DEVELOPMENTAL AND

GENETIC DISORDERS
Dr Siddaganga S Mangshetty
Assistant professor
Objectives of this class
By the end of this class you people should know
What are genetically normal human being

How it differs from genetically abnormal

What are chromosomal aberrations

What are Mendelian disorders with their clinical imp.

Multifactorial inheritance
Contents
1. Introduction to genetics
2. Basic concepts of genetic disorders
3. Developmental defects with examples
4. Classifications of developmental defects
5. Genetic disorders
6. Chromosomal aberrations with clinical implications
7. Chromosomal aberrations involving autosomes
8. Chromosomal aberrations involving sex chromosomes
9. Key points/ Concepts.
Genetics
Introduction
Definition : is the sciences deals with the study of
‘genes’.
“The word genetic was coined by William Batson(1902)
Gregor Mendel in the 19th century observed –
transmission of certain characteristic features from
PARENTS OFFSPRINGS
HEREDITY
Common questions
 What is the basic unit of heredity ?
GENE
Where genes are located?
CHROMOSOME
 What is chromosome?
COLOUR BODIES CARRY HEREDITARY
MATERIAL
Tajio and Levan described normal human somatic cells
contains 46 chromosomes
Are arranged in 2 sets of 23 each
Autosomal chromosomes identified from 1-22
Identical shape and size chromosome-homologous pair
Sex chromosome
Identified as X and Y
FEMALES------XX
MALES---------XY
Human germ cells---- haploid(N)---- 23 chromosomes
Somatic cells---- diploid(2N)---- 46chromosomes
“Lyon hypothesis”
In females one of the 2X chromosomes (paternal or
maternal derived) is inactivated during embryogenesis.
Germ cells have 2 active X chromosomes but in somatic
cells inactive X chr is transferred to all somatic cells
and lies as condensed in the nucleus sex chromatin.
30% cells positive for barr bodies indicative of
genetically female.
Barr body/ Sex chromatin
Cont……
For karyotyping circulating lymphocytes are used

Photographic representation of stained preparation of

chromosome.
1.Metacentric chromosome
2. Sub metacentric
3.Acrocentric
4.Telocentric
Developmental and Genetic disorders have been
categorized
 Developmental defects
 Cytogenetic defects
 Single gene defects( Mendelian disorders)
 Multifactorial inheritance disorders(Polygenic)
 Storage disorders
Deals with the group of disorder affecting the fetus
during intrauterine life.
50% mortality in infancy and childhood – in western
countries
Developing countries- infections and PEM(90%)
GENETIC
DISORDERS
 Genetic Disorders
1. Chromosomal 2. Single gene 3.Complex
disorders mutation with multigenetic
large effect disorders

A. structural *Single gene oVery rare

B. numerical mutation with oInteraction
autosomes high penetrance. between various
sex chromosomes *They may cause factors (Genetics
diseases or expose and
to diseases. environmental)
*They follow oPolymorphism
classis Mendelian oMultigenic or
pattern of poly genic
inheritance.
 Chromosomal aberrations
*Cytogenetic is the study of chromosomes and their
abnormalities*.
Chromosomal abnormalities

I Numerical II Structural
• Not affect basic functions
Of cells and thus be silent. -DO-
• Interfere with one or more
Cellular key functions.
• Increased mitotic activity
But doesn’t cause cell death.
• MC in mitosis
both in mitosis
and meiosis
Structural Chromosomal aberrations
Translocations: it means crossing over or exchange of
fragments of chromosome.(homologous or non homologous)
Reciprocal: exchange of Robertsonian: involvement of
genetic material between centromere of acrocentric
non homologous without chromosome.
involving centromere Includes 2 homologous are
broken near centromere.
Exchange of 2 arms to form
one long and one small chr
fragment.
*phenotypically normal but
suffers from infertility and
produces malformed
children*.
Deletions
Loss of genetic material
from chromosome is
called deletion.
1.interstitial
2.Terminal
a)cri du chat[chr 5]
b)Retinoblastoma[chr13]
c)wilms tumor[chr 11]
Inversion
Form of rearrangement
involving breaks of single
chromosome at two points.
Para centric- on one side
of centromere
Peri centric- on either side
of centromere
Ring chromosome
*Formed by a break at
both the telomeric ends of
chromosome followed by
deletion of the broken
fragments and end to end
fusion.
Ring chr 20--- Epilepsy
Ring chr 13&14---
intellactual disability
Turner syndrome.
Isochromosome
When centromere rather
than dividing parallel to
the long axis divides
transverse to the long axis
of chromosome.
Numerical chromosomal aberrations
 Either increased or decreased in total number of chromosome.
 Exact multiple of haploid is known as euploidy
 Cells acquires chromosome compliment which is not an exact
multiple of haploid known as aneuploidy
Non disjunction anaphase lag
 During gamatogenesis one homologous chr in meiosis
 Either extra(2n+1) one chromatid in mitosis
 Either less(2n-1) ) either normal cell or monosomy
 Multiple of haploid known as polyploidy
 Triploidy(69), tetraploidy(92) incompatible with life results in
spontaneous abortions
 Cytogenetic Disorders Involving
Autosomes
Trisomy 21 or Downs syndrome.

