:
 one of the two sex chromosomes in humans
 The Y chromosome spans more than 59 million building blocks of DNA
(base pairs) and represents almost 2 percent of the total DNA in cells.
 The Y chromosome is present in males, who have one X and one Y
chromosome, while females have two X chromosomes.
 The Y chromosome likely contains 50 to 60 genes that provide instructions
for making proteins.
 Because only males have the Y chromosome, the genes on this chromosome
tend to be involved in male sex determination and development. Sex is
determined by the SRY gene, which is responsible for the development of a
fetus into a male.
 The following chromosomal conditions are associated with changes in the
structure or number of copies of Y chromosome.
 46,XX testicular disorder of sex development
 47,XYY syndrome
 48,XXYY syndrome
 Y chromosome infertility
14. Karyotyping

Answer:

o Chromosomes are conventionally displayed cut out from a photograph or captured from an
electronic image, and arranged as a “paste-up,” with p arms upward, in their matching pairs.
This paired-up presentation is called a karyotype , or karyogram. The procedure to obtain
the photograph is called karyotyping.
o Procedure:
1. Chromosome preparation: to 5 ml of peripheral (venous) blood,
phytohemagglutinin is added, which stimulates T lymphocytes to divide. The cells
are cultured under sterile conditions at 37°C for about 3 days, during which they
divide, and colchicine is then added to each culture. This drug prevents formation of
the spindle, thereby arresting cell division during metaphase. Hypotonic saline is
then added, which causes the red blood cells to lyze and results in spreading of the
chromosomes, which are then fixed, mounted on a slide and stained ready for
analysis
2. Banding: The chromosomes are treated with trypsin, which denatures their protein
content, and then stained with a DNA-binding dye–—also known as ‘Giemsa’–—that
gives each chromosome a characteristic and reproducible pattern of light and dark
bands
3. Karyotype analysis: analysis involves first counting the number of chromosomes
present in a specified number of cells, sometimes referred to as metaphase spreads,
followed by careful analysis of the banding pattern of each individual chromosome in
selected cells.
15. Abnormalities of chromosome

Answer:

o Chromosomal abnormalities can be divided into three categories

1. Numerical
2. Structural
3. Constitutions in two or more cell lines
o Types of chromosomal abnormalities
1. Numerical
 Aneuplody – monosomy, trisomy, tetrasomy
 Polyploidy – triploidy, tertraploidy
2. Structural
 Translocations
 Deletions
 Insertion
 Inversion
 Ring chromosome
 Iso chromosomes
3. Different cell lines (mixoplody)
 Mosaicism
 Chimaerism

o Numerical abnormalities:
i. Aneuploidy : loss or gain of one or more chromosomes
 Monosomy: The absence of a single chromosome is referred to as
monosomy. Monosomy for an autosome is almost always
incompatible with survival to term. Lack of contribution of an X or a
Y chromosome results in a 45,X karyotype which causes Turner
syndrome
 Trisomy: presence of an extra chromosome is referred to as
trisomy. (eg: Down syndrome-trisomy 21;Edward syndrome-trisomy
18. Patau syndrome-trisomy 13)
 Tetrasomy: presence of 2 extra chromosome is referred to as
tetrasomy
 ii. Polyploidy: addition of one or more complete haploid complements, known
as polyploidy
 Triploidy: presence of multiple of the single haploid number of
chromosomes (eg.69, triploidy)
 Tetraploidy: presence of multiple of the 2 haploid number of
chromosomes (eg.92, tetraploidy )
1. Structural: Structural chromosome rearrangements result from chromosome
breakage with subsequent reunion in a different configuration
i. Translocations: transfer of genetic material from one chromosome to
another.
 Reciprocal: A reciprocal translocation is formed when a break
occurs in each of two chromosomes with the segments being
exchanged to form two new derivative chromosomes.
 Robertsonian: A Robertsonian translocation is a particular type of
reciprocal translocation in which the breakpoints are located at, or
close to, the centromeres of two acrocentric chromosomes.
 ii. Deletions: A deletion involves loss of part of a chromosome and results in
monosomy for that segment of the chromosome. A very large deletion is
usually incompatible with survival to term, and as a general rule any deletion
resulting in loss of more than 2% of the total haploid genome will be lethal.

