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EPIDEMIOLOGY OF GENETIC DISEASES AND ITS CONTROL MEASURES
Framework
Introduction
Some concepts
Genetic basis of diseases
Epidemiology of diseases
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Global
India
Epidemiology of some common disorder
Control measures
INTRODUCTION
All over the world, particularly in developed and developing countries standard of living and healthcare is
improving.
All though limit of intelligence, physical ability and longevity are genetically determined, environmental and
external influences such as infections malnutrition and war have hitherto been the main determinants of health
and survival. Now, however, with increased control of environment, genetic makeup is becoming a
progressively more important determinant of health of the individual. In developed countries, genetic disorders
are responsible for a large proportion of infant mortality and childhood disability, and genetic predisposition
may lead to premature onset of common disorder of adult life such as diabetes, cancer, hypertension, coronary
heart disease and dementia.
SOME CONCEPTS
The human genome project is an international venture that aims, through systematic analysis to achieve a
complete picture of human DNA.
A mutation is a spontaneous change in the sequence or the complement of DNA
Point mutation arises in only one of a pair of genes. When a single altered gene is sufficient to cause evident
change, the mutation is termed as dominant. If the presence of the remaining, unmutated genes prevents such
change, the mutation is recessive.
DNA sequences that perform essential functions often differ very little between individuals, and even between
species, because mutations in sequences are usually harmful and are eliminated by natural selection. These are
called “conserved” sequences.
Congenital anomaly is defined as any structural, functional or biochemical abnormality present at birth,
regardless of whether or not it is detected at that time(this definition covers the overlapping categories of
genetic disorders and congenital abnormalities).
GENETIC BASIS OF DISEASES
Chromosomal abnormalities
Two full sets of chromosome sets are required for balanced gene experission leading to normal
embryonic development and functioning. However, errors of cell division leading to aneuploidy are common
during gamete formation. Aneuploidy usually causes failure of fertilization or of early embryonic development,
or miscarriage. Only a few fetuses with abnormalities such as additional chromosome 21(down syndrome),
18(Edward syndrome) or 13(Patau syndrome) or an additional or missing sex chromosome, survive to birth.
The frequency of chromosomal aneuploidy, and hence of spontaneous abortion and of chromosomally abnormal
infants, increases with maternal age.
Chromosomal rearrangements, in which two chromosomes exchange unequal portions of their DNA, can also
occur during gamete formation, and are another important cause of genetic disease.
Mutations
In double stranded structure makes the DNA molecule very stable, but single-base changes often occur
spontaneously; these changes are termed as point mutation. The natural mutation rate is increased by exposure
to mutagens such as ultraviolet light, radiation or chemical carcinogens. Even the smallest change causes the
mismatch between complementary strands and distort the DNA helix. In most of the cases DNA is repaired by
enzymes that recognize distortion, cut out the “wrong” base, and replace it with correct one. Mutations are the
rare changes that escape DNA repair, and, since this is most likely to occur during DNA replication
spontaneous mutations arise at cell division.
Most mutation occurs in somatic cells, most have no effect or lead simply to cell death, but those involving
growth-controlling genes sometimes lead to cancer.
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Sickle-cell hemoglobin is the result of a specific, single-base change in the β-globin gene.
β –thalassemia can be due to any one of more than 100 different mutationin and around the β-globin gene.
Cystic fibrosis is caused by any of more than 400 different changes in and around the cystic fibrosis
transmembrane conductance regulator gene.
Population movements
Because of industrialization, people are moving from one place to other. This population movement will
lead to changes in the distribution of the genes. The intermixing of people makes new genetic combinations
possible.
Public health measures
Advances in Medical Care services do affect the genetic endowment of the people as whole. More lives
are saved and the life expectancy has increased. The carriers of hereditary diseases are able to survive for a long
time and pass on the genes to other progeny.
Most of the common congenital malformations(eg cleft lip, cleft palate, neural tube defect) and common
diseases of adult life(eg diabetes mellitus, hypertension, obesity, coronary heart disease, schizophrenia) have
significant genetic etiology.
