Human heritable diseases

The 46 human chromosomes consist of almost 3 billion base pairs of DNA that contains about 30,000 -
40,000 protein-coding genes. The coding regions make up less than 5% of the genome (the function of
the remaining DNA is not clear). Changes of hereditary material can result in obvious physical defects
or progressive deterioration in individuals with inborn errors of metabolism.

The branch of Human Genetics applied to the etiology, pathogenesis, diagnosis, prognosis,
management, and prevention of genetic diseases is called Medical Genetics. It is a relatively new field
of study. The chromosomal basis of many recognizable syndromes, for instance, was not known until
1958 when the underlying cause of Down syndrome (trisomy 21) was discovered.

Genetic classification of hereditary diseases

Genetic disease - a disease caused by an abnormality in an individual's genome.

According to the type of mutation and character of gene – environment interaction genetic disorders
can be classified into six categories.

1. Single gene inheritance, or gene disorders (also called Mendelian or monogenic inheritance)
caused by changes or mutations that occur in the DNA sequence of a single gene. There are more
than 6000 known single-gene disorders, which occur in about 1 out of every 200 births. Single-gene
disorders are inherited in recognizable patterns: autosomal dominant, autosomal recessive, and X-
linked.
2. Chromosome diseases caused by chromosomal and genomic mutations, i.e., structural and
numerical abnormalities of chromosomes, respectively.
3. Multifactorial diseases (also called complex or polygenic diseases) caused by a combination of
environmental factors and mutations in multiple genes (i.e., both genetic and non-genetic or
environmental factors are involved in determining the trait). For example, different genes that
influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22.
Some common chronic diseases are multifactorial disorders (e.g., atherosclerosis, hypertention, ulcer
disease, Alzheimer disease, arthritis, diabetes, cancer, and obesity).
4. Genetic diseases of somatic cells. Examples are cancer, autoimmune diseases.
5. Diseases due to incompatibility of genes. Example is haemolytic disease of newborns, in which
fetal red blood cells die earlier due to the action of antibodies formed by the mother against fetal Rh-
antigen.
6. Mitochondrial inheritance. This type of genetic disorder is caused by mutations in the
nonchromosomal DNA of mitochondria. Each mitochondrion may contain 5 to 10 circular pieces of
DNA. Examples of mitochondrial disease include an eye disease called Leber's hereditary optic
atrophy; a type of epilepsy called MERRF which stands for Myoclonus Epilepsy with Ragged Red
Fibers; and a form of dementia called MELAS for Mitochondrial Encephalopathy, Lactic Acidosis
and Stroke-like episodes.
concordance with the affected organ or organ system. For examples, hereditary diseases of
nervous system, immune system, respiratory system, muscle and bone diseases, etc.

Gene diseases and their patterns of inheritance

Gene diseases – hereditary disorders caused by an alteration (mutation) in a single gene. Errors that
occur within a gene can result in absent, deficient or abnormal protein products. The chromosomes, or
karyotype, of a patient with a single gene disorder are expected to be normal, 46,XX or 46,XY.
Therefore, chromosome analysis (cytogenetic analysis) is not recommended for patients who are
thought to have a single gene disorder.
It is known nearly 3000 such conditions, most of which are serious, none are curable and relatively few
are treatable or manageable.

Single-gene diseases typically describe classic simple Mendelian patterns of inheritance. There are
1364 disorders, where the mode of inheritance has been firmly established. These include 736
autosomal dominant, 521 autosomal recessive and 107 X-linked disorders. There are further 1447
disorders where unifactorial inheritance is suspected, but not yet proven.

The patterns followed by single-gene traits within families over a number of generations are
determined by the following factors:

1. Whether a trait is dominant or recessive.

2. Whether a gene determining a trait is autosomal or X-linked.
3. Chance distribution of genes from parents to children through their gametes.
4. Factors affecting the expression of a gene, which include
a. heterogeneity
b. pleiotropy
c. reduced penetrance
d. variable expressivity
e. variability of age of onset
f. sex limitation, complete or partial
g. interaction of two or more gene pairs
h. environmental effects

Classical methods applied to study of single gene disorders are pedigree analysis (genealogical
method), twins method, population method. Modern methods include biochemical method and DNA
molecular diagnosis.
The traditional method used to study an inherited disease is to observe the pattern of its
distribution in families through examination of a pedigree, the construction of which begins with the
individual first known to have the disease. The pedigree pattern allows one to judge whether or not the
distribution conforms to Mendelian principles of segregation and assortment, and thus represents
singlefactor inheritance. Patterns that do not conform to Mendelian principles may represent polygenic
traits, which represent the cumulative effects of a number of different genes. These complex patterns
underlie the vast majority of human diseases.