iii. Insertions: An insertion occurs when a segment of one chromosome

becomes inserted into another chromosome.
iv. Inversions: An inversion is a two-break rearrangement involving a single
chromosome in which a segment is reversed in position
 Paracentric: If it involves only one arm of the chromosome it is
known as a paracentric inversion
 Pericentric: If the inversion segment involves the centromere
  it is termed a pericentric inversion

v. Rings: A ring chromosome is formed when a break occurs on each arm of a

chromosome leaving two ‘sticky’ ends on the central portion that reunite as a
ring

vi. Isochromosomes: An isochromosome shows loss of one arm with

duplication of the other. This results because the centromere has divided
transversely rather than longitudinally.
2. Different Cell Lines (Mixoploidy)
 Mosaicism: presence in an individual, or in a tissue, of two or more cell lines
that differ in their genetic constitution but are derived from a single zygote,
that is, they have the same genetic origin.
 Chimerism: presence in an individual of two or more genetically distinct
cell lines derived from more than one zygote; that is, they have a different
genetic origin.
16. Nondisjunction

Answer:

o Normally the bivalent pair of homologous chromosomes separate during anaphase of cell
division. Failure of separation of one of the pairs of homologous chromosomes during
anaphase is called non-disjunction.
o Non disjunction in meiosis: usually results in trisomy/monosomy/tetrasomy

o Non disjunction in mitosis: usually results in mosaicism

o Cause of non-disjunction: Advanced maternal age

o Clinical implications: non disjunction results in
o Trisomies
o Monosomies
o Mosaicism
17. Downs syndrome/Trisomy 21

Answer:

 This condition derives its name from Dr. Langdon Down, who first described it.
 Karyotype: 47,XX,+21 or 47,XY,+21 (Trisomy 21)
 Incidence : 1 in 700
 Clinical features:
o Head and face: Small, flattened head, short neck with excess nuchal skin. Face
broad. Tongue without a central fissure. Low nasal root, ears small.
o Eyes: Eyes slanting upwards, with marked epicanthic folds; cataracts, squint and
nystagmus (involuntary eye movements). Most have white speckles on the iris.
o Hands and feet: Half have a single palmar flexion crease (Simian crease). Limbs
and fingers short, little finger in-turned, with single crease. Large ‘sandal gap’.
Webbing of toes 2 and 3.
o Muscle tone: Babies are always ‘floppy’ (hypotonic) and tend to be sleepy.
o IQ: intellectual delay
o Cardiac: Atrial and ventricular septal defects, common atrioventricular canal, patent
ductus arteriosus
o Other features: Anal atresia, duodenal atresia, Hirschsprung disease, short stature,
strabismus
o Life expectancy: 50–60 years

A child with Down syndrome.

 Close-up view of the eyes and nasal bridge of a child with Down syndrome showing upward
sloping palpebral fissures, Brushfield spots, and bilateral epicanthic folds.

The hands of an adult with Down syndrome. Note the single palmar crease in the left hand plus
bilateral short curved fifth fingers (clinodactyly).
18. Klinefelter’s syndrome

Answer:

 Klinefelter’s syndrome is a chromosomal disorder affecting sex chromosomes

 Genotype
o Karyotype 47,XXY; or 48,XXXY; 49,XXXXY, etc.;
o Abnormal presence of Barr bodies, one less than the number of X chromosomes.
 Frequency: 1/500–1/1000 male births.
 Life expectancy: Normal, but 50% die before birth.
 Body form: Phenotype is basically male, tall with elongated lower legs and forearms, but
with a feminine body shape and low muscle mass. There is gynaecomastia in one-third and
risk of osteoporosis and breast cancer.
 Fertility: Small, soft testes (<10 mL, 2 cm); most are sterile or produce few sperm, as a
result of atrophy of the seminiferous tubules. Testicles and penis remain small; there is low
libido and impotence. Blood tests show high gonadotrophin and low testosterone levels.
Pubic, axillary and chest hair are sparse.
 IQ: 10–15 points reduced, representing around 1% of men in institutions for the learning
disabled.
 Other features: There may be scoliosis, emphysema, varicose veins and leg ulcers, diabetes
mellitus in 8% and thyroid problems are common.
 Etiology: Around 15% show 46,XY/47,XXY mosaicism. Mental deficiency and physical
abnormality increase with the number of supernumerary X chromosomes.
 Management: Klinefelter syndrome presents in childhood with clumsiness, learning
difficulties and poor verbal skills.
19. Turners syndrome
 Turner syndrome is a chromosomal disorder affecting sex chromosomes
 Genetics: Karyotype 45, X; body cells abnormal for females in containing no Barr bodies.
 Frequency: 1/2000–1/3000 female births
 Clinical features:
• Body form: Phenotype basically female; short stature from age of 3 years, no
adolescent growth spurt. Mature height averages 145 cm (4 ft 9 in; 20 cm below
average); shield-shaped chest with widely spaced nipples.
• Head and face: Heart-shaped face with micrognathia and low posterior hairline;
excess skin forms a web between neck and shoulders; high arched palate with
overcrowding of teeth.
• Ears: Ears are low-set and posteriorly rotated, otitis media is frequent and can lead to
conductive deafness.
• Hands and feet: Short fingers and toes, especially 4th metacarpals (in 50%), frail
nails; increased carrying angle at elbow (cubitus valgus).
• Fertility: Breasts, pubic hair and menstruation are usually absent. Ovaries may
appear normal at birth, but atrophy progressively.
• Heart: 50% have a bicuspid aortic valve, 15–30% coarctation of aorta,
• Cognition: Patients have difficulty with specific visual–spatial coordination tasks
and mathematics.
• Thyroid: Hypothyroidism due to lymphocytic thyroiditis.
 Etiology:
• Sixty to 80% are caused by loss of the paternal-derived sex chromosome during
paternal meiosis or early cell division in the embryo.
 Management
• Sexual development: Oestrogen administration at 12–13 years can ensure breast
development, growth of pubic hair and maturation of the uterus and vaginal
epithelium.
• Short stature: Height can be increased by growth hormone administration.
• Aorta: Coarctation is corrected surgically
• Eyes: Optical checks and provision of spectacles, correction of strabismus.
• Ears: Regular hearing checks
• Hypothyroidism: Thyroxine administration if necessary.
 Short answers

1. X chromosome
 The X chromosome is one of the two sex chromosomes in humans (the other is the Y
chromosome).
 The X chromosome spans about 155 million DNA building blocks (base pairs) and represents
approximately 5 percent of the total DNA in cells.
 The X chromosome contains 800 to 900 genes that provide instructions for making proteins.
 Females have two X chromosomes, while males have one X and one Y chromosome. Early in
embryonic development in females, one of the two X chromosomes is randomly and
permanently inactivated in cells other than egg cells. This phenomenon is called X-
inactivation or Lyonization. X-inactivation ensures that females, like males, have one
functional copy of the X chromosome in each body cell.
 The following chromosomal conditions are associated with changes in the structure or
number of copies of X chromosome.
o Klinefelter syndrome
o Turner syndrome
o 48,XXYY syndrome
o intestinal pseudo-obstruction
o microphthalmia with linear skin defects syndrome
o triple X syndrome
o other chromosomal conditions