Chromosome 22q11.2 deletion syndrome

Patau syndrome (Chromosome 13)

Edward syndrome (Chromosome 18)

 Down syndrome
Most common chromosomal disorder.
No 1 cause of mental retardation.
Epidemiology
In US incidence in new born is 1:700
(95%) affected individuals have trisomy 21.
Genetics
Presence of an extra chromosome at 21
4% cases also shows Robertsonian translocation.
1% of individual will show mosaic pattern.
*mosaicism – in an individual different cells have different
chromosomal compliments*
Cont ……
Etiology
Maternal age has significant influence on incidence of
trisomy.
1:1550 live births in woman under age of 20years
1:25 live birth for mother older than age 45.
Clinical features
Complications:-
Mental retardation(IQ)- Neuropathologic
25 to50 changes- Alzheimers
Congenital heart disease
GIT- umblical hernia,
diseases- ASD, VSD, AV
malformation megacolon
Hematological
disorders- acute
leukemia(Lymphoid or
myeloid)
Investigations
Its one chromosomal disorder can be diagnosed prenatally.
Ultrasonography at second trimester
a) Congenital anomalies
b) Congenital heart diseases
c) Nuchal thickness(≥3mm)
 Triple marker( in mother)
 βHCG
 Estradiol
 Αfetoprotein.
Chromosome 22q11.2 deletion syndrome
Fairly uncommon
1:4000 births
Depending on clinical features this syndrome
represents 2 different entities.
I) Di George syndrome II) Velo cardiofcial

syndrome
Clinical features
CHD
Abnormalities of the palate
Facial abnormalities
Developmental delay
Variable degree of T cell immunodeficiency
Hypocalcaemia
Investigations
These cases can be diagnosed on clinical features but
can be established by FISH.
Cytogenetic Disorders Involving Sex
Chromosomes
these disorders are more common than autosomal related.
2 factors that are play an imp role in these disorders
1) Lyonization hypothesis
2) The modest amount of genetic materials are carried by Y
chromosome
In general sex chromosome disorders cause chronic
problems leading to sexual development and infertility
Difficult to diagnose at birth
The greater the number of X chromosome in both males and
females the greater the likelihood of MR
Klinefilter syndrome (Male
hypogonadism)
Introduction
One of the most frequent forms of genetic disease
involving sex chromosome.
Most common cause of hypogonadism and infertility in
males.
Incidence 1:660 live births.
Etiology: maternal age and exposure to radiation during
pregnancy.
Cont……………..
Genetics
Classical pattern of klinefilter syndrome 47XXY
Extra X chromosome may be either from maternal and
paternal.
 non disjunction of sex chromosomes
15% of patients show mosaic pattern
46XY/47XXY 47,XXY/48XXXY
Clinical features
Investigations
Decreased testosterone level

Increased urinary gonadotropin level.

Barr body examination.

 Turners syndrome
Introduction
Primary hypogonadism in phenotypic females
Most common chromosomal abnormality in females.
1:2500 live born females.
Genetics
57% of patients resulting in 45X
Monosomy ( absence or loss of one chromosome)
43% patients with Turner syndrome have either
mosaics or structural abnormalities.
Clinical features
Most severely affected patients present during
infancy with oedema of the dorsum of the hand and
foot
Swelling of the nape of the neck– cystic hygroma
Neck webbing
CHD in 25% to 50% Featous.
At puberty failure to develop secondary sexual
characteristic
Genitalia remain infantile
Inadequate breast development
Little pubic hair
Single most important cause of amenorrhea
Short stature (not more than 150cm)
Ovary reduced to atrophic fibrous strands( Streak
ovaries)
They attain menopause before menarche
investigations
USG during antenatal
Nape of neck webbing
Cystic hygroma
CHD
Objectives of this class
By the end of this class you people should know
What are single gene disorders and its clinical
implications
Autosomal dominant, recessive and X linked disorders
with clinically important examples
Complex multigenetic disorders
What is the role of you people in diagnosis, counseling
and interviewing patients with genetic disorders.
Contents
Classifications of genetic disorders
General features of Mendelian disorders
Pattern of inheritance
Gene mutation and different entities
Autosomal dominant
Marfan syndrome
Autosomal recessive
Gaucher disease
X linked disorders
Multigenetic disorders
Key concept/points
 Genetic Disorders
1. Chromosomal 2. Single gene 3.Complex
disorders mutation with multigenetic
large effect disorders

A. structural *Single gene oVery rare

B. numerical mutation with oInteraction
autosomes high penetrance. between various
sex chromosomes *They may cause factors (Genetics
diseases or expose and
to diseases. environmental)
*They follow oPolymorphism
classic Mendelian oMultigenic or
pattern of poly genic
inheritance.
Single gene mutation
disorders(Mendelian Disorders)
Mendelian disorders are result of single gene mutation
with large effect.