EPIDEMIOLOGY OF DISEASES
Disorder with a genetic component can be of any degree of severity and have their onset at any stage in life.
However, those presenting at birth are particularly burdensome, as they may cause early death or lifelong
disability.
Global
Accurate prevalence data are difficult to collect because of the great diversity of disorder and many cause early
death remains undiagnosed in absence of specialist services.
Table 1: Contribution of genetic and congenital disorders of infant and child mortality in atypical developed
country (UK)1
Main causes of the death at <1 year %
Main causes of the death at 1 to 4 years %
Perinatal factors
38
Accidents
31
Congenital & genetic disorders
25
Congenital & genetic disorders
23
Sudden infant death syndrome
22
neoplasms
16
Infections
9
Infections
11
other
6
other
9
Typical data of developed country, Congenital & genetic disorders are second most common cause of death in
infancy and childhood.
Table 2: importance of the genetic component in chronically disabling congenital disorders in a typical
developed country(UK) 1
Type of disorder
Incidence per 1000 births
Genetic component
Mental handicap:
Severe
3.5
most
Moderate/mild
25.0
Up to 30%
Cerebral palsy
2.5
Very small
Blindness
0.6
50%
Deafness(severe)
Approx 1.0
>50%
Congenital anomalies
>50
Approx 50%
Shows important contribution of these disorders to chronic childhood disability.
Also the birth incidence of the infants with congenital disorders, including those that are trivial or relatively
easily corrected is about 25-60 per 1000.
Table 3: Incidence of genetic disorders and congenital anomalies up to the age of 30 years in a typical
developed country
Category
Single-gene disorders
Dominant
Estimated birth per 1000Commonest diagnosis
7.0
Familial hypercholesterolemia
Adult polycystic disease of the kidney
Huntington disease
Neurofibromatosis
chondrodystropy
X-linked
1.33
Recessive
1.66
Chromosomal
Autosomes
Sex chromosome
Congenital abnormalities
3.49
1.69
1.8
52.8
26.6
No genetic component
Other multifactorial
26.2
10.06
Genetic, unknown type
Total genetic
Total genetic + non-genetic
congenital anomalies
1.2
51.34
77.54
Muscular dystrophy
Haemophilia and Christmas disease
Colour vision disorders
X-linked mental retardation
Glutathione deficiency
Cystic fibrosis
Phenylketonuria
Amino-acid disorder
Werdnig-Hoffman disease
Thalassaaemias
> 70% Down Syndrome
Mostly Klinefelter and turner syndromes
Congenital heart disease
Club foot
CDH
pyloric stenosis
cleft palate/lip
Strabismus
Inguinal hernia
Epilepsy
Diabetes
Mild mental retardation
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If multifactorial conditions of late onset such as thyroid disease, DM, psychoses, HT, MI, ulcers and familial
cancers are are added then it is estimated that 60-65% of the population will suffer from genetically determined
disorder during the life time.
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Advancing age influence the incidence of chromosomal disorder s, birth incidence of children with
chromosomal disorder may reach to 6/1000 and of children with down syndrome about 3/1000.
Over 4% of the global population carry a haemoglobin disorder and more than 7% carry a gene for
G6PD deficiency
Consanguious marriage favoured by at least 20% of world’s population and 8.4% are children born to
them, in these couples the general risk of still birth , neonatal or childhood death or serious congenital
malformationis about 2.5% and there is additional risk of 3% mental retardation.
India
India has a population of more than a billion people, with almost 25 million annual births. Combine this with
high rates of consanguinity in many communities, endogameous marriages in various ethinic groups, poor
nutritional status(low folate levels) of the mothers and high incidence of infections and the stage is set for high
frequency of genetic disorder s and birth defects.
Genetic diseases occur in two waves- one at birth and one later on in adult life.