2. Y chromosome

 The Y chromosome is one of the two sex chromosomes in humans (the other is the X
chromosome).
 The Y chromosome spans more than 59 million building blocks of DNA (base pairs) and
represents almost 2 percent of the total DNA in cells.
 The Y chromosome is present in males, who have one X and one Y chromosome, while females
have two X chromosomes.
 The Y chromosome contains 50 to 60 genes that provide instructions for making proteins.
 Because only males have the Y chromosome, the genes on this chromosome tend to be involved
in male sex determination and development. Sex is determined by the SRY gene, which is
responsible for the development of a fetus into a male. Other genes on the Y chromosome are
important for male fertility.
 The following chromosomal conditions are associated with changes in the structure or number of
copies of Y chromosome.
o 46,XX testicular disorder of sex development
o 47,XYY syndrome
o 48,XXYY syndrome
o Y chromosome infertility

3. Genetic counselling
 Definition: A process of communication and education that addresses concerns relating to the
development and/or transmission of a hereditary disorder.
 Indications:
 Personal or family history of a genetic condition, birth defect, chromosomal disorder, or
hereditary cancer.
 Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
 A child with a known inherited disorder, a birth defect, mental retardation, or
developmental delay.
 A woman who is pregnant or plans to become pregnant at or after age 35.
 Abnormal test results that suggest a genetic or chromosomal condition.
 An increased risk of developing or passing on a particular genetic disorder on the basis of
a person’s ethnic background.
 People related by blood (for example, cousins) who plan to have children together.
 Steps of genetic counselling:
a. Diagnosis—based on accurate family history, medical history, examination, and
investigations
b. Assessment of risk
c. Communication
d. Discussion of options
e. Long-term contact and support

4. Difference between metacentric, sub metacentric, acrocentric and telocentric chromosomes

5. List 6 acrocentric chromosomes
 Group D: chromosome 13, chromosome 14, chromosome 15
 Group G: Chromosome 21, chromosome 22, Y chromosome
6. Metacentric chromosomes- group and number
 Group A: chromosome 1, chromosome 3
 Group F; chromosome 19, chromosome 20
7. Ring chromosome
 A ring chromosome is formed when a break occurs on each arm of a chromosome
leaving two ‘sticky’ ends on the central portion that reunite as a ring

8. Satellite bodies
  In acrocentric chromosomes, distal to the secondary constriction small segment of the
chromosome is present. This segment is called satellite body.
 Chromosomes bearing satellites are called SAT-chromosomes
 In humans chromosome 13,14, 15, 21, 22 and Y chromosomes have satellite bodies.

9. Anaphase lag
 Normally during cell division the chromosomes separate during the anaphase. This is
called as disjunction.
 Failure of this separation is known as non-disjunction
 Delay in the process of the separation is known as “anaphase lag”
 Anaphase lag and non-disjunction are the causative factors for aneuploidy.

10. Mention any 3 structural abnormalities of chromosomes

 Translocation
 Deletions
 Insertions
 Inversions
 Ring chromosome
 Iso chromosome
11. Satellite chromosomes
 Acrocentric chromosome have terminal structures called as satellite bodies. Hence are
also called as satellite chromosomes.
 Examples:
o Group D : chromosome 13-15
o Group F: chromosome 21, 22 and Y chromosome

Secondary constriction
conconstriction
12. Name the chromosmes with satellite bodies
 Acrocentric chromosome have terminal structures called as satellite bodies. Hence are
also called as satellite chromosomes.
 Examples:
i. Group D : chromosome 13-15
ii. Group F: chromosome 21, 22 and Y chromosome

13. Mention examples for x linked recessive inheritance

 Haemophilia A (Factor VIII)
 Haemophilia B (Factor IX)
 G6PD deficiency
 Red and green colour blindness
 Duchenne muscular dystrophy (dystrophin)
 Fragile X syndrome
 Becker muscular dystrophy (dystrophin)
 Agammaglobulinaemia (X-linked)

14. Name any 2 conditions affecting autosomes

 Trisomy 21/ Down syndrome
 Trisomy 13/ Patau Syndrome
 Trisomy 18/ Edward syndrome