Disorders caused by single mutant genes show one of four simple (Mendelian) patterns of inheritance:

(1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, or (4) X-linked recessive.

Autosomal dominant inheritance

Features of autosomal dominant inheritance are -
1. Among children, whose parents both have a dominant inherited trait i.e., both are heterozygous for
the gene responsible for the trait, the genotypic expectations follow Mendel's ratio 1:2:1. One-
fourth of the children are homozygous affected and one-fourth homozygous normal.
2. The trait appears in every generation. Normally, there is no skipping of generation.
3. The trait is transmitted by an affected person (heterozygous) to half his children on an average.
4. Unaffected persons do not transmit the trait to their children.
5. The occurrence and transmission of the trait are not influenced by sex. Males and females have
equal chances of having the trait and transmitting it.
Autosomal dominant disorders often show two additional characteristics that are rarely seen in
recessive disorders: (1) marked variable expressivity (severity) of the disorder and (2) delayed age of
onset. In heterozygotes, the expression of the abnormal gene can be so weak that a generation appears
to be skipped because the carrier of the abnormal gene is clinically normal. In such fortunate
individuals, the trait is said to be "non-penetrant." In some diseases, such as Huntington's disease and
adult polycystic kidney disease, the disorder may not become manifest clinically until adult life even
though the mutant gene has been present since conception.

In every autosomal dominant disease, some affected persons owe their disorder to a new mutation
rather than to an inherited allele. A reasonable estimate of the frequency of mutation is on the order of
5×10-6 mutations per allele per generation. Because a dominant trait requires a mutation in only one of
the parental gametes, the expected frequency for a new autosomal dominant disease in any given gene
is one in 100,000 newborns.

Examples of dominant traits in humans:

1. Huntington’s Disease
2. Marfan’s Syndrome
3. Ehlers Danlos Syndrome
4. Neurofibromatosis
5. Tuberous Sclerosis
6. Familial hypercholesterolemia
7. Achondroplasia
8. PTC taste
9. Retinoblastoma

1. Huntington’s Disease is a fatal hereditary disease that destroys neurons in areas of the brain
involved in the emotions, intellect, and movement. Lethal dominant allele on chromosome 4 and has no
obvious phenotypic effect until the individuals is about 35 to 45 years old (but can develop in younger
and older people). The gene encodes a protein known as huntingtin. Gradually, this protein accumulates
within brain cells. The course of the disease is characterized by jerking uncontrollable movement of the
limbs, trunk, and face (chorea); progressive loss of mental abilities; and the development of psychiatric
problems (some people stop recognizing family members; others are aware of their environment and are
able to express emotions).

2. Marfan’s Syndrome is a connective tissue disorder that has been linked to the FBN1 gene on
chromosome 15. The gene encodes the glycoprotein fibrillin, a major building block of microfibrils. The
disease so affects many structures, including the skeleton (the patient's limbs are long compared with the
trunk; arachnodactyly, pectus deformities (scoliosis / kyphosis) and mild joint laxity and high arched
palate), lungs, eyes (lens subluxation, angle anomaly, glaucoma, hypoplasia of dilator muscle, axial
myopia and retinal detachment), heart and blood vessels (aneurysms of the ascending aorta and aortic
regurgitation), muscular underdevelopment, leading to a high incidence of hernias. The disease is
believed to have affected the US president Abraham Lincoln.

3. Ehlers Danlos Syndrome is a heterogeneous group of inherited connective-tissue disorders It is

characterized by joint hypermobility, cutaneous fragility, and hyper-extensibility. According the modern
classification there are 6 main types of the disease. Symptoms of classic type: joint and cardiac effects,
hypermobility. Infants with hypermobile joints often appear to have weak muscle tone, which can delay
the development of motor skills such as sitting, standing, and walking. Soft, highly elastic, velvety skin
which may tear, bruise, or scar easily and/or be slow to heal, and which has a tendency to develop benign
fatty growths as well as benign fibrous growths on pressure areas.