Burden of genetic disease at birth in India2,3
Disorder
Congenital malformations
G-6-PD deficiency
Down Syndrome
Congenital hypothyroidism
Beta thalassemia
Sickle cell disease
Amino-acid disorder
Other metabolic disorders
Duchenne muscular dystrophy
Spinal muscular atrophy
Incidence
1 in 50
1 in 10-30(M)
1:1139
1:2500
1:2347
1:2500
1:5000(M)
1:10,000
Number per year
595,096
390,000
21,412
10,400
9,000
5,200
9,760
9,000
2,250
2,250
Role of genetic predisposition in some common disorder
Disease
Remarks
Coronart heart disease
 Familial hypercholesterolaemia
 Serum cholesterol
 Blood pressure
 Familial hyperlipidemias
 High levels of fibrinogen, homocystine, Lp(a) lipoprotein & apolipoprotein E4
Cancer
 Retinoblastoma
 Familial polyposis coli
 Breast: chromosome 17,
 Colon cancer
 Neurofibromatosis
Asthma & allergy
 Specific genes that affects plasma IgE level
Diabetes
 IDDM- chromosome 6
 NIDDM:
Mental disorder
 schizophrenia
Alzheimer disease
 strong familial tendency with increase prevalence with advancing age
CONTROL MEASURES
Prevention of genetic disorder
Eugenics
Eugenics is "the study of, or belief in, the possibility of improving the qualities of the human species or a
human population by such means as discouraging reproduction by persons having genetic defects or presumed
to have inheritable undesirable traits (negative eugenics) or encouraging reproduction by persons presumed to
have inheritable desirable traits (positive eugenics).
It has got both positive and negative aspects
Negative eugenics: the aim of negative eugenics is to reduce the frequency of hereditary disease and disability
in the community to be as low as possible. This is done by debarring the people who are suffering from serious
hereditary disease from producing children.
Positive eugenics: it seeks to improve the genetic composition of the population by encouraging the carriers of
desirable genotypes to assume parenthood.
Euthenics:
Euthenics deals with human improvement through altering external factors such as education and the
controllable environment, including the prevention and removal of contagious disease and parasites,
environmentalism, education regarding home economics, sanitation, and housing.
For the prevention of genetic disorder effective action can be taken at two level
GENERAL POPULATION
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Population education
Genetic screening
Preconception vitamin therapy
Basic public health measures
Population education
Population education can be of great help in decreasing the incidence of genetic diseases. People must be
informed about various risk factors which are responsible for the occurrence of genetic disorders in the families
so that they may take necessary precautions with this knowledge.
Risk factors
1. Consanguinity: Consanguious marriage/unions pose the risk of having children with congenital malformation
and abnormalities in the offspring
2. Advanced maternal age: relation between advanced maternal age and occurrence of chromosomal abnormalities
is present in all ethnic groups
Awareness should be created for general population especially for elected representatives, policy makers and
community influencers. Necessary scientific information should be made available to school and college
students as well as for non student youth. This will facilitate them to take responsible decisions. Training of
medical/paramedical and other health care providers will help in not only preventing the disorders but also will
help in the management of the cases.
Genetic screening
Genetic screening is the method to identify the person with in population who is at the risk of transmitting
disease to themselves or to their descendents by virtue of genetic constitution. The primary objectives of the
screening are
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To enumerate the frequency of variation in a population and to investigate biological significance and genetic
epidemiology of the variation
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To detect those at risk for their own health and for whom medical intervention may decrease the harmful effects
of the gene expression.
To detect those at risk of transmitting the harmful genes to their offspring. They may benefit from genetic
counseling regarding their reproductive options.
Preconception vitamin therapy
Cleft lip and /or palate and neural tube defect are caused by a deficiency in folic acid and its receptor s in the
mother. The neural tube closes by 23rd day in embryo. Any defect in this closure gives rise to neural tube defect
these defect can be prevented by Preconception vitamin therapy in which the prospective mother consumes 4
mg of folic acid 4 weeks prior to her conception and continue for 12 weeks after she conceives during the
organogenesis period. This prevents the occurance of these birth defects in the population and will reduce the
incidence by 70%.
