GENETIC

DISORDERS
Presented By: Dr. Ayushi Baghel
Guided By: Dr. Seema Patel Mam

20/05/2024
TABLE OF CONTENT:

1 INTRODUCTION

2 GENETIC DISORDERS- TYPES

3 GENE RELATED HEMOGLOBINOPATHIES

4 PREVENTIVE AND SOCIAL MEASURES

5 ADVANCES IN MOLECULAR GENETICS

INTRODUCTION

GENETICS - Study of inheritance, dealing

with transmission of hereditary
characters from generation to
generation.
HUMAN GENETICS - Inheritance of
human traits and their relationship to
health.
It has emerged as basic science of
understanding endogenous factors in
health and disease and the complex
interaction between nature and nurture.
 Dolly the Gregor Mendel-
sheep-1st 1997 1866 Trait inheritance
Animal clone in pea plants

James Watson &

Simpson- DNA
Testing
1995 1953 Francis Crick-
Structure of DNA

Arthur
Kary Mullis-
PCR technique 1993 HISTORY 1957 Kornberg- DNA
in test tube

Dr. French Har Gobind

Anderson- Gene 1990 1966 Khurana,Nirenberg
therapy Holley-Genetic
Code
Alec Jeffreys- McClintock- Genes
DNA 1980's 1983 change position on
Fingerprinting chromosomes
 World~>3 million children born
PROBLEM with serious genetic defect per
STATEMENT year.

Western World-Chances having

inherited disease at birth <1%

Children with birth defect~6-

7/100 year;~1.7m birth defects
annually out of 26m births
~5% World’s population-carry
trait genes for hemoglobin
disorders, e.g. SCA
World-Incidence of Down
Syndrome-1 in 1000 to 1 in 100 live
births.
India-highest incidence of Down
syndrome-1/850-900 live
births.
PUBLIC HEALTH IMPORTANCE
Genetic disorders affect physical,
psychological and social well-being of
patients as well as their families.
India-establishment of comprehensive
medical genetic services - need of the
hour.
People unaware - treatment, management
and care options available for individuals
with genetic conditions.
Understanding role of genetic information
and predict the due course of genetic tests
and diagnosis can help minimise stress and
maximise benefits.
 GENETIC
DISORDERS

A genetic disorder is a disease

caused in whole or in part by a
change in the DNA sequence away
from the normal sequence.
TYPES OF GENETIC DISORDERS

1. MONOGENIC(MENDELIAN)

CHROMOSOMAL
2. ABNORMALITIES

3. POLYGENIC/
MULTIFACTORIAL

4. MITOCHONDRIAL
 MONOGENIC DISORDERS

Changes occur in the DNA sequence of a single gene.

Inherited in
recognizable patterns:
Autosomal
Dominant
Autosomal
Recessive
X-linked

1 out of every 200 birth suffers from any of the 6000 known
single gene disorders.
Huntington’s disease
Marfan’s Syndrome
Ehler Danlos Syndrome
Hypercholeresterolemia
Hereditary
Spherocytosis
Osteogenesis
imperfecta
Dystrophica Myotonica
Albinism
Cystic Fibrosis
Galactosaemia
Haemoglobinopathies
Hemochromatosis
Phenylketonuria
Alkaptonuria
Tay Sach’s Disease
Autosomal recessive
PCKD
Vitamin D resistant rickets
Rett’s Syndrome
Alport Syndrome
Haemophilia
Colour blindness
G6PD Deficiency
Retinitis Pigmentosa
Duchenne’s muscular dystrophy
 CHROMOSOMAL
ABNORMALITIES
Chromosomes carry genetic material; any abnormality in
chromosome number or structure- result in genetic disease.

This may be in form of alterations in the number or structure of

chromosomes. autosomes or sex chromosomes.

Incidence of chromosomal abnormalities- 5.6/1000 live births.

 Cat Cry
Syndrome
Down
syndrome

Fragile X
Turner Syndrome
Syndrome

Klinfelter’s
Syndrome

AML
 DOWN SYNDROME/ MONGOLISM
WHO DESCRIBED IT? Langdon down in 1866.
WHO DOES IT AFFECT?
1 in 1000 to 1 in 100 live births(WHO).
3000-5000 children in US, born with Down’s syndrome
affecting ~250,000 families(Verma IC et al., Community
Genet 2002).
India- highest number in world with incidence- 1 per 850-900
live births(Pankaj G et al., BJMMR, 2015).
WHEN IS IT DIAGNOSED? At birth.
WHAT IS THE CAUSE? Due to extra chromosome on 21st
pair- “TRISOMY 21”.
WHAT ARE THE CONSEQUENCES? Mild to moderate mental
retardation
 The prevalence of Down syndrome increases as the
mother’s age increases.
The risk for a woman of 20 is about 1 in 3000 and that
for a woman of 45, 1 in 50.
Typical features seen in Down’s Syndrome

World Down Syndrome Day-21st March.

