23 CHAPTER

Genetics

COMMON GENETIC AND CHROMOSOMAL DISORDERS

Q. Write short essay/note on various types (classification) of chromosomal disorders/aberrations.
Classification of Chromosomal Disorders (Box 23.1)
Numerical Chromosomal Aberrations
Normal cells are diploid containing 46 chromosomes, 22 pairs of autosomes and 1 pair of sex chromosomes. The 23 chromosomes
(22 autosomes and one sex chromosome) constitute a haploid. Any exact multiple of the haploid number is called euploid.
Types of numerical aberrations
Aneuploidy: It is defined as a chromosome number that is not a multiple of 23 (the normal haploid number). It is caused by
either loss or gain of one or more chromosomes. Aneuploidy may result from nondisjunction or anaphase lag.
z Trisomy: Numerical abnormalities with the presence of one extra chromosome are referred to as trisomy (2n + 1). It may
involve either sex chromosomes or autosomes. Examples: Down syndrome (patients have three copies of chromosome
21, i.e., 47 XX, +21, hence Down syndrome is often known as trisomy 21), Patau syndrome (trisomy 13; 47 XY, +13), and
Edwards syndrome (trisomy 18; 47 XY, +18).
z Monosomy: Numerical abnormalities with the absence or loss of one chromosome (2n – 1) are referred to as monosomy.
It may involve autosomes or sex chromosomes. Monosomy of autosomes is almost incompatible with survival. Example:
For monosomy of sex chromosomes is Turner syndrome (45 XO) instead of normal XX (46 XX).
Polyploidy: It is chromosome number that is a multiple greater Box 23.1: Types of chromosomal abnormality.
than two of the haploid number (multiples of haploid number 23). Numerical abnormalities
Triploidy is three times the haploid number (69), tetraploidy is four • Aneuploidy
times the haploid number (92). Polyploidy is incompatible with life – Monosomy
and usually results in spontaneous abortion. – Trisomy
Causes of numerical aberrations – Tetrasomy
z Numerical aberrations can occur during meiosis and/or mitosis. • Polyploidy
These errors are due to nondisjunction and anaphase lag. – Triploidy
z Nondisjunction: It is failure of paired chromosomes to separate – Tetraploidy
during meiosis or mitosis. Meiotic nondisjunction is the most Structural abnormalities
common cause. • Translocations (exchange)
z Anaphase lag: Anaphase lag results in the loss of a chromosome • Deletions (loss)
during meiosis or mitosis. • Duplications
• Insertions
Structural Chromosomal Aberrations (Box 23.1) • Inversions
Q. Discuss chromosomal translocations with examples. • Nondisjunction
• Ring chromosome
Q. What is reciprocal translocation?
Isochromosomes
Q. Write a note on Robertsonian translocation. Mixoploidy
Structural chromosomal aberrations may occur either during • Mosaicism
mitosis or meiosis. • Chimerism
1418 CHAPTER 23: Genetics

Causes of structural alterations: It may occur spontaneously at a low rate and is increased by exposure to environmental
mutagens, such as chemicals and ionizing radiation.

Types of Structural/Chromosomal Aberrations (Figs. 23.1A to H)

Translocations: It is a structural alteration between two chromosomes in which a segment of one chromosome gets
detached and is transferred to another chromosome. There are two types of translocations:
1. Balanced reciprocal translocations: It is characterized by single break in each of the two chromosomes with exchange
of genetic material distal to the break. There is no loss of genetic material. A balanced reciprocal translocation between
the long arm of chromosome 5 and the short arm of chromosome 10 would be written 46, XX, t (5; 10) (q31; p14).
„ Simple translocation: In this case, terminal segment of a chromosome is integrated at one end of a nonhomologous
region. Simple translocations are rather rare.
„ Shift: In shift, an intercalary segment of a chromosome is integrated within a nonhomologous chromosome.
2. Robertsonian translocation/centric fusion:
„ This results from the breakage of two acrocentric chromosomes (i.e., chromosome 13, 14, 15, 21, 22) at or close to
their centromeres and subsequent fusion of their long arms.
„ The short arms of each chromosome are lost, this being of no clinical importance as they contain genes only for
ribosomal RNA, for which there are multiple copies on various other chromosomes.
„ The total chromosome number is reduced to 45.
„ The overall incidence of this translocation is 1 in 1,000, the most common being 13q14q.
„ The major practical importance is that this can predispose to the birth of babies with Down syndrome.

Inversion: When a segment of chromosome is oriented in the reverse direction, such segment said to be inverted and the
phenomenon is termed as inversion.
Isochromosomes: They are formed due to faulty centromere division. Normally, centromeres divide in a plane parallel to
long axis of the chromosome. If a centromere divides in a plane transverse to the long axis, it results in pair of isochromosomes.
One pair consists of two short arms and the other of two long arms.
Deletion: It is the loss of a part of a chromosome. It is of two types namely: (1) interstitial (middle) and (2) terminal (rare).
z Interstitial deletion: It occurs when there are two breaks within a chromosome arm. This is followed by loss of the
chromosomal material between the breaks and fusion of the broken ends of the remaining portion of the chromosome.
It has to be specified in which region(s) and at what bands the breaks have occurred. For example, 46, XY, del (16)

A B C D

E F G H

FIGS. 23.1A TO H: Types of structural abnormalities of chromosome.

 CHAPTER 23: Genetics 1419

(p11.2p13.1) describes breakpoints in the short arm of chromosome 16 at 16p11.2 and 16p13.1 with loss of material
between breaks.
z Terminal deletion: It results from a single break at the terminal part in a chromosome arm, producing a shortened
chromosome bearing a deletion and a fragment with no centromere. The fragment is then lost at the next cell division.
Ring chromosome: It is a special form of deletion. Ring chromosomes are formed by a break at both the ends of a chromosome
with fusion of the damaged ends.
Insertion: It is a form of nonreciprocal translocation in which a fragment of chromosome is transferred and inserted into
a nonhomologous chromosome.

Mixoploidy
Mosaicism: Defined as the 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, i.e., they have the same genetic origin. Seen in Down syndrome (1–2%) and
Duchenne muscular dystrophy.
Chimerism: Defined as the presence in an individual, or in a tissue, of two or more cell lines that are derived from more than
one zygote, i.e., they have different genetic origin.

DOWN SYNDROME (TRISOMY 21)

Q. PE32.1 Discuss the genetic basis, risk factors, complications, prenatal diagnosis, management and genetic counseling
in Down’s syndrome.
The best known and most common chromosome related syndrome. Formerly known as “Mongolism”.
It is the most common chromosomal disorder and is a leading cause of mental retardation. The incidence of Down syndrome
in newborns is about 1 in 700 live births.

Etiology and Pathogenesis

z Maternal age: It has a strong influence on the incidence of trisomy 21. Children of older mothers have much greater risk
of having Down syndrome. The risk for mothers < 25 years of age to have the trisomy is about 1 in 1,500 births. At 40 years
of age, 1 in 100 births. At 45 years, 1 in 40 births.
z Other factors: Increased incidence may be associated with exposure of mother to pesticides, electromagnetic fields,
anesthetic drugs, alcohol, and caffeine.
Mechanism of trisomy 21: The three copies of chromosome 21 in somatic cells cause Down syndrome. It may be due to:
1. About 95% of these individuals have nondisjunction during the first meiotic division of gametogenesis.
2. Robertsonian translocation of an extra long arm of chromosome 21 to another acrocentric chromosome causes about 5%
of cases.
3. About 1% mosaicism having two different cell lines, one with normal chromosomal constitution and the other with an
extra chromosome 21.

