EPIDEMIOLOGY OF GENETIC DISEASES AND

ITS CONTROL MEASURES

Pravin Pisudde

Moderator: Dr Subodh Gupta

Framework

• Introduction• Categories of genetic diseases• Epidemiology of genetic diseases• Control measures • Genetic counseling• Newer advances

– DNA technology– The human genome project– Human genome diversity project– Gene therapy– Genetic engineering

• Organization of genetic services in health system

Introduction

• Determinants of health• Majority of determinants are being controlled• Standard of living and healthcare is improving.• 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

• Basic principles of genetics were laid down by Mendel and Galton towards the close of the 19th century

Categories of Genetic Diseases

• Chromosomal abnormalities– Chromosome 21(down syndrome), 18(Edward

syndrome) or 13(Patau syndrome) or an additional or missing sex chromosome, survive to birth.

• Point mutations– 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 mutation in 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.

Categories of Genetic Diseases • Single gene disorder– Dominant inheritance• Early-onset: eg osteogenesis imperfecta , brittle bone

disease

• Late onset: e.g. Huntington disease, adult polycystic disease of the kidney, familial cancer syndrome, tuberculous sclerosis, neurofibromatosis

– Recessive inheritance• Carriers are healthy themselves but have reproductive

risk

• Eg-haemoglobin disorders, cystic fibrosis, phenylketonuria and werdnig-hoffman disease

• X-linked inheritance – Unaffected carrier females(with two X

chromosomes) and affect mainly, but not exclusively male.

– E.g. duchnee muscular dystrophy, fragile X mental retardation and G6PD deficiency

– About 60% of carriers of X linked disorders might be detected by family studies.

– Family carriers are high genetic risk; in each pregnancy there is 25% risk of affected son and 25% risk of carrier daughter

Multifactorial disorders• With the genetic etiology other factors also plays

important role

Neonatal jaundice

infection

G6PD deficiency

Rh incompatibility

Congenital hypothyroidism

Inherited disorder of Bi metab

Genetic By breast feeding

prematurity

Enviromental

EPIDEMIOLOGY OF DISEASES

• Congenital anomaly– Structural, functional, or biochemical abnormality

present at birth regardless of whether or not it is detected at that time

• Accurate data is difficult to collect

Contribution of genetic and congenital disorders of infant and child mortality in atypical developed country

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

Importance of the genetic component in chronically disabling congenital disorders in a typical developed country

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%

The birth incidence of the infants with conginital disoreder include those that are trival or relatively easily corrected, is about 25-60 per 1000

The birth incidence of the infants with conginital disoreder include those that are trival or relatively easily corrected, is about 25-60 per 1000

Category Estimated birth /1000

Commonest diagnosis

Single-gene disorders

Dominant 7.0 Familial hypercholesterolemia, Adult polycystic disease of the kidney,

Huntington disease, Neurofibromatosis, ChondrodystropyX-linked 1.33 Muscular dystrophy, Haemophilia and Christmas disease, Colour vision

disorders, X-linked mental retardation., Glutathione deficiencyRecessive 1.66 Cystic fibrosis, Phenylketonuria, Amino-acid disorder, Werdnig-Hoffman

disease, ThalassaaemiasChromosomal 3.49

Autosomes 1.69 > 70% Down SyndromeSex chromosome 1.8 Mostly Klinefelter and turner syndromesCongenital abnormalities

52.8

26.6 Congenital heart disease, Club foot, CDH, pyloric stenosis, cleft palate/lip

No genetic component

26.2 -

Other multifactorial 10.06 Strabismus, Inguinal hernia, Epilepsy, Diabetes, Mild mental retardationGenetic, unknown type

1.2 -

Total genetic 51.34

Total genetic + non-genetic congenital anomalies

77.54

• Incidence of genetic disorders and congenital anomalies up to the age of 30 years in a typical developed country

• If multifactorial conditions of late onset are added to this figure, it is estimated that 60-65% of population will suffer from the genetic diseases in lifetime

• If major environmental causes of death avoided, people must die of their constitutional, often genetically determined limitation