Basic public health measures
Routine antenatal screening tests done for the public are
 Scan for fetal viability, number, gestational age
 Blood test, including:
o Haemoglobin
o ABO and rhesus blood groups
o Rubella antibodies
o Hepatitis B virus
o Human immunodeficiency virus
 Carrier screening for
o Haemoglobin disorder
o Tay-sachs disease
o Cystic fibrosis
 Maternal serum alpha-fetoprotein(AFP) or triple screen for risk of neural tube defects or Down
syndrome
 Route fetal anomaly scan
FAMILIES AND INDIVIDUAL AT RISK
Families with cases of congenital or inherited disease.
In this situation the aim is to educate the family members about the occurrence of genetic disorders. The close
relatives are to be convinced to seek genetic counseling and take appropriate decisions.
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Genetic counseling
Carrier screening
Neonatal screening
Early detection and treatment inborn errors of metabolism of single gene disorders.
Genetic counseling
Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of
the consequences and nature of the disorder, the probability of developing or transmitting it, and the options
open to them in management and family planning in order to prevent, avoid or ameliorate it. This complex
process can be seen from diagnostic (the actual estimation of risk) and supportive aspects.
The main components are
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A correct diagnosis
The estimation of genetic risk; this often requires a pedigree and may call for investigations involving
other family members
The provision of information on existence of risk and on any option for avoiding it; options will depend
on :
o The nature of disorder involved, the prognosis and the availability of treatment or palliative care;
o The chances that other family members may be at risk and , in particular, of passing the risk of
children;
o The possibility of avoiding risks to the individual’s own health
o Possibilities of avoiding transmission of the risk to children(techniques, problems, risk of error
or complication)
o Accessibility for long-term contact; people at genetic risk may need counseling and support at
several times in their lives.
Prospective genetic counseling
This approach requires identifying heterozygous individuals for any particular defect by screening procedures
and explaining to them the risk of having affected children if they marry another heterozygote for the same
gene.
Retrospective genetic counseling
Most genetic counseling at present are retrospective, i.e. the hereditary disorder has already occurred within the
family. The couples and family members seek genetic counseling in connection with congenital abnormalities;
mental retardation, etc. and only a few seek premarital advice.
Carrier screening
Screening for the carrier state of recessive traits would identify carriers who have a 25 percent risk of getting
affected children. Screening of certain genetic carrier states can be recommended in selective situation.
Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two
copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a
genetic disorder and to people in ethnic groups with an increased risk of specific genetic conditions. If both
parents are tested, the test can provide information about a couple's risk of having a child with a genetic
condition.
Neonatal screening
Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. The
routine testing of infants for certain disorders is the most widespread use of genetic testing—millions of babies
are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder
that causes mental illness if left untreated) and congenitalhypothyroidism (a disorder of the thyroid gland).
Early detection and treatment inborn errors of metabolism of single gene disorders.
Newborn screening is done for inborn errors of metabolism can be incorporated in community health care. A
drop of blood that is collected from 3 to 4 day old babies onto a filter paper can be mailed to the reference
laboratories and thus the metabolic disorders can be detected. This test will definitely help in early detection and
for providing prompt treatment to reduce morbidity and mortality due to the metabolic disorder.
References
1. Forfar JO. Demography, vital statistics and the pattern of disease in childhood. In: Campbell AGM, McIntosh
N, eds. Forfar and Arniel’s textbook of paediatrics, 4th ed. Edinburgh, Churchill Livingstone, 1992.
2. Verma IC. Genetic disorders need more attention in developing countries. World Health Forum. 1986;7:69-70
3. Verma IC, Bijarnia S. The Burden of genetic disorders in India and a framework for community control.
Community Genetics 2002;5:192-6
4. WHO. Control of herediatary disease: Report of a WHO scientific group. WHO technical report series;865.
5. Gogate S. Preventive Genetics. New Delhi: Jaypee Brothers Medical Publishers(P) ltd. 2006.