15. Name any 3 autosomal dominant disorders

 Marfan syndrome
 Ehrler Danlos syndrome
 Achondroplasia
 Polyscystic kidney disease
 Huntington disease
 Neurofibromatosis
 Tuberous sclerosis

16. Name any 4 autosomal recessive disorders
  Cystic fibrosis
 Phenylketonuria
 Galactosemia
 Homocystinuria
 Lysosomal storage disorders
 Α-1 antitrypsin deficiency
 Wilson disease
 Hemochromatosis
 Glycogen storage diseases
17. Name the types of chromosomes
 Classification:
o Morphological: Morphologically chromosomes are classified according to the
position of the centromere.
 Metacentric : centromere is located centrally
 Acrocentric: centromere is present terminally
 Submetacentric: centromere is in an intermediate position

o Denver classification: Based on the three parameters of length, position of the centromere,
and the presence or absence of satellites, divided into group labeled A to G on the basis of
overall morphology
o Group A : 1,2,3. Metacentric except 2 (SM)
o Group B : 4,5. SM
 o Group C : 6 – 12, X. SM
o Group D : 13 – 15. AC
o Group E : 16 – 18. SM
o Group F : 19 – 20. M
o Group G : 21,22, Y. AC

18. What is Philadelphia chromosome

 The Philadelphia chromsomome is a tiny chromosome that is now known to be a
chromosome 22 from which long arm material has been reciprocally translocated to
and from the long arm of chromosome 9, i.e., t(9;22)(q34;q11).
 This chromosomal rearrangement is seen in 90% of those with Chronic Myeloid
Leukemia.
 This translocation has been found to transfer the cellular ABL (Abelson) oncogene from
chromosome 9 into a region of chromosome 22 known as the breakpoint cluster
region(BCR)
19. Prenatal diagnosis
 Prenatal diagnosis’ refers to the diagnosis of genetic (and other) disorders in established
pregnancies.
 They are of 2 types: invasive and non-invasive
 Invasive procedures:
o Amniocentesis
o Chorionic villus sampling
o Cordocentesis
o Fetoscopy
 Non invasive procedures:
o Ultrasound
o Triple test
o Quadruple test

20. Name 2 indications of amniocentesis

 Previous child with chromosome abnormality;
 Family history of a detectable genetic defect;
 Elevated serum AFP or family history of neural tube defects;
 Increased risk of trisomy based on maternal serum/ ultrasound screening;
 Parental consanguinity in families with testable recessive disease;
 Maternal illness, medication or teratogen exposure;
 Abnormal amniotic fluid volume
21. Name any 2 prenatal diagnosis
 Invasive procedures:
o Amniocentesis
o Chorionic villus sampling
o Cordocentesis
o Fetoscopy
 Non invasive procedures:
o Ultrasound
o Triple test
o Quadruple test
22. Chromosomal bandings
 Several different staining methods can be used to identify individual chromosomes but G
(Giemsa) banding is used most commonly.
 The chromosomes are treated with trypsin, which denatures their protein content, and
then stained with a DNA-binding dye–—also known as ‘Giemsa’–—that gives each
chromosome a characteristic and reproducible pattern of light and dark bands.
 G banding generally provides high-quality chromosome analysis with approximately 400
to 500 bands per haploid set. Each of these bands corresponds on average to
approximately 6000 to 8000 kilobases (kb) (i.e., 6 to 8 megabases [mb]) of DNA.