2024 theme- “End the Stereotypes”
 TURNER’S SYNDROME
WHO DOES IT AFFECT? Incidence of 1 in 7500 live born
females.
~ 98% of conceptuses abort spontaneously; remaining
2% reach term. Increased risk of dying in the neonatal
period.
WHEN IS IT DIAGNOSED? At adolescence.

WHAT IS THE CAUSE? Due to non-disjunction of sex

chromosomes; missing X chromosome.
They have 45 chromosomes(44 X0) instead of normal
complement of 46(44 XX).
WHAT ARE THE CONSEQUENCES? Infertility,
mental retardation.
 KLINFELTER’S SYNDROME
WHO DOES IT AFFECT? Incidence of 1 in 500 among males at
birth.

WHEN IS IT DIAGNOSED? Only 25% diagnosed and that too

later in life, mostly during adulthood.

WHAT IS THE CAUSE? Due to an extra X chromosome(s)

in addition to one Y chromosome(XXY,XXXY)

WHAT ARE THE CONSEQUENCES? Infertility,

Gynaecomastia, mental retardation.
Klinfelter’s is not rare...but is
rarely diagnosed.
World Klinfelter’s Syndrome
Awareness day on 10th May.
 GENE RELATED HEMOGLOBINOPATHIES
Disorders affecting the structure, function, or production
of hemoglobin.

Hemoglobinopathies are the commonest genetic

disorders worldwide.

An estimated 7% of the world’s population carries an

abnormal hemoglobin gene, while about 300,000- 500,000
are born annually with significant hemoglobin disorders.
 Hemoglobinopathies are more widely prevalent among
the tribal population than the non-tribal communities in
India.

They consist of two major groups – Thalassemia and Sickle

cell syndromes

Sickle cell syndromes are more frequent and constitute

70% of affected births worldwide.
 SICKLE CELL ANAEMIA
An autosomal recessive disorder in which an abnormal
hemoglobin leads to chronic hemolytic anaemia with a
variety of clinical consequences.

The disease is common among people of sub-Saharan

Africa,South America, the Carribean, Central America,
Saudi Arabia, India and Mediterranean countries like
Turkey,Greece and Italy.

India- Majority in tribal population- 1 in 86 births among

STs have SCD.
Higher prevalence
states India- Sickle gene common-
tribal groups- prevalence
vary 1-40%.

SCA common in malaria

endemic areas.

Due to population migration,

the disease is also seen in
non-tribal population
subgroups.
SICKLE CELL
BELT- MP
Inheritance patterns of SCA

Classic example of
point mutation in DNA.

Occur as result of change

in amino acid from
glutamic acid to valine at
6th position in beta globin
gene.
 ONSET- Occurs in fetal life;
MANIFESTATIONS- During first
year of life when HbS replace HbF.

Patients-chronically ill; Death- due

to ATS, spleen crises, and strokes.

No specific tretment, only

symptomatic care & proper hydration
improve QOL.

Prenatal diagnosis and genetic

counselling helpful.
 GOAL
Eliminate sickle cell disease
as a public health problem
in India before 2047

OBJECTIVES
1. Provision of affordable, accessible, and quality care to all
SCD patients
2. To reduce the prevalence of SCD and sickle cell trait
SICKLE CELL CARDS
 THALASSEMIA
An autosomal recessive disorder caused by reduction or lack
of synthesis of globin chains [alpha or beta] resulting in
hereditary form of anemia .
People of Mediterranean, Middle Eastern, African and Asian
descent are at higher risk of carrying the genes for
thalassemia.

Every year 10,000-15,000 children with

thalassemia major are born in India, which constitutes 10%
of the total number in the world , and one out of every 8
carriers of thalassemia worldwide lives in India.
 BURDEN IN INDIA
In India-Thalassemia is prevalent across the country, with an
average frequency of carriers being
3-4%.

A higher frequency observed in certain communities, such as

Sindhis, Punjabis,
Gujaratis, Bengalis, Mahars, Kolis, Saraswats, Lohanas and Gaurs.

HbS is highly prevalent in the tribal

populations of Southern, Central and Western states reaching as
high as 48% in some communities.

HbE is common in the North Eastern states, and has a carrier

frequency as high as 50%, in some areas.
 Alpha thalassemia
Gene deletion- alpha globin protein of Hb chain.
Occur in Southeast Asia, the Middle East, and China and in
African descent.
India- milder form of alpha thalassemia predominant.

Beta thalassemia

Point mutation- beta globin protein of Hb chain.