Clinical Features (Fig. 23.2)

Craniofacial and Skeletal Features
z Flat face and occiput, with a low-bridged nose, reduced interpupillary distance and oblique palpebral fissures.
z Epicanthal folds of the eyes impart an almond shape to the eyes and an oriental appearance (obsolete term mongolism).
z A speckled appearance of the iris (brushfield spots), enlarged and malformed ears.
z A protruding furrowed tongue (macroglossia), which typically lacks a central fissure and protrudes through an open
mouth (scrotal tongue).
z Broad, short neck, brachycephaly, Simian crease-single palmar flexion crease (50% cases), clinodactyly-incurved fifth finger
with hypoplastic mid phalanx (60%), short stature, hypotonia and space between the first and second toes (sandal gap).
Brain: Mild to moderate intellectual disability, attention-deficit hyperactivity disorder, autism, dementia, atlantoaxial
dislocation.
Heart: Congenital cardiac anomalies are responsible for the majority of the deaths in infancy and early childhood. The
genetic band in 21q22 critical region is considered responsible for the cardiac anomalies. Complete atrioventricular septal
defect (CAVSD)—37%, ventricular septal defect (VSD)—31%, atrial septal defect (ASD)—15%, partial atrioventricular septal
defect (PAVSD)—6%, and patent ductus arteriosus (PDA)—4%.
1420 CHAPTER 23: Genetics

FIG. 23.2: Major clinical features of Down syndrome.

Gastrointestinal tract: It may show esophageal/duodenal stenosis or Box 23.2: Down syndrome screens.
atresia, imperforate anus and Hirschsprung disease (megacolon). • Triple screen (75% sensitive): Maternal serum alpha-
Genitourinary: Hypospadias, cryptorchidism. Males are infertile fetoprotein, estriol, and human chorionic gonadotropin.
due to impaired spermatogenesis. • Quad screen (79% sensitive): Maternal serum alpha-
fetoprotein, estriol, human chorionic gonadotropin, and
Immune system: Affected children are susceptible to infections due high inhibin-alpha (INHA).
to defective immunity. • Nuchal translucency/free beta-hCG>/PAPPA screen
Endocrine system: Antithyroid antibodies may cause hypothyroid- (91% sensitive): Ultrasound to measure nuchal
ism and type 1 diabetes. translucency in addition to the free Beta-hCG and PAPPA
(pregnancy-associated plasma protein A).
Hematologic disorders: They have increased risk of acute myeloid or • The full integrated test (first-trimester nuchal
lymphoblastic leukemia. Polycythemia, macrocytosis, leukopenia, and translucency and PAPPA plus second-trimester
leukemia (acute megakaryoblastic, and acute lymphoblastic). quadruple markers) detects 85% of Down syndrome
Other features: Refractive errors, strabismus, sensorineural hearing fetuses.
loss, obesity, obstructive sleep apnea, palmoplantar hyperkeratosis,
juvenile idiopathic arthritis.
Down syndrome screens are mentioned in Box 23.2.

KLINEFELTER SYNDROME
Q. PE32.11 Discuss the genetic basis, risk factors, complications, prenatal diagnosis, management and genetic
counseling in Klinefelter syndrome.
It is an important genetic cause of male hypogonadism and is associated with reduced spermatogenesis and male infertility.

Pathogenesis
z Most patients with Klinefelter syndrome have one extra X chromosome (47, XXY karyotype). It is due to nondisjunction
of X chromosome during meiosis.
 CHAPTER 23: Genetics 1421

z A minority is mosaic (e.g., 46, XY/47, XXY) or has more than two X chromosomes
(e.g., 48, XXXY) and one or more Y chromosomes.

Clinical Features (Fig. 23.3)

z Klinefelter syndrome is usually diagnosed after puberty.
z Most patients are tall and thin with relatively long legs (eunuchoid body habitus).
Mental retardation is uncommon, although average intelligence quotient (IQ) is
reduced.
z At puberty, testes and penis remain small with lack of secondary male characteristics.
„ Female characteristics develop which include a high-pitched/deep voice,
gynecomastia, and a female pattern of pubic hair. Sparse facial, body and
sexual hair.
„ Azoospermia results in infertility.

All of these changes are due to hypogonadism and reduced levels of testosterone.

Diagnosis
z Buccal smear for Barr body: Extra X chromosome may be seen as a Barr body on
buccal smears.
z Nuclear sexing of leukocytes: Neutrophils in the peripheral smear may also
be examined for nuclear sexing. In a normal female (XX), the neutrophils in a
peripheral smear show a drumstick which is counterpart of Barr body in buccal
smear. One extra drumstick is found in males with Klinefelter syndrome (XXY). FIG. 23.3: Clinical features of Klinefelter syndrome.
z Chromosomal analysis
z Hormonal status:
„ Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are remarkably high.
„ Testosterone: Low to low-normal level.
„ The ratio of estrogens and testosterone determines the degree of feminization. Complications of Klinefelter syndrome
are listed in Box 23.3.
Box 23.3: Complications of Klinefelter syndrome.
• Increased risk of breast carcinoma in 47, XXY (relative risk exceeding 200 times).
• Endocrine complications: Diabetes mellitus, hypothyroidism and hypoparathyroidism.
• Autoimmune diseases: Systemic lupus erythematosus, Sjogren’s syndrome and rheumatoid arthritis.
• Decreased bone density:
– Increased risk of ischemic heart disease, mitral valve prolapse, lower extremity varicose veins, venous stasis ulcers, and deep venous
thrombosis and pulmonary embolism
– Extragonadal germ cell cancer and non-Hodgkin lymphoma occur in more frequency

Management
• Testosterone: It should be started at puberty (around 12 years age) and increasing its dosage sufficient to maintain serum concentrations
of testosterone, estradiol, FSH, and LH appropriate to the age. It promotes normal body proportions and development of normal
secondary sex characteristics. However, it does not affect infertility, gynecomastia, and atrophy of testis. It decreases the long-term
complications such as breast cancer, autoimmune disease, and osteoporosis.
• Speech therapy.
• Physiotherapy for hypotonia or delayed motor skills.

TURNER SYNDROME
Q. PE32.6 Discuss the genetic basis, risk factors, clinical features, complications, prenatal diagnosis, management and
genetic counseling in Turner’s syndrome.
z Turner syndrome is a sex chromosomal abnormality. Turner syndrome is characterized by a spectrum of abnormalities
due to complete or partial monosomy of the X chromosome in a phenotypic female.
z It is characterized by hypogonadism and is the most common sex chromosome abnormality in females.
1422 CHAPTER 23: Genetics

Karyotypic Abnormalities
z Missing of an entire X chromosome: This resulting in a 45,
X karyotype due to nondisjunction of X chromosomes during
meiosis. Genetic constitution hence becomes 45 XO.
z Structural abnormalities of the X chromosomes: These
includes isochromosome of the long arm, translocations, ring
chromosome, and deletions (Xp/Xq).
z Mosaics: The mosaic patients have combination of a 45, X cell
population along with one or more karyotypically normal or
abnormal cell types. Examples: (1) 45, X/46, XX; (2) 45, X/46,
XY. It is known as mosaic Turner syndrome.

Clinical Features (Fig. 23.4)

Turner syndrome is usually not discovered before puberty. It presents
with failure to develop normal secondary sex characteristics.
Important diagnostic features are:
z Adult women with short stature (<5 feet tall) primary
amenorrhea and sterility. Raised FSH levels are noted.
z Other features are:
„ Webbed neck, and low posterior hairline, wide/increased
carrying angle at the elbows (cubitus valgus), Madelung
deformity of the forearm and wrist, broad chest (shield FIG. 23.4: Clinical features of Turner syndrome.
chest) with widely spaced nipples and hyperconvex
fingernails.
„ The genitalia remains infantile, breast development is inadequate, and there is little pubic hair. The ovaries are
converted to fibrous streaks. Lack of secondary sexual characteristics.
„ Pigmented nevi and pilomatricoma as the age advances.
„ Congenital lymphedema, short fourth metacarpals and/or metatarsals, horseshoe kidney, osteoporosis.
„ Cardiovascular anomalies such as congenital heart disease particularly coarctation of the aorta or bicuspid aortic
valve may be present. Aortic dissection or rupture is a common cause of death. Systemic hypertension is seen in 30%
of cases. No mental retardation.

INTELLECTUAL DISABILITY
Q. PS15.1 Describe the etiology of mental retardation.
Definition: It is a neurodevelopmental disorder that begins in childhood and is characterized by limitations in both intel-
ligence and adaptive skills, affecting at least one of three adaptive domains (conceptual, social, and practical), with varying
severity. Earlier was termed as mental retardation.

Causes of Intellectual Disability

See Box 23.4.