4. Neurofibromatosis (NF) is a genetic neurological disorder that affects cell growth in nerve
tissue. NF produces tumors of the skin, internal organs, and nerves that may become cancerous
(malignant). It also can affect bones, causing severe pain and debilitation and may result in learning
disabilities, behavioral dysfunction, and hearing and vision loss. There are two types: NF-1 & NF-2.
NF-1 neurofibromatosis, also called von Recklinghausen NF, is transmitted on chromosome 17 is the
most common subtype and is referred to as peripheral NF. This type causes multiple areas of
hyperpigmentation (i.e., birthmarks) that appear shortly after birth. In late childhood, a few to
thousands of tumors appear on the skin (cutaneous lesions) and under the skin (subcutaneous lesions).
These tumors may become cancerous.

NF-2 neurofibromatosis results from mutation (or rarely, deletion) of the NF2 gene and is transmitted
on chromosome 22, this type is referred to as central NF. In this type, tumors form in the nervous
system. This type causes hearing loss and loss of sense of balance (equilibrium), usually during the late
teens or early 20s. These tumors may become cancerous. There is no cure for NF.
5. Tuberous Sclerosis is a rare, multi-system disease characterized by the growth of numerous
benign (noncancerous) tumors in many parts of the body (skin, brain, heart, lungs, kidneys, eyes and
other organs), in some cases leading to significant medical problems. A combination of symptoms may
include seizures, developmental delay, behavioural problems, skin abnormalities, lung and kidney
disease. Tumors on the face (facial angiofibromas) are also common, beginning in childhood.

6. Familial hypercholesterolemia, disorder characterized by elevation of serum cholesterol bound

to low-density lipoprotein (LDL). Cause of disease is mutations in the LDL receptor (LDLR) gene on
chromosome 19. Heterozygotes develop fatty collections on their tendons, a corneal arc, and, of greatest
concern, coronary artery disease, which typically presents in the fourth or fifth decade of life.
Homozygotes develop these features at an accelerated rate. However, among patients with a history of
myocardial infarction (heart attacks), the heterozygote frequency is about one in twenty.

7. Achondroplasia is one of a group of disorders called chondrodystrophies or

osteochondrodysplasias. Cause of disease is mutation in the fibroblast growth factor receptor gene 3
(FGFR3), which causes an abnormality of cartilage formation. In achondroplasia, the mutated form of
the receptor is constitutively active and this leads to severely shortened bones. The disorder causes the
most common type of dwarfism. Cinical features of achondroplasia: nonproportional short stature with
an average adult height of 131 cm (4 feet 3.8 inches) for males and 123 cm (4 feet 0.6 inches) for females;
shortening of the proximal limbs, short fingers and toes, a large head with prominent forehead, small
midface with a flattened nasal bridge, spinal kyphosis (convex curvature) or lordosis (concave
curvature), frequent ear infections (due to Eustachian tube blockages), and hydrocephalus.
8. Taste blindness of PTC (Phenyl Thio-Carbamide) PTC is compound have sour taste. Only
persons having genotypes homozygous (TT) and heterozygous (Tt) dominant gene have ability to taste
PTC and recessive genotype (tt) lack the ability to taste PTC. The gene recognize for taste of PTC present
on chromosome 7.
9. Retinoblastoma is a cancer of the retina. It occurs mostly in children younger than 5 years and
accounts for about 3% of the cancers occurring in children younger than 15 years. Adult cases have also
been clinically recorded. The tumor may begin in one or both eyes. Retinoblastoma is usually confined
to the eye but can spread to the brain via the optic nerve.
As the retina is the light-sensitive part of the eye necessary for vision, loss of vision occurs.

Autosomal recessive inheritance

Autosomal recessive conditions are clinically apparent only in the homozygous state – when both
alleles at a particular genetic locus are deleterious. In most autosomal recessive disorders the clinical
presentation tends to be more uniform than in dominant diseases, and the onset is often early in life.
Consanguinity increases the likelihood of a child presenting with a recessive disease because the
likelihood of inheriting the same rare mutation from a distant common ancestor, or "founder" increases.
First cousins share, on the average, 1/8 of their genes. When two first cousins marry, an offspring has,
on average, 1/16 of the loci homozygous for a gene derived from a common ancestor. In general,
offspring of first cousins are slightly more likely to have congenital malformations, as well as mental
defects and metabolic diseases, than are children born to unrelated parents. Increased frequency of
consanguinity is not observed if the recessive disease is common.