Occur in Mediterranean region.
Disease starts manifesting after 6
months age; Hb synthesis switch
from HbF to HbA.
Mild blood abnormalities to fatal
anemia.
Blood transfusion- only mode of
treatment-severe thalassemia.
Only few cured by bone marrow
transplantation.
Genetic counselling and avoiding
consanguineous marriage-helpful.
 May 8, 2024, marks International
Thalassaemia Day. The theme of
the event this year is
”Empowering Lives, Embracing
Progress: Equitable and
Accessible Thalassaemia
Treatment for All.”

The day is observed to encourage those who struggle to live

with the disease. This day is a commemoration day in honour
of all patients suffering from thalassemia and their parents
who have never lost hope for life, despite the burden of their
disease.
 HEMOPHILIA

X-linked recessive bleeding disorder occuring with

frequency~ 1:10,000 male newborns.
According to National Health Portal of India(2018),
hemophilia A (clotting factor VIII deficiency)- MOST
COMMON-~1 IN 5000-10,000 births.
Hemophilia B (FACTOR IX deficiency) occurs, ~ 1 in
20,000-34,000 births.
10-80% hemophiliacs present in developing countries
like India(Ghosh K et al., Hemophilia Federation of
India,2010
 Most commonly
occur in males than
females; females are
carriers.
Severe hemophilia-
bleeding inside brain-
fatal or permanent
debility.
 MULTIFACTORIAL
INHERITANCE
Occur- Combination of mutation-multiple genes with
environmental factors contribute to outcomes.

Also known as COMPLEX/POLYGENIC INHERITANCE.

Mainly include Non-Communicable diseases-

cardiovscular diseases, diabetes, cancer,
hypertension,Alzheimer’s,arthritis and obesity.

Minority cancers- familial cancer syndromes - inherited.

 MITOCHONDRIAL
INHERITANCE
Cause- Mutation in non-chromosomal DNA of
mitochondria.
Mode of inheritance- strictly maternal.

E.g.- Leber’s hereditary optic atrophy,

Myoclonus epilepsy,
Mitochondrial encephalopathy,
Lactic acidosis,
Stroke like episodes.
These diseases manifest- more than one mutation.
PREVENTIVE AND SOCIAL
MEASURES
 PRIMARY PREVENTION
EUGENICS
EUTHENICS
GENETIC COUNSELLING
SECONDARY PREVENTION
EARLY DIAGNOSIS &
TERTIARY PREVENTION
DISABILITY LIMITATION & REHABILITATION
 EUGENICS
FRANCIS GALTON(1883) coined the term EUGENICS from
the Greek, good(“eu”) and born (“genics”).

DEFINED as “ The science of

improvement of human race through
better breeding”.

2 Types-
Positive eugenics and
Negative eugenics
POSITIVE EUGENICS
Promotes Breeding between people called “desirable” -
good breed for future generations.

NEGATIVE EUGENICS
Improving quality of human race- excluding/ eliminating
biologically inferior people from population.
e.g. Elderly and sick people killed under Hitler’s policy of
eugenics.
 EUTHENICS
Science concerned with improving well-being of manklind
through improvement of environment.
Improved genotype-access to suitable environment-
enables gene express readily.

Example- Children with mild mental

retardation when placed in encouraging
environment-improvement in IQ.
GENETIC COUNSELLING
Genetic counselling
is a communicative
process that serves
to inform, educate
and support
patients and
families with a
suspected or
confirmed diagnosis
of genetic disease.
How a Genetic Counselor Can Help You?
Help identify families at possible
risk of a genetic condition.
They provide information about
genetic testing and related
procedures.
They help families understand the
significance of genetic conditions in
relation to cultural, personal, and
familial contexts.
They also discuss available options
and can provide referrals to
educational services advocacy and
support groups, other health
professionals, and community or
state services.
What Does Genetic Counselling Involve?
TYPES OF GENETIC COUNSELLING
Offered to all couples
with or without any
genetic condition in the
family.
Mainly for a couple
who are planning to
get married
consanguineously.
Also, for couples
where, both the
partners are deaf/
mute, or both the PRE-MARITAL COUNSELLING
partners are blind.
 PRECONCEPTUAL COUNSELLING

Available to couples
who are planning a
pregnancy, to discuss
risks to a future
pregnancy as well as
available testing
options.
In this type, genetic
disorder has not yet
expressed itself.
Prospective
counselling.
 COMMON REASONS TO SEEK PROSPECTIVE
COUNSELLING:
1. A woman who is (or will be) 35 years or older at delivery
(singleton pregnancy), or 33 years or older at delivery (twin
gestation).
2. A man who is (or will be) 40 years or older at delivery of his
child.
3. Both partners are blood relatives, or from the same
community, to discuss carrier screening.
4. A positive carrier screening test for a genetic condition such
as thalassemia, sickle cell anemia, cystic fibrosis, Tay-Sachs,
etc.
 PRENATAL COUNSELLING
Available for couples who are
pregnant.
For a woman with an abnormal
marker test, abnormal scan.
Previous child affected with a
genetic condition.
Both partners being carrier for the
same condition.
One partner being affected with a
condition.
Either member of the couple with
personal or family history of a
known genetic condition.
SPECIFIC PROTECTION
Individuals as well as community protection
against mutagens, such as X-rays or other
ionising radiations.