Assessment of Degree of Intellectual disability

z Adaptive function: Impaired functioning in at least one of the following three domains, affecting participation
in multiple everyday settings: conceptual domain, social domain, and practical domain. The American Psychiatric
Association’s DSM-5 categorizes adaptive impairment from mild to profound.
z Intellectual function: It is assessed by IQ testing (Table 23.1).
Mental age
IQ =
Chronological age

INHERITANCE
Inheritance patterns are classified as either monogenic (Mendelian and non-Mendelian) or polygenic.
 CHAPTER 23: Genetics 1423

Box 23.4: Causes of intellectual disability.

• Genetic and chromosomal disorders, e.g., Down syndrome and fragile X syndrome
• CNS lesions:
– Hydrocephalus
– Microcephaly
– Cerebral palsy
– Post-traumatic, postmeningitic and postencephalitic states
– Birth trauma, kernicterus
• Environmental causes:
– Associated intrauterine infections: Congenital infections, congenital rubella syndrome, cytomegalovirus, and other viruses
– Intrauterine exposure to toxins and other insults: Alcohol, hypoxia or malnutrition
– Postnatal causes: Exposure to toxins, infection, and heavy metals
• Metabolic disease, e.g., cretinism, phenylketonuria, mucopolysaccharides, inborn errors of metabolism (e.g., glycogen storage diseases)

Single-Gene or Monogenic Disorders/Mendelian Disorders TABLE 23.1: Intellectual disability by IQ range.

Severity of mental retardation IQ range
Genetic disorders that result from mutations in single gene are called
Mild 50–55 to 70
as single-gene or monogenic (Mendelian) disorders. This type of
Moderate 35–40 to 50–55
inheritance is called Mendelian inheritance.
Severe 20–25 to 35–40
Polygenic Profound Below 20–25

Examples: Hypertension, diabetes—caused by the cumulative and interactive effects of genetic variation in more than one gene.
Q. List the characteristics of autosomal dominant inheritance with examples. What do you mean by penetrance and
variable expressivity?

Autosomal Dominant Pattern of Inheritance

z It is determined by the presence of one abnormal gene on one of the autosomes (chromosomes 1–22)
z Disease is in heterozygotes (These disorders generally manifest when one of the two homologous (paired) chromosomes
carries a mutant gene).
The general characteristics of autosomal dominant inheritance:
z Location of mutant gene: These are found on autosomes.
z Required number of defective genes: Only one copy of the mutant (abnormal) gene is required for effects.
z The disorder is transmitted in a vertical (parent to child) pattern, appearing in multiple generations.
z Sex affected: Males and females are equally affected.
z Pattern of inheritance: Every affected individual has one affected parent.
z Unaffected individuals (family members who do not manifest the trait) do not pass the disorder to their children.
z Risks of transmission (Figs. 23.5A to C) to children (offspring): Affected males and females have an equal risk of passing
on the disorder to children.

A B C

FIGS. 23.5A TO C: Pedigree illustrating autosomal dominant transmission. (A and B) One parent is affected; (C) Both parents are affected.
Note that both males and females are affected equally.
1424 CHAPTER 23: Genetics

„ When only one parent is affected and TABLE 23.2: Examples of autosomal dominant and autosomal recessive disorders.
other is normal: An affected individual Autosomal dominant
has a 50% (1 in 2) chance of passing on the System disorder Autosomal recessive disorder
deleterious genes for each pregnancy, and Nervous ¾ Huntington disease ¾ Friedreich’s ataxia
therefore of having a child affected by the Neurofibromatosis ¾ Spinal muscular atrophy
¾ Tuberous sclerosis ¾ Ataxia telangiectasia
disorder. This is called as the recurrence ¾ Myotonic dystrophy
risk for the disorder.
Skeletal/ ¾ Marfan syndrome ¾ Alkaptonuria
„ When both parents are affected: It has 75%
Dermatological ¾ Achondroplasia ¾ Ehlers-Danlos syndrome
chance of children being affected and a 25% ¾ Osteogenesis imperfecta ¾ Albinism
chance to be normal. ¾ Noonan syndrome

z Finding of male-to-male transmission Metabolic ¾ Familial hypercholesterolemia ¾ Cystic fibrosis

¾ Intermittent porphyria ¾ Phenylketonuria
essentially confirms autosomal dominant ¾ Lysosomal storage diseases
inheritance. ¾ Galactosemia
Examples of autosomal dominant and ¾ Hemochromatosis
autosomal recessive disorders are listed in ¾ Glycogen storage diseases
¾ Alkaptonuria
Table 23.2.
Hematopoietic ¾ Hereditary spherocytosis ¾ Sickle cell anemia
z Additional properties: ¾ Von Willebrand disease ¾ Thalassemia
„ Penetrance: Penetrance is the percentage ¾ Homocystinuria
of individuals with the mutation who Renal Polycystic kidney disease ¾ Congenital adrenal hyperplasia
present with clinical symptoms. Gastrointestinal Familial polyposis coli ¾ Wilson’s disease
 With complete penetrance, all ¾ Dubin-Johnson syndrome
individuals show clinical symptoms. Pulmonary ¾ Alpha-1 antitrypsin deficiency
 With incomplete penetrance or reduced ¾ Cystic fibrosis

penetrance, only some individuals show

disease and in nonpenetrance (gene is not expressed at all) individuals may not show any symptoms.
 For example, retinoblastoma: AD malignant eye tumor is a good example of reduced penetrance. About 10% of the
obligate carriers of the RB susceptibility gene (affected parent and affected child or children) do not have the disease.
„ Variable expressivity: It refers to variations in expression (qualitatively or quantitatively) of severity of the same
disorder among individuals (even within the same family), who have the abnormal gene. In some, the disorder may
be mild and in others it may show significant symptoms. Penetrance may be complete, but severity of disease can vary
greatly. Well-studied example is neurofibromatosis type 1, or von Recklinghausen disease.
Q. Discuss autosomal recessive inheritance with examples.

Autosomal Recessive Pattern of Inheritance

z Autosomal recessive inheritance involves mutations in both copies of a gene.
z These disorders generally manifest when both the homologous chromosomes carry mutant genes (homozygous state).
The general features of these disorders are:
z Location of mutant gene: These genes are located on autosomes.
z Required number of defective gene: Symptoms of the disease appear only when an individual has two copies of the
mutant gene. The heterozygote state is called as a carrier. In the carrier state, the product of the normal gene is able to
compensate for the mutant allele and is hence the patients are asymptomatic.
z Horizontal transmission: The observation of multiple affected members of kindred in the same generation, but no
affected family members in other generations.
z Pattern of inheritance: For a child to be at risk, both parents must be having at least one copy of the mutant gene. Almost
all inborn errors of metabolism are autosomal recessive disorders.
z Sex affected: Males and females being equally affected, though some traits exhibit different expression in males and
females (ovarian cancer, hypospadias).
z Consanguineous marriage: It is common predisposing factor.
z Recurrence risk of 25% for parents with a previous affected child.
z Risks of transmission (Figs. 23.6A to E) to children (offspring):
„ When both parents are heterozygous for the condition: Heterozygous parents carry one mutated gene and normal
gene. When two heterozygotes mate, 25% of the children will be affected, 50% will be unaffected heterozygotes and
25% will be normal.
 CHAPTER 23: Genetics 1425

A B C

D E
FIGS. 23.6A TO E: Pedigree illustrating mechanism of autosomal recessive transmission. (A) Both parents are unaffected heterozygotes; (B and C) One parent is sufferer
(homozygous) and other is normal; (D) One parent is sufferer and other is unaffected heterozygote; (E) One parent is normal and other is an unaffected heterozygote.

„ When one parent is affected and the other is normal: All the children will be unaffected heterozygote.
„ When one parent is affected and the other is heterozygote: The chances are that 50% of children will be unaffected
heterozygote and 50% homozygous affected.
„ When one parent is normal and the other is heterozygote: This may result in 50% unaffected heterozygote carriers
and 50% normal children.
z If the frequency of an autosomal recessive disease is known, then frequency of the heterozygote or carrier state can be
calculated from the Hardy-Weinberg formula: p2 + 2pq + q2 = 1, where p is the frequency of one of a pair of alleles and
q is the frequency of the other.
Examples of autosomal dominant and autosomal recessive disorders are listed in Table 23.2.