Single gene mutation with high penetrance.

They may cause diseases or expose to diseases.

They follow classic Mendelian pattern of inheritance.

Every individual carries 5-8 mutated genes

Greoger Mendel suggested that “genes (Factor) occur
in pairs”
A Dominant (AA)
a Recessive (aa)
Co dominance (Aa, aA)
Some autosomal mutations produce partial expression
in the heterozygote and full expression in
homozygous.
ex: Sickle cell anaemia (Pleotropism)
One gene from each parent however the inheritance
may not be equal

One gene may overpower the other in their coded

characteristic

The gene that overshadows the other is called

dominant genes
GENE MUTATION
DELETION OF A SINGLE BASE
SUBSTITUTION OF A SINGLE BASE
POINT MUTATION within a coding sequence:
VAL-GLU
MUTATIONS in NON-coding sequences defective
transcription, regulation
DELETIONS/INSERTIONS frame shift mutation,
involvement is NOT a multiple of 3
Tri-nucleotide REPEATS, e.g., CGG repeats many
times in fragile X syndrome
POINT MUTATION
INTERFERE with protein synthesis

SUPPRESS transcription, DNARNA

PRODUCE abnormal mRNA

DEFECTS carried over into TRANSLATION

ABNORMAL proteins WITHOUT impairing syntheses

Pattern of inheritance
Definition – Mode of inheritance is defined as the
manner in which a particular gene trait or disorder is
transmitted from one generation to the next
generation.
Mutations involving single gene typically follow
one of three patterns.
Autosomal dominant
Autosomal recessive
X linked disorders
AUTOSOMAL DOMINANT DISORDERS
GENERAL CHARACTERSTIC FEATURES.
1. Location : mutated genes located on autosomes
2. Required number of defective genes: only one copy
3. Sex affected: both M and F equally affected
4. Pattern of inheritance: every affected individual has
an affected parents
5. Additional properties
a) Penetrance (variable)
b) Variable expressivity
AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

 Autosomal Dominant Disorders
System Disorders
Nervous 1)Huntington
2)Neurofibromatosis
3)Tuberous sclerosis
Urinary 1)Polycystic kidney disease
Gastrointestinal 1)Familial polyposis coli
Hematopoietic 1)Heriditary spherocytosis
2)Von willebrand disease
Skeletal 1)Marfan syndrome
2)Ehlers Danlos syndrome
3)Achondroplasia
Metabolic 1)Familial hypercholesterolemia
 STRUCTURAL PROTEIN DEFECTS

Marfan Syndrome
 AD CT disorder
Incidence in US is 1:10,000
Fibrillin-1 defect (not -2 or -3)
Skeleton, eyes, skin and cardiovascular system
Tall stature long fingers, B/L dislocated lens, aortic arch
aneurysms, MVP
Biochemical abnormality
Defect in gene FBN1 on chromosome 15
Defect in gene FBN2 on chromosome 5 which
encodes fibrillin (microfibrills) connective
tissue.
Approximately 70-85% of cases are familial and rest
are sporadic.
Autosomal Recessive Pattern of
Inheritance
Diseases is in HOMOZYGOUS

More uniform expression

Often complete penetrance

Include all inborn errors of metabolism

More common than AD disorders.

General characteristic features
Location of gene: autosomes
Required no of defective genes: 2 copies
Heterozygous state ----carrier (when individual has
one mutated gene and one normal gene)
Pattern of inheritance: Parents must have one copy
of mutant gene
Consanguineous marriage: common predisposing
factor.
If both parents are heterozygous (Aa), each of their 
children has a 25% chance of
expressing the trait of recessive allele. 
If both parents are homozygous recessive (aa), all of
 the children will express the trait. 
If one parent is homozygous recessive and the other i
s homozygous dominant (AA), none of the children wi
ll express the trait, but all will be carriers (Aa). 
Autosomal Recessive Disorders
Diseases Frequency Chromosome
Cystic fibrosis 1 in 2.500 7q
Α thalassemia High 16p
Β thalassemia High 11p
Sickle cell anaemia High 11p
Gauchers disease 1 in 1000 1q
Phenylketonuria 1 in 10,000 12q
Wilsons disease 1in 50,000 13q
Oculocutaneous 1 in 20.000 11q
albinism
Alkaptonuria 1 in 100.000 3q
Hemochromatosis 1 in 1000 6p
 Lysosomal Storage Diseases
GLYCOGEN STORAGE DISEASES
SPHINGOLIPIDOSES (Gangliosides)
SULFATIDOSES
MUCOPOLYSACCHARIDOSES
MUCOLIPIDOSES
OTHER
Fucosidosis, Mannosidosis, Aspartylglycosaminuria
WOLMAN, Acid phosphate deficiency
 Gaucher Disease
 Autosomal recessive disorder
Most common Lysosomal storage disorder
GLUCOCEREBROSIDE BUILDUP( affected gene
encodes glucocerebrosidase)
ALL MACROPHAGES, liver spleen, nodes, marrow
99% are type
Type I NO CNS involvement
Type II predominantly CNS involvement
Type III has both features.
GAUCHERS CELL
Clinical Features
Depends on the clinical sub types