Features of autosomal recessive inheritance

1. An autosomal recessive trait characteristically is seen only in sibs — brothers and sisters.
It is not seen in their parents, offsprings or other relatives.
2. On an average the ratio of affected, carrier and non-affected is 1:2:1 in sibs; the recurrence
risk in such a family is 1 in 4 for each birth.
3. The parents of the affected child may be closely related consanguineously.
4. Males and females are affected equally and transmit the trait equally.
Examples of autosomal recessive traits are -
1. Phenylketonuria : (disease related gene present on chromosome 12)
2. Alkaptonuria (chromosome 3)
3. Albinism (chromosome 11)
4. Galactosemia (chromosome 9)
5. Thalassemia (thalassemia beta chromosome 16 & thalassemia alpha chromosome 16)
6. Cystic fibrosis (chromosome 7)
7. Sickle-cell Anemia (chromosome 11)
8. Wilson’s Disease
9. Lysosomal Storage Diseases
a. Gauchers Disease (chromosome 21)
b. Niemann – Pick Disease
c. Tay – Sachs Disease (chromosome 15)

1. Phenylketonuria (PKU) is metabolic disorder characterized by a deficiency in the enzyme

phenylalanine hydroxylase (PAH) which is necessary to metabolize the amino acid phenylalanine (Phe)
to the amino acid tyrosine. When PAH is deficient, Phenylalanine amino acid accumulates and is
converted into phenylketones, which are detected in the urine. Left untreated, this condition can cause
problems with brain development, leading to progressive mental retardation and seizures. However,
PKU is one of the few genetic diseases that can be controlled by diet. A diet low in phenylalanine and
high in tyrosine can bring about a nearly total cure.
2. Alkaptonuria is a recessive human trait caused by inactivation of a gene present on chromosome
3. Suffering person excrete large amount of homogentisic acid (alkapton) in urine. When such urine
come in contact with air turn black. In normal condition homogentisic acid is oxidized by a liver enzyme
homogentisic acid oxidase to maleyl acetoacetic acid.
3. Albinism is a form of hypopigmentary disorder, caused by mutations in genes that regulate the
melanin synthesis, distribution of pigment by the melanocyte, and/or melanosome biogenesis are the
basis for these diseases. There are 2 main categories of albinism in humans:
a. oculocutaneous albinism
b. ocular albinism, only the eyes lack pigment. People with ocular albinism have generally normal
skin and hair color, and many even have a normal eye appearance. c.
4. Galactosemia is a rare metabolic disorder which affects an individual's ability to properly
metabolize the sugar galactose. Cause: Inability of the body to metabolize the simple sugar galactose,
causing the accumulation of galactose-1-phosphate in the body. This causes damage to the liver, CNS,
and other body systems. After drinking milk for a few days, a newborn with disease refuses to eat and
develop such symptoms: jaundice (yellowish discoloration of the skin and the whites of the eyes),
vomiting, poor feeding (baby refusing to drink milk-containing formula), poor weight gain, lethargy,
irritability, convulsions. The only treatment for classic galactosemia is eliminating lactose and galactose
from the diet.
5. Thalassemia is a human anaemia caused due an autosomal mutant gene and when this gene is
present in homozygous condition causes death in Childhood. The disease is called thalassemia major
and diseased person unable to produce beta chain of haemoglobin. The haemoglobin contains delta chain
like foetus which is unable to transport oxygen. In case of heterozygous condition patient survive and
show mild symptoms of anaemia. This disease is called thalassemia minor or also called Cooleys anemia.
6. Cystic fibrosis (CF) is a disease of the mucus and sweat glands. It affects mostly lungs, pancreas,
liver, intestines, sinuses and sex organs. CF causes mucus to be thick and sticky. Disorder leads to the
disruption of pancreatic exocrine function and chronic bronchitis with emphysema (The mucus clogs
the lungs, causing breathing problems and making it easy for bacteria to grow), as well as biliary
cirrhosis, meconium ileus, and an enhanced loss of salt through the skin, which is the basis of the "sweat
test" used for screening purposes.
The symptoms and severity of CF vary widely. Disease is common among individuals of Northern
European descent. In the United States, an estimated 1 in 29 Caucasian Americans have the CF gene.
The frequency of individuals affected with cystic fibrosis is one in 2,500, and typically the parents are
unrelated.
7. Sickle cell Anemia is a group of disorders that affects hemoglobin of RBCs. Sick people have
atypical hemoglobin molecules called hemoglobin S, which can distort RBCs into a sickle, or crescent,
shape.
Symptoms of the disease usually begin in early childhood. Characteristic features include anemia,
repeated infections, and periodic episodes of pain. The severity of symptoms varies from person to
person. Some people have mild symptoms, while others are frequently hospitalized for more serious
complications. Anemia can cause shortness of breath, fatigue, and delayed growth and development in
children. The rapid breakdown of RBCs may also cause yellowing of the eyes and skin, which are
signs of jaundice. Painful episodes can occur when sickled RBCs, which are stiff and inflexible, get
stuck in small blood vessels. These episodes deprive tissues and organs of oxygen-rich blood and can
lead to organ damage, especially in the lungs, kidneys, spleen, and brain. A particularly serious
complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs
(pulmonary hypertension). Pulmonary hypertension occurs in about one-third of adults with disease
and can lead to heart failure.
8. Wilson’s disease, or hepatolenticular degeneration - excessive deposition of copperin the
body's tissues (liver, brain, kidneys, and the eyes). A cause of disease is a mutation, localized on
chromosome 13q, affects the Cu-transporting ATPase gene (ATP7B) in the liver. Frequency ranges
worldwide from 1:30,000 in Japan to 1:100,000 in Australia; is more common in females than in males
(4:1).