23. Chromosomes
 In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called
chromosomes.
 Each chromosome is made up of DNA tightly coiled many times around proteins called
histones that support its structure.
 The word chromosome is derived from the Greek [chroma (= color) and soma (= body)]
 Morphology of chromosomes
o Chromosomes are not visible in the cell’s nucleus—not even under a microscope—
when the cell is not dividing. However, the DNA that makes up chromosomes becomes
more tightly packed during cell division and is then visible under a microscope.
o At this time each chromosome can be seen to consist of two identical strands known
as chromatids, or sister chromatids,
o These sister chromatids can be seen to be joined at a primary constriction known as the
centromere. Centromeres consist of several hundred kilobases of repetitive DNA and
are responsible for the movement of chromosomes at cell division.
o Each centromere divides the chromosome into short and long arms, designated p (=
petite) and q (‘g’ = grande), respectively.
o The tip of each chromosome arm is known as the telomere. Telomeres play a crucial
role in sealing the ends of chromosomes and maintaining their structural integrity.
o Telomeres consist of many tandem repeats of TTAGGG sequence.

 Number of chromosomes
o Tjio and Albert Levan described the total number of chromosomes in human beings.
 o In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46.
Twenty-two of these pairs, called autosomes, look the same in both males and females.
The 23rd pair, the sex chromosomes, differ between males and females. Females have
two copies of the X chromosome, while males have one X and one Y chromosome.

24. Sex chromosomes

 The X and Y chromosomes are known as the sex chromosomes because of their crucial role
in sex determination.
 They are also called as allosomes/gonosomes
 X chromosome:
i. Belongs to group C and is submetacentric in type.
ii. The X chromosome spans about 155 million DNA building blocks (base pairs)
and represents approximately 5 percent of the total DNA in cells.
iii. The X chromosome contains 800 to 900 genes that provide instructions for
making proteins. These proteins perform a variety of different roles in the body.
iv. Females have two X chromosomes, while males have one X and one Y
chromosome. Early in embryonic development in females, one of the two X
chromosomes is randomly and permanently inactivated in cells other than egg
cells. This phenomenon is called X-inactivation or Lyonization.
v. The following chromosomal conditions are associated with changes in the
structure or number of copies of X chromosome.
1. Klinefelter syndrome
2. Turner syndrome

 Y chromosome:
i. Belongs to group G and is acrocentric in type
ii. The Y chromosome spans more than 59 million building blocks of DNA (base
pairs) and represents almost 2 percent of the total DNA in cells.
iii. The Y chromosome likely contains 50 to 60 genes that provide instructions for
making proteins.
iv. Because only males have the Y chromosome, the genes on this chromosome tend
to be involved in male sex determination and development. Sex is determined by
the SRY gene, which is responsible for the development of a fetus into a male.
 v. The following chromosomal conditions are associated with changes in the
structure or number of copies of Y chromosome.
1. 46,XX testicular disorder of sex development
2. 47,XYY syndrome
3. 48,XXYY syndrome
25. Autosomes
 Human beings have 46 chromsomes which are arranged as 22 pairs of sutosomes and 1
pair of allosmes/sex chromsomes
 Chromosome 1-22 are called as autosomes.
 Autosomes are essential for life. Loss of even one autosome is fatal
 Gain of 1 or 2 autosomes is called as trisomy and tetrasomy respectively.

26. Define chromosome. Give the chromosomal complement of normal male and female
 A chromosome is a large macromolecular complex comprising a single molecule of DNA
and multiple proteins.
 Chromosomal complement
o Normal male: 46,XY
o Normal Female: 46, XX

27. Karyotype
 The chromosome constitution of an individual is known as a karyotype.
 This term is also used to describe a photomicrograph of an individual’s chromosomes,
arranged in a standard manner.

28. Karyotyping
 The procedure of obtaining karyotype of an individual is known as karyotyping.
29. Write any 3 differences between mitosis and meiosis

Mitosis Meiosis

Daughter cells are diploid Daughter cells are haploid

Occurs in somatic cells and early stages Occurs only in late stages of gamete
of gamete formation: maturation
Mitosis is single step process Meiosis includes meiosis I and meiosis II
Duration: 2-3 hours Duration: days-years