X-Linked Pattern of Inheritance

Q. Discuss X-linked inheritance with examples.
Almost all sex-linked Mendelian disorders are X-linked. Males with mutations affecting the Y-linked genes are usually infertile.
Expression of an X-linked disorder is different in males and females. Though X-linked disorders may be inherited either as
dominant or recessive, almost all X-linked disorders have recessive pattern of inheritance.
Characteristics of X-linked inheritance:
z Males are more commonly and more severely affected than females.
z Female carriers are generally unaffected, or if affected, they are affected more mildly than males.
z Affected males will have only carrier daughters.
z Carrier women have a 25% risk for having an affected son, a 25% risk for a carrier daughter, and a 50% chance for a child
that does not inherit the mutated X-linked gene.

X-linked Recessive Traits

z Location of mutant gene: Mutant gene is on the X chromosome and there is no male-to-male transmission.
z Required number of defective gene: One copy of mutant gene is required for the manifestation of disease in males, but
two copies of the mutant gene are needed in females.
z Sex affected: Males are more frequently affected and manifest disease than females; daughters of affected male are all
asymptomatic carriers. In many diseases, males do not survive.
z Pattern of inheritance (Figs. 23.7A to D): Transmission is through female carrier (heterozygous). Mothers are always
carriers and all their sons are affected. The disease is never passed from father to son.
z Very rarely, a female can develop the disease due to:
„ Female having Turner syndrome (XO) with only one X chromosome.
„ Presence of testicular feminization syndrome.
1426 CHAPTER 23: Genetics

A B C

FIGS. 23.7A TO D: Mode of X-linked recessive transmission. Note the absence of male-to-male transmission. (A) Male is normal and female is a carrier; (B) Male is sufferer and
female is normal; (C) Male is a sufferer and female is a carrier; (D) Male is normal and female is a sufferer.

„ Father with mutation in X chromosome and a carrier TABLE 23.3: Examples of X-linked recessive disorders.
female. System Related X-linked recessive disease
„ Affected father and carrier mother. Musculoskeletal ¾ Duchenne muscular dystrophy
„ Inactivation of normal X chromosome in most cells ¾ Beckers muscular dystrophy
(Lyon hypothesis). Blood ¾ Hemophilia A and B
¾ Glucose-6-phosphate dehydrogenase deficiency
Examples of X-linked recessive disorders are shown in Table ¾ Wiskott-Aldrich syndrome
23.3. Immune ¾ Agammaglobulinemia
Metabolic ¾ Diabetes insipidus
X-linked Dominant Conditions ¾ Hunter disease
z Disorders are relatively uncommon (very rare). For ¾ Lesch-Nyhan syndrome

example, vitamin D resistance rickets, Alport’s syndrome, Nervous ¾ Fragile-X syndrome

¾ Retinitis pigmentosa
Rett syndrome ¾ Color blindness
z Location of mutant gene: It is located on the X chromosome
and there is no transmission from affected male to son. This
is because the son’s “normal” X chromosome is from mother.
z Required number of defective gene: One copy of mutant gene is required for its effect.
„ Often lethal in males and so may be transmitted only in the female line.
„ Often lethal in affected males and they have affected mothers.
„ There is no carrier state as the disease will manifest, even if single chromosome has abnormal gene.
„ These are more frequent in females than in males.
z Risks of transmission to children (offspring) (Figs. 23.8A to C):
„ When female is affected and the male is normal: They transmit the disorder to 50% of their sons and 50% of their
daughters.
„ When male is affected and the female is normal: They transmit to all their daughters but none to their sons. All
daughters of an affected father develop disease because the daughter gets abnormal X from the father.
„ When both male and female are affected: All the females will be affected and half of males will be affected.

Y-linked Diseases
Characterized by:
z Only males are affected.
z An affected male transmits the disorder to all his sons but not to his daughters.
z Most Y-linked genes are related to male sex determination and reproduction, and are associated with infertility. Therefore,
it is rare to see familial transmission of a Y-linked disorder.
z For example, Leri-Weill dyschondrosteosis, Langer mesomelic dwarfism, hairy ears.
 CHAPTER 23: Genetics 1427

A B C

FIGS. 23.8A TO C: X-linked dominant transmission. Only females are affected. Usually males who inherit the mutant allele die in utero.
(A) Normal male and female affected (sufferer); (B) Affected male and normal female; (C) Both male and female are affected.

Digenic Inheritance
z Digenic inheritance explains the occurrence of retinitis pigmentosa (RP) in children of parents who each carry a different
RP-associated gene.
z Both parents have normal vision, but the offspring who were double heterozygotes developed RP.
z Digenic pedigrees exhibit characteristics of both autosomal dominant (vertical transmission) and autosomal recessive
inheritance (1 in 4 recurrence risk).
z Other disorders with digenic inheritance—Bardet-Biedl syndrome, Hirschsprung disease, Long QT syndrome.

Mitochondrial Inheritance
z An individual’s mitochondrial genome is entirely derived from the mother.
z Examples include Leber optic atrophy, MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes),
MERRF (myoclonic epilepsy associated with ragged red fibers), and Kearns-Sayre syndrome (ophthalmoplegia,
pigmentary retinopathy, and cardiomyopathy).

Pseudodominant Inheritance
Pseudodominant inheritance of a recessive trait in two generations of a family without consanguinity mimics a dominant
pattern. Pseudodominant inheritance of hereditary hemochromatosis (HH), an autosomal recessive disorder, can be attributed
to the high carrier frequency of HFE alleles in individuals of European descent. In this case, the father is homozygous for the
mutated alleles and the mother is the carrier of the genetic mutation; therefore, there are 50% chances that the offspring will
inherit mutated genes from both the parents and will have hemochromatosis.

Triplet Repeat Expansion Disorders

z Caused by expansion in the number of three-base-pair
repeats.
z An error in replication can result in expansion of that TABLE 23.4: Examples of triplet repeat expansion disorders.
number, referred to as premutation. Triplet Triplet
z There is a clinical correlation to the size of the Disease repeated Disease repeated
expansion, with a greater expansion causing more Huntington CAG Fragile X syndrome CGG
(FRAXA)
severe and/or earlier age of onset for the disease.
Myotonic dystrophy CTG FXTAS (Fragile CGG
The observation of increasing severity of disease and X-associated tremor/
early age of onset in subsequent generations is termed ataxia syndrome)
genetic anticipation and is a defining characteristic of X-linked spinal and CAG Machado-Joseph CAG
triplet repeat expansion disorders. bulbar muscular atrophy disease (MJD)
Examples of triplet repeat expansion disorders are Spinocerebellar ataxia CAG Friedreich’s ataxia GAA
listed in Table 23.4. type I
1428 CHAPTER 23: Genetics

Simple Tandem Repeat Mutation

z Variations in the length of simple tandem repeats of DNA are thought to arise as the result of slippage of DNA during
meiosis and are termed microsatellite (small) or minisatellite (larger) repeats.
z These repeats are unstable and can expand or contract in different generations. This instability is related to the size of the
original repeat, in that longer repeats tend to be more unstable.
z For example, Huntington disease, sickle cell anemia, Machado-Joseph disease, Fragile X, myotonic dystrophy.

Genetic Imprinting
z The two copies of most genes are functionally equivalent. In a small number, only one of the pair is transcribed.
z The active gene will be that inherited from a specific parent, and the other copy is silenced associated with methylation
of DNA (epigenetic modification of a gene not due to a DNA mutation).

Conditions Associated with Genetic Imprinting

z Prader-Willi syndrome with paternal chromosome deletion.
z Angelman syndrome with maternal chromosome deletion.
z Uniparental disomy (UPD): Rare occurrence of a child inheriting both copies of a chromosome from the same parent is
another genetic mechanism that can cause Prader-Willi and Angelman syndromes.
z Other conditions associated with imprinting are Beckwith-Wiedemann syndrome and Russell-Silver syndrome, Duchenne
muscular dystrophy (DMD) in females and epigenetic silencing in oncogenesis, e.g., colon cancer 3p21 MLH1.