• Demographic factors– Advanced materal age

• Chromosomal disorder & down

• syndromeHaemoglobin disorder and G6PD deficiency

– Consangious marriage• Still birth, neonatal & childhood death and Congenital malformation

Burden of genetic disease at birth in IndiaDisorder Incidence Number per year

Congenital malformations

1 in 50 595,096

G-6-PD deficiency 1 in 10-30(M) 390,000

Down Syndrome 1:1139 21,412

Congenital hypothyroidism

1:2500 10,400

Beta thalassemia 9,000

Sickle cell disease 5,200

Amino-acid disorder 1:2347 9,760

Other metabolic disorders

1:2500 9,000

Duchenne muscular dystrophy

1:5000(M) 2,250

Spinal muscular atrophy 1:10,000 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 MeasuresEugenics

– The study of, or belief in, the possibility of improving the qualities of the human species or a human population

Negative eugenics:

– To reduce the frequency of hereditary disease and disability in the community to be as low as possible.

– Done by debarring the people who are suffering from serious hereditary disease from producing children.

Positive eugenics:

– To improve the genetic composition of the population by encouraging the carriers of desirable genotypes to assume parenthood.

Control Measures(cont…)

• 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.

Approaches for prevention

• Basic public health measures

• Detection of genetic risk

• Genetic family studies

• Genetic population screening– Preconception counseling and screening

– Antenatal screening and Perinatal diagnosis

– Screening of neonate

Basic public health measures

Diseases Preventive measures

Rhesus haemolytic disease Screening for rhesus blood group

Congenital rubella Immunizing children and non pregnant women Testing pregnant women for antibody

Congenital toxoplasmosis Pregnant women to eat only well cooked meat

Neural tube defects Supplementation of folic acid around the time of conception

Severly malformed babies of IDDM mother

Control of blood sugar before pregnancy begins

G6PD deficiency Screening of neonates

Detection of genetic risk

Type of programme Primary objective Secondary objective

Preconception screening Reducing risks to the health of the fetus

Informed reproductive choice

Antenatal screening Identification of at-risk couples and affected fetuses in time for possible abortion

Diagnosis of affected fetus, and prenatal or neonatal treatment

Neonatal screening Case detection for early treatment

Data on disease incidence

General population screening

Identification of high risk factors

Prevention, early diagnosis and treatment

Objectives of different types of genetic population-screening programmes

Type of service Condition Preventive or screening action

Primary prevention

Rhesus haemolytic disease Postpartum use of anti-D globulin

Congenital rubella Immunization of girls

Congenital malformation Addition of folic acid to maternal diet Control of maternal diabetes Avoidance of mutagens and teratogens

such as alcohol, certain drugs and possibly tobacco

Antenatal screening

Congenital malformation Ultrasound fetal anomaly scan, maternal serum alfa protein estimation

Chromosomal abnormalites Noting maternal age and maternal serum factors

Inherited disease Checking family history Carrier screening for

haemoglobinopathies, tay-Sachs disease

Neonatal screening

Congenital malformation Examination of the newborn for early treatment e.g. congenital dislocation of hip

Phenylketonuria, congenital hypothyroidism, sickle cell disease

Biochemical tests for early treatment

Genetic Family Study

• Genetic diagnosis has implications for whole families as well as the individuals

• Correct diagnosis not only benefits the individual patient but is also valuable for the others

• Detailed family history has to be taken for all diagnosed genetic diseased patient.

Genetic population screening

• A genetic population-screening programme• A simple “primary screening test” is usually offered to

the whole population• A screening programme is a public health policy. The

classical requirements are– A common and potentially serious condition– A clear diagnosis in each case– Sound knowledge of the natural history of the condition– An effective and acceptable method of treatment or

prevention– Affordable test

Flow chart of genetic screening and Perinatal diagnosis for carriers of a recessive gene, indicating the non financial benefits and cost of each step in the sequence

Preconception screening and counseling• When to go

– The significance of a family history if

– With increase in maternal age

• Parents must know– Importance of balanced nutrition

– Effect of folic acid and multivitamin supplementation

– Importance of immunity to rubella

– Indication for testing for specific genetic task

– eg: rhesus blood group, haemolglobin disorder, Tay-Sachs disease, cystic fibrosis