30. Simian palmar crease

 Single transverse palmar crease seen in hands of Down syndrome patients is known as
simian palmar crease.
 Believed to be caused by hypotonic muscles.
 Called so because of resemblance to palmar crease of monkeys.
31. Name 3 syndromes having trisomy
 Trisomy 21/ Down syndrome
 Trisomy 13/ Patau Syndrome
 Trisomy 18/ Edward syndrome
32. Nondisjunction
 Normally the bivalent pair of homologous chromosomes separate during anaphase of cell
division. Failure of separation of one of the pairs of homologous chromosomes during
anaphase is called non-disjunction.
 Non disjunction in meiosis: usually results in trisomy/monosomy/tetrasomy
 Non disjunction in mitosis: usually results in mosaicism

33. Down syndrome-karyotype and clinical feature

 Karyotype: 47,XX,+21 or 47,XY,+21 (Trisomy 21)
 Clinical features:
i. Head and face: Small, flattened head, short neck with excess nuchal skin. Face
broad. Tongue without a central fissure. Low nasal root, ears small.
ii. Eyes: Eyes slanting upwards, with marked epicanthic folds; cataracts, squint
and nystagmus (involuntary eye movements). Most have white speckles on the
iris.
iii. Hands and feet: Half have a single palmar flexion crease (Simian crease).
Limbs and fingers short, little finger in-turned, with single crease. Large ‘sandal
gap’. Webbing of toes 2 and 3.
iv. Muscle tone: Babies are always ‘floppy’ (hypotonic) and tend to be sleepy.
v. IQ: intellectual delay
vi. Cardiac: Atrial and ventricular septal defects, common atrioventricular canal,
patent ductus arteriosus
 vii. Other features: Anal atresia, duodenal atresia, Hirschsprung disease, short
stature, strabismus

34. Klinefelter syndrome- karyotype and clinical feature

 Karyotype: 47,XXY; or 48,XXXY; 49,XXXXY, etc.; Abnormal presence of Barr bodies,
one less than the number of X chromosomes.
 Body form: Phenotype is basically male, tall with elongated lower legs and forearms and
there is gynaecomastia.
 Fertility: Small, soft testes (<10 mL, 2 cm); most affected men are sterile Testicles and
penis remain small; there is low libido and impotence. Pubic, axillary and chest hair are
sparse.
 IQ: 10–15 points reduced, representing around 1% of men in institutions for the learning
disabled.

35. Mention the phenotype of Klinefelter syndrome

 Phenotype is basically male
 Tall with elongated lower legs and forearms, but with a feminine body shape and low muscle
mass.
 Gynaecomastia.
 Small, soft testes (<10 mL, 2 cm);
 Testicles and penis remain small
 Pubic, axillary and chest hair are sparse.

36. Monosomy
 Monosomy refers to Absence of a single chromosome
 Monosomy of autosomes is incompatible with life
 Monosonmy of Allosomes – Turner’s syndrome
 Cause for monosomy- non disjunction during meiosis
37. Trisomy
 Trisomy refers to Presence of an extra chromosome
 Examples:
i. Trisomy 21 / Down’s syndrome
ii. Trisomy 13/ Patau syndrome
 iii. Trisomy 18/ Edward syndrome
 Cause for trisomy : Non disjunction

38. Turners syndrome- karyotype and clinical feature

 Karyotype: 45,X
 Most common features:
o Primary ovarian failure
o Widely spaced nipples
o Low hairline
o Webbed neck
o Short stature
 Variable features:
o Learning disabilities
o Coarctation of aorta
39. What is the cause of turner syndrome
 Monosomy of x chromosome causes Turner syndrome
 During gametogenesis because of non disjunction one of the gamete fails to receive x
chromosome. When this gamete fuse with normal gametes they lead to monosomy.
 What brings about non disjunction is not clear.

40. Give 3 clinical features of turners syndrome

 Most common features:
o Primary ovarian failure
o Widely spaced nipples
 o Low hairline
o Webbed neck
o Short stature
 Variable features:
o Learning disabilities
o Coarctation of aorta
41. 2 syndromes affecting sex chromosomes
i. Turner syndrome
ii. Klinefelter syndrome