Pleiotropy
z Genes that exert effects on multiple aspects of physiology or anatomy are pleiotropic.
z For example: Marfan syndrome (affects eye, the skeleton, and the cardiovascular system), cystic fibrosis (affects sweat
glands, lungs, pancreas, and genitourinary system), osteogenesis imperfecta (affects bones, teeth, and sclera), sickle cell
anemia (affects RBCs, bone, and spleen).

Locus Heterogeneity
z Disease that can be caused by mutations at different loci in different families is said to exhibit locus heterogeneity.
z Osteogenesis imperfecta (OI): Subunits of procollagen triple helix are encoded by two genes, one on chromosome 17 and
the other on chromosome 7. Mutation in either of these genes can alter the structure of the collagen molecules and lead
to OI, disease states are often indistinguishable.

Polymorphisms
z A polymorphism is defined as one that exists with a population frequency of >1%.
z Most common polymorphisms are neutral but some cause subtle changes in gene expression or in protein structure
and function. For example, cystic fibrosis, hemochromatosis, alpha-1 antitrypsin deficiency, spinomuscular
dystrophy.

GENE THERAPY
Q. Write short note on gene therapy.
Definition: Gene therapy is the insertion of genes into an individual’s cells and tissues to treat a disease, such as a hereditary
disease in which a deleterious mutant allele is replaced with a functional one.
To be effective, the gene therapy requires methods that ensure the safe, efficient and stable introduction of genes into
human cells. Gene therapy uses genes to treat or prevent disease. First done on September 14, 1990 for Ashanthi DeSilva
suffering from severe combined immunodeficiency (SCID) where the missing gene introduced through processed WBC.

Approaches for Correcting Faulty Genes

z A normal gene may be inserted into a nonspecific location to replace a nonfunctional gene.
z An abnormal gene could be swapped through homologous recombination.
z Repair through selective reverse mutation.
z The regulation of a particular gene could be altered.
 CHAPTER 23: Genetics 1429

Types of Gene Therapy

The cells in the body can be divided into two main categories: (1) somatic cells and (2) germ cells.
1. Somatic cell therapy: It involves delivering a correcting gene to somatic cells in the affected tissues. Somatic cells are the
nonreproductive cells and its therapeutic effect ends with the individual receiving it and is not passed on to the future
generations. Hence, somatic cell therapy is considered as a safer approach. This type of gene therapy is used for disorders
such as cystic fibrosis, muscular dystrophy, cancers, and certain infectious diseases.
2. Germ cell therapy: In germ cell therapy, germ cells (egg or sperms) are used and it results in permanent changes that
are passed on to the future generations. Thus, it offers the possibility of permanently eliminating some diseases from a
particular family and ultimately from the population. It is not accepted at present due to ethical reasons.

Arguments for Germline Gene Therapy

z Medical utility: The potential of a true “cure”.
z Medical necessity: May be only way to cure some diseases.
z Prophylactic efficacy: Better to prevent a disease rather than to treat pathology.
z Parental autonomy: Parents can make choices about what is best for their children.
z Easier, more effective than somatic gene therapy.
z Eradication of disease in future generations.
z Part of being human: Supporting human improvement.

Forms of Gene Therapy

There are two basic forms of somatic gene therapy: (1) ex vivo and (2) in vivo.
1. Ex vivo: Transfer of gene in cultured cells and finally these cultured cells are reintroduced into patients.
2. In vivo: Delivery of genes into cells of particular tissues. The gene may be transferred by a viral vector or by a nonviral
method. This is most often used technique.

Vectors in Gene Therapy

The most common form of gene therapy involves insertion of normal gene into the genome with the help of certain carriers
called vectors. These vectors can be divided into two main types: (1) viral and (2) nonviral vectors.
Viral vectors: The various viruses include retroviruses, adenoviruses, adeno-associated viruses, and herpes simplex
viruses.
Nonviral methods: Gene delivery can also be carried by nonviral methods. These have some advantages. They do not elicit
an immune response, safer and simpler to use and allow large-scale production. The nonviral methods include: direct
inoculation/naked DNA, liposomal-mediated DNA transfer, gene gun method, and dendrimers. Pure DNA constructs and
lipoplexes are used for in vivo transfer while bone marrow cells are used for ex vivo transfer.

Problems/Limitations of Gene Therapy

z Short-lived nature of gene therapy. Hence, patients will have to undergo multiple rounds of gene therapy.
z Immunotoxicity: Gene therapy may stimulate the immune response against introduced gene and reduce the effectiveness
of gene therapy.
z Problems with viral vectors: Viral vectors may sometimes cause potential problems to the patient like: toxicity
and inflammatory responses. In addition, the viral vector, once inside the patient, may recover its ability to cause
disease.
z Gene silencing—repression of promoter.
z Multifactorial disorders: Genetic disorders due to single gene mutations usually show best response to gene
therapy. Unfortunately, some the most commonly occurring disorders (e.g., atherosclerosis, hypertension, diabetes,
Alzheimer’s disease, and rheumatoid arthritis) are multifactorial and are difficult to treat effectively using gene
therapy.
z Phenotoxicity—complications arising from overexpression or ectopic expression of the transgene
z Risk of inducing a tumor (insertional mutagenesis): If the gene is integrated in the wrong place in the genome (e.g., in
a tumor suppressor gene), it could induce a tumor.
z Risk of death: Deaths have occurred due to gene therapy.
1430 CHAPTER 23: Genetics

Therapeutic Applications (Table 23.5) TABLE 23.5: Therapeutic application of gene therapy.
z Not been approved for clinical use. Disease Gene therapy trials
z Trials are being conducted on using gene therapy in the Inherited single gene disorders—to provide a normally functioning
gene
treatment of various genetic disorders, cancers, infectious
Severe combined Adenosine deaminase (ADA)
diseases, and other diseases such as Alzheimer’s disease
immunodeficiency
and atherosclerosis.
Cystic fibrosis Cystic fibrosis transmembrane
regulator (CFTR)
HUMAN GENOME PROJECT Familial hypercholesterolemia LDL receptor
Q. Write short note on human genome and human genome Emphysema Alpha-1 antitrypsin
project. Hemophilia B Factor IX
Thalassemia Alpha- or beta-globin
Introduction Sickle cell anemia Beta-globin
Duchenne muscular dystrophy Dystrophin
z Genome: A genome is the entire DNA in an organism,
Cancer therapy—to augment the immune response/to direct tumor
including its genes. The human genome is estimated to
lysis
contain 30,000–40,000 genes that are divided among the
Nasopharyngeal cancer P53
23 chromosomes. The 23 different chromosomes, 22 are
Melanoma Tumor necrosis factor
autosomes (numbered 1–22) and 1 pair of sex chromosomes
Retinoblastoma and Thymidine kinase (suicide gene
(X and Y). The functions of over 50% of discovered genes mesothelioma therapy)
are not known. Antibody delivery—not been used clinically
z Gene mapping: It is the process of identifying and
sequencing each and every human gene of the human TABLE 23.6: Organisms and their genomic size.
genome. The map of the human genome provides a picture Organism Genomic size in base pairs
of locations, and structures of genes. Epstein-Barr virus 0.172 × 106
z Genetic mapping (linkage analysis): A genetic map
Bacteria (E. coli) 4.6 × 106
describes the order of genes and defines the position of a Yeast 12.1 × 106
gene relative to other loci on the same chromosome. Nematode worm (C. elegans) 95.5 × 106
z Physical mapping: Physical mapping indicates the position
Fruit fly 180 × 106
of genes in a chromosome, which is determined by physical Human 3200 × 106
distances (measured in base pairs) between genes.
(E. coli: Escherichia coli; C. elegans: Caenorhabditis elegans)
Organisms and their genomic size are presented in Table 23.6.
The human genome project (HGP) is an international scientific research project to understand the genomes of humans and
other organisms. It was started in 1990 under Dr James D Watson at the United States National Institute of Health. In addition
to the United States, the international consortium comprised geneticists in the United Kingdom, France, Germany, Japan,
China, and India.