It causes tissue damage, death of the tissues, and scarring, which causes the affected organs to stop
working correctly. Liver failure and damage to the CNS (brain, spinal cord) are the most predominant,
and the most dangerous, effects of the disorder. If not caught and treated early, Wilson's disease is fatal.

In diagnosis an eye examination may show Kayser-Fleischer rings (rusty or brown-colored ring around
the iris). Eye movement may be restricted.

9. Lysosomal storage diseases (LSD) are caused by a lack of enzymes that normally eliminate
unwanted substances in the cells of the body. The enzymes are found in lysosomes. The lack of certain
enzymes causes a buildup of the substance that the enzyme would normally eliminate, and deposits
accumulate in many cells of the body. Abnormal storage causes inefficient functioning and damage of
the body's cells, which can lead to serious health problems.
There are more than 40 known LSDs, including:

a. Tay-Sachs disease - a LSD that occurs more commonly in people of Eastern European
Ashkenazi descent and causes degeneration of the brain in infants.
The most common form of Tay-Sachs disease becomes apparent in infancy. Infants with this
disorder typically appear normal until the age of 3 to 6 months, when their development slows
and muscles used for movement weaken. Affected infants lose motor skills such as turning
over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As
the disease progresses, children with Tay-Sachs disease experience seizures, vision and hearing
loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which
can be identified with an eye examination, is characteristic of this disorder. Children with this
severe infantile form of Tay-Sachs disease usually live only into early childhood. Even with the
best of care, children with Tay-Sachs disease usually die by age 4.

b. Gauchers disease causes the spleen to enlarge, anemia and bone lesions if untreated
c. Niemann-Pick disease leads to enlargement of the spleen and liver, as well as lung disease

Disease Deficiency Accumulated Affected organs Notes

of enzyme substance & Symptoms
Tay-Sachs hexosaminidase gangliosides, Brain (neurological Child usually dies by
disease (ganglioside deterioration), blindness the age of 4 or 5 years.
GM2)
Gaucher glucocerebrosidase glucocerebroside Enlargement of liver, There are 3 clinical
disease spleen, anemia and bone subtypes
lesions if untreated
Niemann- sphingomyelinase sphingomyelin, Enlargement of the spleen There are 3 clinical
Pick disease cholesterol, and and liver, as well as lung subtypes that may or
other kinds of disease may not involve the
lipids CNS or respiratory
system

X-Linked Inheritance
Diseases or traits that result from genes located on the X chromosome are termed "X-LINKED."
Because the female has two X chromosomes, she may be either heterozygous or homozygous for the
mutant gene, and the trait may exhibit recessive or dominant expression. The terms "X-LINKED
dominant" and "X-LINKED recessive" refer only to expression of the trait in females. The male has
only one X chromosome and therefore is hemizygous for X-linked traits. Males can be expected to
express X-linked traits regardless of their recessive or dominant behavior in the female. This accounts
for the large numbers of X-linked diseases. Affected males do not transmit an X chromosome to their
sons; thus an important feature of X-linked inheritance is the absence of male-to-male transmission. In
contrast, since all females inherit their fathers' single X chromosomes, their daughters are all obligate
carriers.