Ensure protection of gonads to

radiation in patients undergoing X-ray.

Prevention of Rh hemolytic disease of

newborn by immunisation with anti-D
globulin.
 SECONDARY PREVENTION
CARRIER DETECTION FOR AUTOSOMAL
RECESSIVE CONDITIONS:
Purpose- Help ‘at risk’ couples plan their reproduction-
reduce chances of birth of an affected child.

1. If detection premarital - client advised not to

marry the carrier.
2. Abstinence from reproduction.
3. Testing the genetic risk- Prenatal diagnosis
4. Continue/ interrupt as per MTP act.
 PRENATAL SCREENING
NON INVASIVE PRENATAL TESTING (NIPT)/NIPS
NONINVASIVE GESTATIONAL AGE FOR CONDITIONS SCREENED
SCREENING TEST SCREENING

Cell free DNA After 9-10 weeks Trisomy 21,18,13

1st trimester screen-Nuchal 10-13 Weeks Trisomy 21

translucency, Papp-A, hCG
Triple screen- 15-22 Weeks Trisomy 21
AFP,hCG,uE3
Quadruple screen- Trisomy 21
15-22 Weeks
AFP,hCG,uE3,,DIA
INVASIVE SCREENING

INDICATIONS-
Advanced maternal age(>35 years old)
Positive maternal serum analyte screen
Previous child with chromosomal
abnormality
Structural fetal anomalies detected by
USG
Family history/exposure to
teratogens(e.g. valproic acid/NTDs)
 FETAL BLOOD SAMPLING
Second trimester- Blood factor
abnormalities(Hemophilia A); diagnose AR/X-linked
immunologic deficiencies(SCID)

FETAL TISSUE SAMPLING

At 17-20 Weeks- Severe hereditary skin
diseases(genodermatoses)
 REHABILITATION
Defects such as Congenital heart defects, cleft lip, cleft
palate, NTDs - SURGICAL TREATMENT only option.

Early referral of children with genetic disorders which

are known to cause physical or mental disablity.
ADVANCES IN MOLECULAR
GENETICS

GENE THERAPY

HUMAN GENOME
PROJECT
 HUMAN GENOME PROJECT

An international collaborative research project

undertaken between 1990 and 2003 to map, sequence
and freely publish the entire human genome.
The largest international collaboration ever
undertaken in biological science, bringing together
researchers from the US, UK, France, Germany,
Japan and China.
The project was launched in 1990 and took 13 years
to complete, costing an estimated $2.9 billion. It was
entirely publicly funded.
 How was it done?
A human genome was fragmented and cloned into bacterial
artificial chromosomes, which were used to create a contiguous
map of overlapping fragments.

The cloned fragments individually sequenced using Sanger

sequencing and entire sequence assembled according to the map.

The finished sequence produced by the Human Genome Project

covers about 99 percent of the human genome's gene-containing
regions, and it has been sequenced to an accuracy of 99.99
percent.
 72% of the rare diseases are genetic and
almost 1 out of 5 cancers is
rare.

Rare Disease Day - opportunity to

advocate for rare diseases as a
human rights priority at local, national and
international level.

Ministry of Health and family Welfare,

Government of India
formulated a National Policy for Treatment of Rare
Diseases
(NPTRD) in July, 2017.
 Conclusion
Genetic disorders-powerful impact- families of affected
individuals- continuous attention.

Once family member diagnosed, other blood relatives also ‘at

risk” even though currently asymptomatic.

Emotional challenges and reproductive implications are at stake.

Major concern amongst family members- Progeny might inherit

disease, leading to multiple tests and treatment options.
 Despite advancements in genetic research and medical
interventions, many genetic disorders still lack effective
treatments, posing ongoing issues for affected individuals.

Ongoing research, improved diagnostic techniques, and the

development of targeted therapies offer hope for better
management and possibly even prevention of these conditions in
the future.

Genetic disorders - multidisciplinary approach involving genetics

specialists, healthcare providers, policymakers, and community
support to improve outcomes and enhance the quality of life for
those affected by these conditions.
“Rare is not Rare…..
Rare is Many – Rare
is Strong – Rare is
Proud”