Goals of Human Genome Project

z Understand and identify all genes of the human genome.
z Determine the human DNA sequence: The primary focus of the HGP was to obtain DNA sequence for the entire human
genome. The goal was to map all genes of the human
genome and also to map human inherited diseases.
Thus included creation of genetic maps, development
of physical maps, and determination of the complete
human DNA sequence.
z Develop software for large-scale DNA analysis,
store all found information in databases and improve
tools for data analysis.
z Transfer-related technologies to the private sector
z Collect and distribute data
z Study the ethical, legal, and social issues (ELSI) of
genetic research that may arise from the project.
Components involved in human genome are
diagrammatically shown in Figure 23.9. FIG. 23.9: Components of human genome.
 CHAPTER 23: Genetics 1431

All humans have unique gene sequences. Therefore, the data published by the HGP does not represent the exact sequence
of each and every individual’s genome. It is the combined genome of a small number of anonymous donors. The HGP genome
is a scaffold for future work in identifying differences among individuals.

Uses of Human Genome Project

Human genome project will shed light on a wide range of basic questions, to identify the number of genes in humans, how cells
work, how living things evolved, how single cells develop into complex creatures, and what exactly happens when we become
ill. The understanding of the genome provides clues for:
1. Etiology of cancers, Alzheimer’s disease, etc.
2. Defining the pathogenesis of a disease and to study the disease processes at molecular level.
3. Susceptibility of an individual to a variety of illnesses, e.g., carcinoma breast, disorders of hemostasis, liver diseases, cystic
fibrosis, etc.
4. Predict new ways to prevent a number of diseases that affect the human beings.
5. To diagnose and treat disease. Target genes for treatment and management of diseases.
6. Human development and anthropology: Analysis of similarities between DNA sequences from different organisms helps
to study evolution.
7. Researcher: By visiting the human genome database on the Worldwide Web, researcher can examine what other scientists
have written about the gene.
Box 23.5: Ethical issues in human genome project (HGP).
Ethical Issues (Box 23.5) • Fairness in the use of genetic information
Human genome project helps to identify disease-causing genes, • Privacy and confidentiality
thereby can lead to improvements in diagnosis, treatment, and • Psychological impact and stigmatization
prevention. It is estimated that most individuals harbor several • Genetic testing
serious recessive genes. However, completion of the human genome • Reproductive issues
sequence and determination of the association of genetic defects • Education, standards, and quality control
with disease has raised many new issues with implications for the • Commercialization
individual and mankind. • Conceptual and philosophical implications.

GENETIC MUTATIONS
Q. BI7.3 Describe gene mutations and basic mechanism of regulation of gene expression.
Mutations are alterations in the genome of a cell.
Mechanism
z As a result of errors during DNA replication or cell division
z Ineffective DNA repair mechanisms
z Damage to DNA caused by endogenous and exogenous toxins

Types of mutations
z Mutations according to affected cell population
z Chromosomal aberrations
z Gene mutations
A. Based on the affected cells
„ Germline mutation (gametic mutation):
 Mutations in the cells from which egg or sperm cells develop
 These mutations can, therefore, be passed on to offspring.
„ Somatic mutation:
 Acquired mutations that are present only in certain somatic cells
 Primarily affect only one allele of a gene
 Do not occur in the germline and therefore cannot be passed on to offspring via the ovum or sperm
 Almost all malignancies are preceded by a somatic mutation.
B. Chromosomal aberrations
„ Chromosomal aberrations are mutations affecting large segments of DNA
„ They may be visible on karyogram
„ Numerical chromosomal aberrations or structural chromosomal aberrations (discussed earlier).
1432 CHAPTER 23: Genetics

Q. Write a short note on gene mutations.

C. Gene mutations
Types of gene mutations include:
„ Point mutation: alteration of a single DNA base pair, e.g., sickle-cell disease
„ Deletion: loss of one or more base pairs, e.g., cystic fibrosis
„ Insertion: addition of one or more base pairs, e.g., beta-thalassemia
„ Substitution: one or more base pairs are replaced by different base pairs
„ Trinucleotide repeat expansion:
 Increased repetition of base triplets that leads to faulty protein synthesis or folding
 Examples: Fragile X syndrome, Huntington disease, myotonic dystrophy.

Gene mutations can be classified based on the outcome:

z Frameshift mutation:
„ Shift in the reading frame caused by insertion or deletion of a number of nucleotides not divisible by 3, which leads to
modified amino acid coding in the gene segments downstream.
„ It results in the synthesis of shorter or longer proteins that have a modified function or are dysfunctional.
„ Examples: Tay-Sachs disease, Duchenne muscular dystrophy.
z In-frame deletion or insertion:
„ Deletion or insertion of three, six, nine, or more base pairs (always in triplets!), without a shift in the reading frame,
but with deletion or insertion of one, two, three, or more amino acids in the protein during translation.
z Silent mutation:
„ Altered codon, which codes for the identical amino acid.
z Nonsense mutation:
„ Formation of a stop codon, which leads to alterations in the splicing process and early termination of translation.
z Missense mutation:
„ Altered codon, which codes for a different amino acid
„ Example: Sickle cell disease (glutamic acid → valine)
„ Considered as “conservative” missense mutation when the new amino acid is similar in chemical structure to the
original amino acid.
z Splice mutation:
„ Alterations (especially point mutations) in the nucleotide sequences required for splicing (e.g., on the exon-intron
border or at the junction) that lead to defective mRNA and shortened proteins.
„ Examples: Some types of b-thalassemia, dementia, cancers, and epilepsy.
z Dominant negative mutation:
„ A gene mutation that results in nonfunctional protein that impairs the function of protein produced by the wild-type
allele in heterozygotes.

MISCELLANEOUS
Q. Write short note on proteomics/proteome.

Proteome
z The term proteome is derived from proteins expressed by a genome. It refers to all the proteins produced by an organism
and proteins are the functional units. Thus, the proteome represents full sets of proteins produced by the body and is
similar to the term genome for the entire set of genes. Human body contains more than 2 million different proteins, each
having different functions.
z Proteomics is the study of the proteome (full set/entire library of proteins in a cell type or tissue) and its variation/
relationship to disease.
z Amino acids are the basic units of proteins and are very small. Each amino acid consists of atoms ranging from 7 to 24 and
cannot be identified under even the powerful microscopes.
z Uses: Proteomic technologies play an important role in drug discovery, diagnostics, and molecular medicine. When a
defective protein-causing particular diseases are found, new drugs can be developed to either alter the shape of a defective
protein or mimic a missing one.
 CHAPTER 23: Genetics 1433

Epigenetics
Q. Write a short note on epigenetics.
Definition: Epigenetics is a reversible, heritable change/alteration in gene expression which occurs without mutation and
is unrelated to gene nucleotide sequence. Epigenomics is the study of epigenetics. Epigenetic alterations are associated with
cancers and other diseases. Unlike genetic changes in cancer, epigenetic changes are reversible.
z In normal cells, the majority of the genome is not expressed. Some portions of the genome are silenced by DNA methylation
and histone modifications.
z In some tumors, epigenetic changes may directly contribute to tumor development. Epigenetic changes involve post-
translational modifications of histones and DNA methylation, both of which affect gene expression.
z In cancer cells, there is global DNA hypomethylation and selective promoter-localized hypermethylation.

Examples:
1. Silencing genes by hypermethylation (epigenetic mechanism)
a. Tumor suppressor genes: Examples: p53 can be indirectly inactivated through silencing ARF by hypermethylation. This
hypermethylated ARF prevents inhibition of the MDM2 oncogenic protein and the enhancement of p53 degradation;
BRCA1 in breast cancer and VHL in renal cell carcinomas.
b. DNA repair genes: Mismatch-repair gene MLH1 in colorectal cancer.
2. Hypomethylation: The genome of cancer cells may also undergo global DNA hypomethylation. Gene hypomethylation
can cause chromosomal instability, derepression of growth regulatory genes, and overexpression of antiapoptotic genes,
which may induce tumors.

Clinical Applications
z Use of epigenetic tumor markers.
z Use of epigenetic therapeutic agents (e.g., azacitidine, decitabine, vorinostat) in the treatment of myelodysplastic
syndromes (MDS) and lymphoma.