X-linked dominant inheritance

Features of X-linked dominant inheritance
1. In rare X-linked dominant disorders, affected females are twice as common as affected males.
 2. Affected males pass on the trait to all their daughters, but to none of their sons. Thus, X-linked
dominant inheritance can be distinguished from autosomal dominant inheritance only by the progeny of
affected males.
3. Transmission by affected females follows the same pattern as autosomal dominant. Affected
heterozygous females transmit the condition to half their children of both sexes. Affected homozygous
females transmit the trait to all their children.
Examples of X-linked dominant inheritance are

1. Familial Hypophosphatemia
2. Vitamin D resistant rickets, or Familial Hypophosphatemia
3. Incontinentia pigmenti (also known as naevus pigmentosus systematicus)
1. Familial Hypophosphatemia

In familial hypophosphatemia, disorder of bone mineralization, the kidneys fail to reabsorb sufficient
phosphate, leading to low levels of serum phosphate. This usually begins after age 6-10 months. Prior
to this occurrence, the glomerular filtration rate is low, which sustains an adequate phosphate level.
Mutations in the PHEX gene are the cause of X-linked hypophosphatemic rickets (XLHR). PHEX
codes for a protease, which is an enzyme that catalyzes the hydrolysis of a protein. However, such a
protein has not yet been identified.

2. Vitamin D resistant rickets, or Familial Hypophosphatemia is an form of rickets

characterized by high concentrations of phosphate in the blood due to defective renal
tubular reabsorption of phosphate and subnormal absorption of dietary calcium.

Cause is the disorder is the mutation in the PHEX gene (Xp.22) and subsequent inactivity of the PHEX
protein. Frequency: 1:20000.

Symptoms include musculoskeletal and dental manifestations.

Musculoskeletal manifestations: smooth bowing of lower extremities when begin to weight bear,
waddling gait, bow leggedness, short stature, dolichocephaly (long head).

Dental Manifestations: pulp deformities, "intraglobular dentin" tooth anomaly, occasional enamal
defects, periapical infections.

3. Incontinentia Pigmenti (IP) is a disorder that affects the skin, hair, teeth, and nails. Cause:
mutations in the IKBKG gene coding for the protein that normally helps protect cells from
self-destructing (undergoing apoptosis). IP is lethal in most, but not all, males. A female
with IP may have inherited the mutant gene from either parent or have a new gene
mutation. Symptoms: blistering and wart-like skin growths in early childhood followed by
changes in skin pigmentation. The condition may also affect the teeth, hair, eyes, and
central nervous system (the brain and spinal cord).

X-linked recessive inheritance

Features of X-linked recessive inheritance
1. An X-linked recessive trait is mostly seen in males. It is uncommon in females.
2. The trait is transmitted from an affected man through all his daughters half of his grandsons.
3. The trait can be transmitted through a series of carrier females.
Examples of X-linked recessive inheritance are -

1. Haemophilia
 2. Colour blindness
3. Duchenne muscular dystrophy
4. Glucose-6-phosphate dehydrogenase deficiency (favism).

1. Hemophilia is a hereditary bleeding disorder. Hemophilia is a hereditary blood disorder,

characterized by a deficiency of the blood clotting protein that results in abnormal bleeding. Babylonian
Jews first described hemophilia more than 1700 years ago.
There are three types; Type A, Type B, and Type C. Haemophilia A is a genetic disorder characterised
by defficiency of Factor VIII in the blood, which is synthesized mainly in the liver, and is one of many
factors involved in blood coagulation. The factor VIII gene is located on the X chromosome. Since
males have only a single copy of most of genes located on the X chromosome, they cannot offset
damage to that genes with an additional copy as can females. Consequently, X-linked disorders such as
hemophilia are far more common in males. Type A is the most common. One in 10,000 males is born
with deficiency or dysfunction of the factor VIII molecule. Although normal hemostasis requires at
least 25% factor VIII activity, symptomatic patients usually have factor VIII levels below 5 percent.
Patients with <1% factor VIII activity have severe disease.

Hemophilia B is caused by the deficiency of Factor IX. It is also known as Christmas disease. It occurs
in 1 in 100,000 male births. Antenatal diagnosis can be done in females having high degree of
probability of being a carrier. This is done by doing chorion villus sampling at 8-9 weeks of gestation.

2. Color blindness, or color vision deficiency, is the inability to perceive differences between some
or all colors that other people can distinguish. The English chemist John Dalton in 1798 published the
first paper on the subject, "Extraordinary facts relating to the vision of colours", after the realization of
his own color blindness; because of Dalton's work, the condition is sometimes called daltonism.
Color blindness is usually classed as disability; however, in selected situations color blind people may
have advantages over people with normal color vision. There are many types of color blindness. The
most common are red-green hereditary (genetic) photoreceptor disorders.

3. Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD) are
the product of mutations in the dystrophin gene on the X chromosome. The most distinctive feature of
DMD is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves.
On average, a typical patient with DMD is diagnosed around the age of five, is wheelchair dependent at
twelve years of age, and is dead before the age of twenty. One-third of cases represent new mutations.

4. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is disease featuring abnormally low

levels of the G6PD enzyme, which plays an important role in red blood cell function. Individuals with
the disease may exhibit nonimmune hemolytic anemia in response to a number of causes. It is closely
linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with
a name derived from the Italian name of the broad bean (fava). Sometimes the name, favism, is
alternatively used to refer to the enzyme deficiency as a whole.

Y – linked inheritance (holandric inheritance):

Features of Y-linked inheritance
Males alone get affected and an affected male transmits the trait to all his sons but to none of his
daughters. As the Y chromosome is single, genes on Y chromosome are always expressed
phenotypically.

Examples of Y-linked inheritance are -

 1. Hypertrichosis pinnae auris (hairy ears) : characterized by excessive hair on pinna.
2. Azoospermia - complete inability to produce sperm, caused by a deletion of the azoospermia
factor (AZF) region,
3. Abnormal or Absent Testicular Development (gonadal dysgenesis), caused by a deletion SRY
gene.
4. Retinitis Pigmentosa is a eye disease caused by mutations in the RPY gene. Symptoms: a
progressive loss of sight starting with decreased night vision, followed by loss of peripheral or
side vision and finally blindness.
Mitochondrial inheritance
Features of mitochondrial inheritance
The diseases caused by mutations in mitochondrial genome are inherited only through the egg, sperm
mitochondria never contribute to the zygote population of mitochondria. All the children of an affected
female but none of the children of an affected male will inherit the disease.
Examples of mitochondrial inheritance are

1. Pearson marrow-pancreas syndrome

2. MELAS syndrome (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-
like episodes)
3. MERRF syndrome (Myoclonic Epilepsy with Ragged-Red Fibers)
4. Leber’s hereditary optic neuropathy (LHON)

Polygenic Traits and Multifactorial Genetic Diseases

Most phenotypic traits are determined by many genes collaborating at different loci (polygenic)
rather than by single gene effects. Parents and offspring, and usually siblings, have 50% of their genes
in common. Second-degree relatives share, on average, one-fourth of all genes, and thirddegree
relatives (cousins) share 1/8. As the degree of relation becomes more distant, the probability of
inheriting the same combination of genes is reduced, and the degree of resemblance is likely to be less.

Many common chronic diseases (e.g., essential hypertension, coronary artery disease, and
schizophrenia) and the common birth defects of children (e.g., cleft palate, cleft lip, and neural tube
defects) that tend to run in families fit best into the category of multifactorial genetic diseases.
Multifactorial genetic diseases have both a polygenic component and an environmental component of
causative factors. Susceptibility, or risk, genes are present in low frequency in the population at large.
However, if any one individual has a particularly large number of such genes, the disease may
manifest. When an individual is unfortunate enough to have inherited just the right (or wrong)
combination of risk genes, he or she passes beyond a "risk threshold" at which environmental factors
may determine the expression and severity of disease. In order for another family member to develop
the same disease, that individual would have to inherit the same, or a very similar, combination of
genes. The likelihood of such an occurrence is clearly greater in first-degree than in more distant
relatives. The chances of another relative inheriting the right combination of risk genes decreases as the
number of genes required to express a given trait increases. For example, the recurrence risk for
siblings in neural tube defects is almost 4%, or ten times greater than the risk in the population as a
whole.