In type I symptoms and signs first appear in adult life

with marked spleenomegaly, bone involvement
pancytopenia and thrombocytopenia.

In type II and III progressive CNS involvement with

dysfunction, convulsions, and progressive mental
retardation.
Sex Linked Pattern Of Inheritance
Almost all sex linked disorders are X linked.
Males mutation affecting Y chromosome are infertile.
 expression of an X linked disorders are different in both
females and males
Females: the clinical expression of the x linked disease in
female is variable depending on whether its dominant or
recessive.
Males : they inherit only one X chr from mother so gene
mutation affecting X chr is fully expressed even with one
copy.
X linked recessive trait
Location of gene: on X chromosome

Required no of defective gene: one copy of mutant

gene in male and two copies of mutant gene in
females

Sex affected: males are more frequently

Pattern of inheritance: females will be carrier.

SEX LINKED PEDIGREE

1) MALES ONLY
2) GENERATION SKIPPING DOESN’T MATTER
X linked recessive diseases
Diseases Frequency in males

Fragile X syndrome 1 in 2,000

Haemophilia A 1 in 10,000

Haemophilia B 1 in 70.000

Glucose 6 phosphate dehydrogenase Up to 30% deficiency

Chronic granulomatous disease Not rare

X linked aggaglobulinemia Not rare

Fabry disease 1 in 40.000

X linked dominant disorders
Very rare disorders.
Location of mutant gene: located on x chromosome
Required no of mutant genes: one copy of mutant
gene
Often lethal in males and may be transmitted in
females line
 affected Males have affected mothers
There is no carrier state
These are more frequent in females.
MULTIFACTORIAL INHERITANCE
Multi-”FACTORIAL”, not just multi-GENIC
Common phenotypic expressions governed by
“multifactorial” inheritance
Hair color
Eye color
Skin color
Height
Intelligence
Diabetes, type II
MULTIFACTORIAL DISORDERS
• Cleft lip, palate
• Congenital heart disease
• Coronary heart disease
• Hypertension
• Gout
• Diabetes
• Pyloric stenosis
• MANY, MANY, MANY, MANY MORE
Role Of You People
Genetic counselling and interviewing
1)Interviewing patients or individual with suspected
genetic disorders
2)Taking detailed clinical history along with detail
family history, drawing and interpreting a pedigree
chart and recognise the possibility of genetic disorder
3)Follow up of positive newborn screening tests
4)Monitoring individual with genetic disorders
Educating the parents with genetic diseases
KEY POINTS/CONCEPTS
 50% total mortality in infancy and childhood---
developmental defects and genetic defects
 Genetic diseases have been categorised into
1) D 2) C 3) S 4) M And 5) S
 Developmental defects are error in morphogenesis
which occur from use of teratogens
 Abnormality in chromosomes may be structural or
numerical
 Most common cause of MR Down syndrome
 Deletion of genes at chromosomal locus 22q11.2– 1) Di
George syndrome 2) velocardifacial syndrome
Cont……….
Lyon hypothesis
In Klinefilter syndrome there are 2 or more X
chromosome with one Y chromosome as a result of
non disjunction of sex chromosome
In turner syndrome there is partial or complete
monosomy of genes on short arm of X
chromosome.
Key points/concepts
Autosomal dominant disorders: expression in
heterozygote state with both sex affected equally
Receptors and structural proteins are affected in AD
Autosomal recessive disorders: 2 mutant copies of gene
required
Enzymes proteins are affected frequently
X linked disorders transmitted by heterozygous females
to their son.
Female carriers are protected because of random
inactivation of X chromosome.
Marfan syndrome is caused by mutation in the FBN1
gene encoding fibrillin.
The major tissue affected are skeleton, eyes and CVS
Familial hypercholesterolemia caused by mutation in
the gene encoding LDL receptor.
Lysosomal storage disorders
Tay sachs disease
Niemann pick disease
Gaucher disease
Mucopolysacchariodosis
complex multigenic disorders are caused by
interactions between variant forms of genes and
environmental factors.