Pharmacogenomics
Q. Write short note on pharmacogenomics and pharmacogenetics.
z Pharmacogenetics or pharmacogenomics is the study of interaction between genetics and therapeutic drugs.
z Pharmacogenetics is the study of unexpected drug response result and to look for a genetic cause.
z Pharmacogenomics is the study of identifying genetic differences within a population that explain certain observed
responses to a drug or susceptibility to a health problem.

Applications
z To develop a drug that has maximum therapeutic effect and produces least damage to adjacent healthy cells.
z To prescribe drugs depending on the patient’s genetic profile so as to reduce the adverse reactions.
z To determine the accurate dosage.
z To determine drug responses in the treatment of cardiac, respiratory, and psychiatric conditions.
z To develop targeted therapy (e.g., psychiatry, dementia, cardiac conditions) and in the treatment of breast cancer (testing
for HER2 receptor for response to trastuzumab) and other cancers (e.g., testing for BCR-ABL for response to imatinib in
CML; testing for epidermal growth factor receptor response to gefitinib and erlotinib in lung cancer).
List of chromosomal disorders are presented in Table 23.7.

TABLE 23.7: List of chromosomal disorders.

Chromosome Abnormality Disease association
X XO Turner syndrome
Y XXY Klinefelter syndrome
Y XYY Double Y syndrome
Y XXX Trisomy X syndrome
Y Xp21 deletion Duchenne/Becker syndrome congenital adrenal hypoplasia, chronic granulomatus disease
1 1p (somatic) monosomy trisomy Neuroblastoma
Contd...
1434 CHAPTER 23: Genetics

Contd...
Chromosome Abnormality Disease association
2 Monosomy trisomy 2q Growth rerdation, developmental and mental delay, and minor physical abnormalities
3 Monosomy trisomy (somatic) Non-Hodgkin lymphoma
4 Monosomy trisomy (somatic) Acute nonlymphocytic leukemia (ANLL)
5 5p deletion Cri du chat; Lejeune syndrome
5 5q (somatic) monosomy trisomy Myelodysplastic syndrome
6 Monosomy trisomy (somatic) Clear-cell sarcoma
7 7q 11.23 deletion William’s syndrome
8 Monosomy trisomy Myelodysplastic syndrome, Warkany syndrome, chronic myelogenous leukemia
9 Trisomy Complete trisomy 9 syndrome: mosaic trisomy 9 syndrome
10 Monosomy trisomy (somatic) Acute lymphoblastic leukemia (ALL) or acute nonlymphocytic leukemias (ANLL)
11 11p- Aniridia: Wilms tumor
11 Monosomy (somatic) trisomy Myeloid lineages affected [ANLL, myelodysplastic syndrome (MDS)]
12 Monosomy trisomy (somatic) Chronic lymphocytic leukemia (CLL), Juvenile granulosa cell tumor (JGCT)
13 13q14 deletion Retinoblastoma
13 Monosomy trisomy Patau syndrome
14 Monosomy trisomy (somatic) Myeloid disorders [myelodysplastic syndromes (MDS), ANLL, atypical CML]
15 15q11-q13 deletion monosomy Prader-Willi, Angelman syndrome
15 Trisomy (somatic) Myeloid and lymphoid lineages affected, e.g., MDS, ANLL, ALL, CLL
16 16q13.3 deletion monosomy Rubinstein-Taybi, papillary renal cell carcinomas (malignant)
trisomy (somatic)
17 17p-(somatic) 17p syndrome in myeloid malignancies
17 Monosomy trisomy (somatic) Renal cortical adenomas
18 Monosomy trisomy Edwards syndrome
19 Trisomy, deletion
20 20p- Trisomy 20p syndrome
20 20q- MDS, ANLL, polycythemia vera, chronic neutrophilic leukemia
20 Monosomy trisomy (somatic) Papillary renal cell carcinomas (malignant)
21 Monosomy trisomy Down syndrome
22 22q11.2 deletion DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, CML-
reciprocal translocation 9:22 Opitz G/BBB syndrome, Cayler cardiofacial syndrome
22 Monosomy trisomy Complete trisomy 22 syndrome

GENETIC TESTING
Indications of genetic testing are listed in Table 23.8.

TABLE 23.8: Indications of genetic testing.

Indications for germ line mutation testing Indications for analysis of genetic alteration
¾ Perinatal analysis ¾ Diagnosis and management of cancer
– >35-year old mother – Identifying tumor suppressor gene or identifying cytogenetic
– Previous child with genetic abnormalities alteration
– Family history – Identifying clonal proliferation confirming neoplasm
– Mother having a known recessive gene or balanced translocation or – Identification of mutations that can alter direct therapeutic choices
X-linked genetic disorders – Determination of therapeutic efficacy
–
Triple test abnormal ¾ Diagnosis and management of infectious disease
–
Fetal abnormalities in USG – Microorganism-specific genetic material to identify and diagnose
¾ Postnatal analysis genetic material
– Multiple congenital anomalies – Identification of genetic changes associated with drug resistance
– Unexplained mental retardation – Determination of treatment efficacy
– Suspected aneuploidy/unbalanced autosome/sex chromosomal
abnormality
– Multiple spontaneous abortions
 CHAPTER 23: Genetics 1435

Genome-wide Association Study

z Genome-wide association studies (GWASs) test hundreds of thousands of genes simultaneously and are used in genetics
research to associate specific genetic variations with particular diseases.
z It involves scanning the genomes from many different people and looking for genetic markers that can be used to predict
the presence of a disease.

POLYMERASE CHAIN REACTION AND ITS APPLICATIONS

Q. Write short essay/note on polymerase chain reaction (PCR).
Kary Mullis discovered polymerase chain reaction in 1983. PCR is a method employed to amplify minute amount of DNA
within a few hours. This technique consists of selective amplification of specific target nucleic acid sequences from total DNA
by using primers specific for the target region to be amplified.

Basic Steps
z Denaturation: In this step, the double-stranded template DNA is denatured by heat (temperature of around 92–96°C)
into single-stranded DNA.
z Annealing: DNA primers of interest are added along with the four basic deoxynucleotides and the solution is cooled.
It causes binding of DNA probes to their specific target regions of the single-stranded DNA at a temperature of around
50–65°C.
z Extension: The primers are extended at a temperature of around 68–78°C in the presence of DNA polymerase, dNTPs
and Mg2+ ions. The newly synthesized DNA strand acts as a template for the next cycle. This cycle is repeated several
times (around 25–30 times) and produces millions of copies of the original specific target DNA. To retain the activity of
DNA polymerase enzyme at such high denaturation temperature, Taq DNA polymerase, extracted from a microorganism
(Thermus aquaticus) is used in the PCR reaction.

Applications of Polymerase Chain Reaction

Polymerase chain reaction is the starting test used in most of the molecular genetic tests.
z Diagnosis of hereditary/genetic diseases: In genetic disorders, genetic mutations can be detected by PCR alone (e.g.,
Huntington disease), PCR followed by digestion with restriction endonucleases (e.g., diagnosis of spinal muscular atrophy),
PCR followed by dot-blot hybridization (e.g., thalassemia mutation detection), PCR followed by capillary electrophoresis
for genotyping (e.g., detection of triplet repeat disorders).
z Sequencing: It is used as first step for DNA amplification for all methods of DNA sequencing.
z Detection of pathogens: To detect small quantities of pathogen DNA (e.g., PCR for Mycobacterium tuberculosis), to detect
viruses, (including use of reverse transcriptase enzyme for RNA viruses), and real-time PCR (RT-PCR) for quantification
of viral load, e.g., hepatitis B and C, human immunodeficiency virus (HIV).
z Forensic genetics: To identify DNA sequences that are unique to each individual.

Reverse transcriptase PCR (RT-PCR): Initial step is to convert RNA to complementary DNA and rest of the process is same
as PCR. It is used to quantify the amount/number of copies of input DNA/RNA.
Real-time PCR: This technique, quantifies the PCR product in “real-time”. It is used to quantify the amount/number of copies
of input DNA/RNA.

Immunoblot (Western Blot)

It is a test to detect antibodies. According to molecular weight, the microbial proteins are separated by polyacrylamide gel
electrophoresis (PAGE). They are transferred (blotted) on to a nitrocellulose membrane, which is incubated with serum of
patient. Binding of specific antibody is detected with an enzyme—anti-immunoglobulin conjugate (similar to in ELISA), and
specificity is confirmed by its location on the membrane. The test is a highly specific and can be used to confirm the results
of less specific tests such as ELISA.