Chromosomal abnormalities
Approximately 0.4 to 0.9% of newborns have chromosomal abnormalities, and about half of them have
an abnormal phenotype. The following paragraphs correlate the most clinically relevant aneuploidies
and important key points on each:
Autosomal Trisomies
Trisomy 13 (Patau Syndrome)
• Incidence: Approximately 1 in 5000 to 1 in 16000 live births (third most common autosomal
trisomy)
• Caused due to deletion of one arm of 13th chromosome.
• Clinical features: Microcephaly, holoprosencephaly, microphthalmia, small or poorly
developed eyes (anophthalmia or cyclopia), cleft lip and palate, polydactyly, rocker-bottom
feet, congenital heart disease, cryptorchidism, brain or spinal cord abnormalities, weak muscle
tone at birth, severe intellectual disability.
• Prognosis: miscarriage, stillbirth, or early death (median survival around one year of age).[4][6]
Trisomy 18 (Edwards Syndrome)
• Incidence: Approximately 1/3000 to 1:5000 live births (second most common autosomal
trisomy)
• Autosomal trisomy caused due to addition of one extra chromosome in 18th pair of
chromosome results affected person karyotype 47, XX or XY, +18
• Clinical features: Low birth weight, microcephaly, micrognathia, low-set, malformed ears,
clenched fists with overlapping fingers, congenital heart and renal abnormalities, rocker-bottom
feet, severe intellectual disability, survival about one year.
• Prognosis: miscarriage, stillbirth, or early death (median survival around one year of age).
Trisomy 21 (Down Syndrome)
• Incidence: Approximately 1:700 to 1/800 live births (most common autosomal trisomy)
• Autosomal trisomy caused due to addition of one extra chromosome in 21th pair of
chromosome. Affected person karyotype is: 47, XX or XY, +21
• Clinical features: Characteristic facial appearance, flat facies, prominent epicanthic folds, flat
occiput, Brushfiel spot in irides, weak muscle tone at birth, single transverse palmar crease
(simian crease), clinodactyly, congenital digestive and cardiac defects, intellectual disability,
increased risk for leukemia, Alzheimer disease and hearing an vision problems
• Prognosis: Approximately 75% of conceptions die in embryonic or fetal life. Nevertheless, if
birth occurs, the prognosis is relatively good (median survival is 47 years). It is the most
common aneuploidy that is compatible with long-term survival.
• Note: Approximately 95% of patients with Down syndrome have trisomy 21. However, 4% of
cases are due to Robertsonian translocation, and 1% is due to mosaicism.

Sex Chromosome Aneuploidies

Klinefelter Syndrome
• Incidence: 1/500 to 1:1000 male births.
• Sex chromosomal trisomy caused due to addition of one extra X chromosome. The affected
person karyotype is 47 (44+XXY).
• Clinical features: Increased height, long extremities, low upper/lower segment ratio,
gynecomastia, reduced facial and body hair (female hair distribution), delayed and incomplete
puberty, small testes (testicular atrophy), infertility, developmental delay (learning disabilities,
delayed speech and language development), increased risk for breast cancer.
 • Prognosis: Variable. It depends on the severity of clinical manifestations and treatment but
overall is fairly good. The life span is slightly reduced.
Triple X Syndrome (Super female)
• Incidence: Approximately 1/1000 female births
• Karyotype: 47, (44+XXX)
• Clinical features: Presents with increased height and risk of learning disabilities, delayed
development of speech, language, and motor skills, weak muscle tone, behavioral and
emotional difficulties, seizures, kidney abnormalities
• Some cases may seem phenotypically normal.
• Prognosis: Variable. It depends on the severity of clinical manifestations and treatment but
overall is fairly good.
• Notes: In this aneuploidy, X chromosomes are inactivated as Barr bodies. Therefore, two extra
Barr bodies are present at karyotyping.
XYY Syndrome (Super male)
• Incidence: Approximately 1:1000 male births
• Karyotype: 47(44+ XYY)
• Clinical features: Increased height and risk of learning disabilities, delayed development of
speech, language, and motor skills, weak muscle tone, hand tremors, seizures, asthma,
scoliosis, behavioral and emotional difficulties
• As with triple X syndrome, some cases may seem phenotypically normal.
• Prognosis: Variable. It depends on the severity of clinical manifestations and treatment but
overall is fairly good.
Turner Syndrome
• Most common sex chromosomal abnormality in females and the most common genetic cause of
primary amenorrhea
• Incidence: Approximately 1 in 2000 to 1 in 2500 live female births
• Karyotype: 45 (44+XO) accounts for 45% of cases because most zygotes cannot survive
extrauterine life.
• Clinical features: Short stature, webbed neck, low posterior hairline, shield chest, amenorrhea,
absence of puberty, the early loss of ovarian function (ovarian dysgenesis), infertility, skeletal
abnormalities (i.e., cubitus valgus), lymphedema, congenital kidney and/or heart disease (i.e.,
horseshoe kidney, coarctation of the aorta).
• Prognosis: Variable. It depends on the severity of clinical manifestations and treatment but
overall is fairly good.