– Effects of smoking, alcohol consumption and medication having risk of miscarriage, congenital, abnormality and fetal growth retardation

– Importance of avoiding certain maternal infection that can harm the fetus

• Preconception screening and counseling requires – The establishment of suitable infrastructure

– Improved medical and community education on genetic matter

– Freely available educational materials for women and health worker

– Basic training in genetic counseling for health workers

– Strengthening of laboratory facilities

Antenatal screening and Perinatal diagnosis

Test Reason

Scan Fetal viabliltyNumberGestational age

Blood test HaemoglobinABO and rhesus blood groupsHepatitis B virusHIV

Carrier screening Haemoglobin disorderTay-Sach diseaseCystic fibrosis

Maternal serum AFP or triple screen

Neural tube defectsDown syndrome

Routine fetal anomaly scan

Fetal Anomaly Scaning

• Grossest morphological abnormalities can be detected• Mostly offered for confirming intrauterine gestation,

gestational age, and fetal viability and number • Congenital abnormalities scaning, 19 weeks. • Scanning is generally offered to women belonging to

recognized risk groups – e.g. those with DM, raised serum AFP level, twins or H/O

fetal abnormality or possible exposure of teratogen. • Trained ultrasonographers can detect over 70% of all

major malformation. 15-30% of the fetuses in which abnormalities are detected are chromosomally abnormal.

Amniocentesis• Medical procedure, in which a small amount of amniotic fluid,

which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for genetic abnormalities.

• 14th-16th week of pregnancy

• The fetal cells are separated from it. The cells are grown in a culture medium, then fixed and stained. Under a microscope the chromosomes are examined for abnormalities.

• Used in prenatal diagnosis of chromosomal abnormalities and fetal infection

• The most common abnormalities detected are Down syndrome, Edward syndrome[Trisomy 18] and Turner syndrome[Monosomy X]. Usually genetic counseling is offered prior to amniocentesis.

• Choriononic villus sampling– Prenatal diagnosis to determine chromosomal or genetic

disorders in the fetus. – Done by catheter passed through uterine cervix or by

inserting needle in abdominal cavity– It entails getting a sample of the chorionic villus (placental

tissue) and testing it. – Carried out 10-13 weeks after the last period

• Fetal blood sampling(cordocentesis)– Fetal blood is obtained after 18 weeks safely by USG-

guided trans-abdominal needle puncture of fetal cord insertion.

– Fetal loss is 1-2%. – Used for Perinatal diagnosis of blood disorder, but now

commonly used for the rapid karyotyping of fetal lymphocytes when a major malformation has been detected by USG.

• Fetal tissue biopsy– Its best done at 19-20 weeks. – Sample like fetal skin, muscle liver are taken to diagnose

the disease.• FISH(fluorescent in situ hybridization)– New method for detecting numerical chromosome

abnormalities in non dividing cells, it uses fluorescent DNA probes for specific sequences

• Polymerase chain reaction– Technique to amplify a single or few copies of a piece of

DNA across several orders of magnitude, generating millions or more copies of a particular DNA sequence.

– Application of PCR • Isolation of genomic DNA, • Amplification and quantitation of DNA,• PCR in diagnosis of diseases

– early diagnosis of malignant diseases such as leukemia and lymphomas

Screening of neonates

Disorder Neonatal assayPhenylketonuria PhenylalanineCongenital hypothyroidism Thyroid stimulating harmoneSickle cell disease Haemoglobin electrophoresisCystic fibrosis Immunoreactive trypsinDuchenne muscular dystrophy

Creatine phosphokinase

Congenital adrenal hyperplasia

17-hydroxy-progesterone

Congenital dislocation of hip Ortolani and barlow manoeuvres

Genetic Counseling

• Complex 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.

• Basic principles of genetic counseling, the feasibility of incorporating counseling into primary health care, and the relief of anxiety of the parents.

• Counseling is important in genetics because of– The predictive nature of much genetic information– The physiological impact of knowledge of genetic risk for the

individual and family– Correct information on risk, on particular disorders and on the

availability of management and prenatal diagnosis.

• The main components are– 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;

– Accessibility for long-term contact; people at genetic risk may need counseling and support at several times in their lives.