Lysosomal Storage Disorders

Classification of Lysosomal Storage Disorders
The classification of lysosomal storage disorders has been shown in Table 23.9.
1436 CHAPTER 23: Genetics

TABLE 23.9: Classification of lysosomal storage disorders. TABLE 23.10: Various types of mucopolysaccharidoses (MPSs).
Disorder Underlying defect Type of disorder Enzyme deficiency
Mucopolysaccharidoses Defective metabolism of glycosaminoglycans MPS I (Hurler syndrome, Hurler- α-L-iduronidase
Scheie syndrome, Scheie syndrome)
Sphingolipidoses and Defective degradation of sphingolipids and
MPS II (Hunter syndrome) Iduronate-2-sulfatase
sulfatidoses their components
MPS III (Sanfilippo disease)
Glycogen storage Defective degradation of glycogen
¾ Type A Heparan N-sulfatase
diseases
¾ Type B α-N-acetylglucosaminidase
Oligosaccharidoses Defective degradation of the glycan portion ¾ Type C α-glucosaminide N-acetyltransferase
of glycoproteins
MPS IV (Morquio disease)
Mucolipidoses Defective degradation of acid ¾ Type A Acetylgalactosamine-6-sulfatase
mucopolysaccharides, sphingolipids and/or ¾ Type B β-galactosidase
glycolipids
MPS VI (Maroteaux-Lamy disease) Arylsulfatase B
MPS VII (Sly disease) β-glucuronidase
Mucopolysaccharidoses
The various types of mucopolysaccharidoses have been shown in Table 23.10.

MPS I (Hurler Syndrome)

z Head/face: Prominence of the forehead, broad nose with a flattened nasal bridge, enlargement and protrusion of the
tongue, chronic hearing loss, corneal clouding, retinal degeneration or glaucoma; tonsillar/adenoidal hypertrophy
(predispose the child to URI), sleep apnea.
z Heart: Cardiomyopathy with asymmetric hypertrophy of the ventricular septum, thickening of the aortic and mitral
valves, which progress to valvular insufficiency.
z Abdomen: Hepatosplenomegaly results in a protuberant abdomen.
z Neurological: Mental retardation.

MPS II (Hunter Syndrome)

z Initial symptoms starts at 2–4 years of age with progressive growth delays, resulting in short stature.
z Head/face: Macrocephaly, delayed tooth eruption, progressive hearing loss, thickening of the lips, tongue, and nostrils.
z Heart: Thickening of the heart valves leading to a decline in cardiac function.
z Lungs: Obstructive airway disease.
z Abdomen: Hepatosplenomegaly.
z Skeletal: Short neck and broad chest, joint stiffness, with restriction of movements.
z Neurological: Hydrocephalus, mental retardation, and seizures.

MPS IV (Morquio Syndrome)

z Widely spaced teeth, corneal clouding (Fig. 23.10A), hearing loss, enlarged heart.
z Abnormal skeletal development: Scoliosis, hypermobile joints, large fingers, knock-knees (Fig. 23.10B), short trunk
with pectus carinatum, bell-shaped chest (ribs flared), severe growth retardation (82–115 cm), odontoid hypoplasia,
compression of spinal cord (cervical myelopathy), and dwarfism.

Phenylketonuria (PKU)
z Autosomal recessive disease, due to deficiency of enzyme phenylalanine hydroxylase causing failure to convert phenyl-
alanine to tyrosine.
z Developmental delay, mental retardation, seizures, eczema, blue eyes, hyperactivity, aggressive behavior, blond hair and
musty/mousy odor.

Galactosemia
Autosomal recessive disease due to deficiency of the enzyme galactose-1-phosphate uridyltransferase. It is due to ingestion
of galactose (lactose).
z Liver failure (hypoglycemia, bilirubinemia), hepatosplenomegaly
z Renal tubular disorder (acidosis, glycosuria, albuminuria)
z Lethargy, feeding intolerance, failure to thrive, cataracts
z Learning disorders in older children—mental retardation
z About 25% will develop sepsis (E. coli) in first 1–2 weeks, if untreated → death.
 CHAPTER 23: Genetics 1437

A B
FIGS. 23.10A AND B: (A) Corneal clouding seen in Hurler and Morquio syndrome; (B) Knock knees in Morquio syndrome.

DIGEORGE SYNDROME
Q. Write a short note on DiGeorge syndrome.
DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal
pouch system. Most cases are caused by a heterozygous chromosomal deletion at 22q11.2. Chromosome 22q11.2 deletion
syndrome (22qDS) includes DGS and other similar syndromes, such as velocardiofacial syndrome.
The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and
hypocalcemia (resulting from parathyroid hypoplasia).

Cardiac anomalies
z Interrupted aortic arch
z Truncus arteriosus
z Tetralogy of Fallot
z Atrial or ventricular septal defects
Hypocalcemia: Hypocalcemia, resulting from underdevelopment of the parathyroid glands and may present with jitteriness,
tetany, or seizures, with low serum calcium, elevated serum phosphorus, and very low parathyroid hormone levels.
Hypoplastic/aplastic thymus: The thymus is absent in patients with complete DGS. In patients with partial DGS, the thymus
is present, although it is often reported as hypoplastic.
Immunodeficiency: Immunodeficiency is common in patients with DGS and can range from recurrent sinopulmonary
infections (termed partial DGS) to SCID.

GENETIC COUNSELING
Q. AN75.5 Describe the principles of genetic counseling.
Genetic counseling is the process of helping people understand and adapt to the medical, psychological, and familial
implications of genetic contributions to disease. This process integrates:
z Collection of a detailed family history, interpretation of the family history with the medical history to assess the chance
of disease occurrence or recurrence.
z Education of the patient and family regarding the inheritance, testing, management, risk reduction, available resources
and research regarding the condition.
z Counseling to promote informed choices and appropriate interventions.
Genetic counseling can be conducted from preconception to old age. This includes preconception and prenatal counseling
about the potential health of a baby, genetic evaluation of a neonate with birth defects or a toddler with developmental delay.
Family history: The initial step in assessing inherited risk for many chronic conditions is collecting data related to the family
history.
1438 CHAPTER 23: Genetics

Key factors that suggest the presence of a genetic disorder include the following:
z Multiple affected individuals in multiple generations from either side of the individual’s family.
z Occurrence of the disease at an earlier age than usual.
z Close degree of relatedness (i.e., first- or second-degree relative) between affected relatives and the individual.
Once the family history is collected, it is used with the medical history to assess the possibility of an inherited etiology and
to identify the chance of disease occurrence or recurrence.
Once an objective risk figure has been determined, the genetic counselor can provide explanations of penetrance and
expressivity and apply these to the patient’s family history and assess personal risk.
Risk modification: The genetic counseling session also provides information about risk modification strategies (if available)
that may be appropriate for the patient and/or family. This may involve more aggressive screening (earlier, more frequent),
lifestyle or dietary modifications, and medical or surgical interventions.
Examples include:
z Familial cancer syndromes: A patient with hereditary breast and ovarian cancer syndrome is at risk for both types of
cancers and may have earlier mammography and clinical breast examinations and prophylactic surgeries.
z Prenatal counseling: Testing for the partner may be indicated for autosomal recessive conditions when a couple is
referred for prenatal counseling.
TABLE 23.11: Enzyme replacement therapy for diseases.
Q. Write a short note on enzyme replacement therapy.
Disease Enzyme therapy
z Enzyme replacement therapy (ERT) is a type of treament Fabry disease Agalsidase beta
which replaces an enzyme that is deficient or absent in Gaucher disease Imiglucerase
the body. Enzymes can be made by recombinant DNA
MPS I Laronidase
technology and can be given by intravenous injection.
MPS II Idursulfase
z ERT has also been successful in treating SCID caused by an
adenosine deaminase (ADA) deficiency. MPS IVA Elosulfase alfa
MPS VI Galsulfase
Enzyme replacement therapy for diseases has been shown in
Pompe disease Alglucosidase alfa (160-L bioreactor)
Table 23.11.