• Types of genetic counseling– Prospective genetic counseling

• 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.

DNA technology

• Deoxyribonucleic acid (DNA), or an organism's genetic material—inherited from one generation to the next—holds many clues that have unlocked some of the mysteries behind human behavior, disease, evolution, and aging.

• Recent advances in DNA technology including– Cloning, – PCR, – Recombinant DNA technology, – DNA fingerprinting, – Gene therapy, – DNA microarray technology

The human genome project

• International scientific research project with a primary goal to determine the sequence of chemical base pairs which make up DNA and to identify and map the approximately 20,000-25,000 genes of the human genome from both a physical and functional standpoint.

• The project began in 1990 initially headed by James D. Watson at the U.S. National Institutes of Health

• It remains one of the largest single investigational projects in modern science

• While the objective of the Human Genome Project is to understand the genetic makeup of the human species, the project also has focused on several other nonhuman organisms such as E. coli, the fruit fly, and the laboratory mouse.

• Goals– identify all the approximately 20,000-25,000 genes in human DNA,

– determine the sequences of the 3 billion chemical base pairs that make up human DNA,

– store this information in databases,

– improve tools for data analysis,

– transfer related technologies to the private sector, and

– address the ethical, legal, and social issues (ELSI) that may arise from the project.

• Key findings of Genome Project– will provide clues to how diseases are caused.– All human races are 99.99 % alike, so racial differences are genetically insignificant. This

could mean all humans are descended from a single original mother.– Most genetic mutation occurs in the male of the species and as such are agents of

change. They are also more likely to be responsible for genetic disorders.– Genomics has led to advances in genetic archaeology and has improved our

understanding of how we evolved as humans and diverged from apes 25 million years ago. It also tells how our body works, including the mystery behind how the sense of taste works.

• Benefits– new avenues for advances in medicine and biotechnology. – easy ways to administer genetic tests that can show predisposition to a variety of

illnesses, including breast cancer, disorders of hemostasis, cystic fibrosis, liver diseases and many others.

– The etiologies for cancers, Alzheimer's disease and other areas of clinical interest are benefited

– A researcher investigating a certain form of cancer may have narrowed down his/her search to a particular gene.

Human genome diversity project

• Started by Stanford University's Morrison Institute and a collaboration of scientists around the world.

• HGDP has attempted to map the DNA that varies between humans, which is less than 1% different.

• Benefit– Yield new data on various fields of study ranging from disease

surveillance to anthropology. The Morrison Institute has maintained that diversity research could create definitive proof of the origin of individual racial groups.

– Potential gain lies in research on human traits. – Disease research. – Diversity research could help explain why certain racial groups

are vulnerable to certain diseases and how populations have adapted to these vulnerabilities

Gene therapy• 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.

• Gene therapy may be classified into the following types:Germ line gene therapy

germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are ordinarily integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations.

Somatic gene therapy

Therapeutic genes are transferred into the somatic cells of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring.

• Advantages/developments in gene therapy– Potential to treat the blood disorder thalassaemia, cystic

fibrosis, and some cancers. – Sickle cell disease is successfully treated in mice. – The success of a multi-center trial for treating children with

SCID (severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002. (Which was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition).

– Treatment for Parkinson's disease, Huntington’s disease– gene therapy can be effective in treating cancer. Eg

successfully treated metastatic melanoma, disease affecting myeloid cells.

– developed a way to prevent the immune system from rejecting a newly delivered gene.

– the world's first gene therapy trial for inherited retinal disease.

Genetic engineering• Genetic engineering, recombinant DNA technology, genetic

modification/manipulation (GM) and gene splicing are terms that apply to the direct manipulation of an organism's genes. Genetic engineering uses the techniques of molecular cloning and transformation to alter the structure and characteristics of genes directly.

• Genetic engineering techniques have found some successes in numerous applications.– Improving crop technology,

– The manufacture of synthetic human insulin through the use of modified bacteria, erythropoietin in hamster ovary cells

– the production of new types of experimental mice such as the oncomouse

– Manufacture of human growth hormone, vaccine for humans, for hepatitis B.

– Creation of GMOs for food use (genetically modified foods