genetics 1-csbrp

Genetic Disorders

Dr.CSBR.Prasad, M.D.

Incidence of genetic disorders

We all carry genes that are potentially hazardous:

1. Some manifest even before our birth

2. Some are recessive3. Some will be triggered by

environmentA working party of the Royal College of Physicians has estimated that 2-3% of births result in babies with either congenital or genetically-determined abnormalities.

Incidence of genetic disorders

~5% of individuals will develop some form of genetic disorder by the age of 25 years

The lifetime risk of genetic diseases is estimated to be 670 per 1000

Some facts <2% of the human genome codes

for proteins >½ represents blocks of repetitive

nucleotide codes whose functions remain mysterious

Humans have a 30,000 genes Any two individuals share 99.9% of

their DNA sequences Humans differ from chimps by 1%

genetic uniqueness

Some terms

GenomicsProteomicsHereditary,

Congenital, Familial

MutationTranslation /

Transcription

HeterozygousHemizygousHomozygusAutosome RecessiveDominant

Genetic Disorder

Advances in Molecular biology involving recombinant DNA technology

Molecular basis of human diseases Functional Cloning - Classical Positional Cloning

Production of human biologically active agents Eg. Growth hormone, Erythropoietin.

Gene therapy Disease diagnosis

Karyotype

Study of chromosomes A karyotype is used to display the

number, types and appearance of chromosomes

Human somatic cell – 46 chromosomes 22 pairs of autosomes 2 sex chromosomes Diploid numbers – 2N

Karyotype

Male – 46, XY Female – 46, XX Human Germ cells – Haploid

cells –N 23 chromosomes Sperms – 23 X or 23 Y Ovum – 23 X

Karyotype - preparation & analysis

1. Cells (from blood, amniotic fluid, etc) are grown in vitro to increase their number

2. Cell division is then arrested in metaphase with colchicine

3. Cells are centrifuged and lysed to release chromosomes

4. Chromosomes are stained, photographed, and grouped by size and banding patterns

Normal karyotype

KaryotypeChromatid - An arm

of a chromosomeCentromere is the

place where two chromatid meet each other

TelomereTelomere – is the distal end of chromosome

Karyotype

Based on the location of centromere chromosome grouped into 4 types – Metacentric – Central centromere Submetacentric - Short arm (p) , Long arm

(q) Acrocentric – Eccentric centromere Telocentric

Karyotype

Each arm is divided into 2 or more regions

Each region is divided into bands and sub bands

They are numbered from centromere outwards ex. Xp 21.2

Karyotype Banding techniques for karyotype study

G Banding – Giemsa stain (400 – 800 bands) Q Banding – Quinacrine florescent stain R Banding – Reverse Giemsa stain C Banding

Based on the length of chromosomes they are divided into 7 groups – A to G (Denver classification)

Normal karyotype

Numerical abnormality

Diploid – 46 (2N)

Haploid – 23 (N)

Numerical abnormality

Polypoidy – No. of chromosomes which is EXACT multiple of haploid numbers

• Triploid – 3N (69 ch)• Tetraploid – 4N (92 ch)

Aneuploidy – No of chromosomes which is not an exact multiple of haploid numbers

Monosomy – 45 Ch - 45 XO (Turner’s) Trisomy – 47 Ch - 47 XY + 21 (Down’s)

Name a normal cell with polyploidy?

Megakaryocyte

Mechanism of Aneuploidy Non disjunction – Failure of

chromosome to separate normally during cell division result in monosomy or trisomy

Anaphase lag - One chromosome fail to reach the pole of dividing cell at the same time and is left out of nucleus of daughter cell

Mosaicism – Individual has 2 or more types of cell lines derived from same zygote

ex. cancers

Structural abnormalities

Structural abnormalitiesStructural abnormalities

Deletion

Inversion

Duplication

Translocation

Ring chromosome

Isochromosome

Structural abnormalities

Translocation – Transfer of a segment of one chromosome to another non-homologous chromosome

1. Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11)

2. Robertsonian translocation

Structural abnormalities - Translocation Balanced translocation

Structural abnormalities

2. Robertsonian translocation – When two acrocentric chromosome lose their short arm and fuse at the centromere so that eventually the cell is left with 45 chromosomes.

Robertsonian Translocation

Structural abnormalitiesTranslocation: Ex: Acute Myelogenous

Leukemia Philadelphia chromosome t(9,22)

Structural abnormalities

Deletion Loss of part of the DNA from a

chromosome. Deletion may be from terminal portion/ Middle portion

Deletion – Terminal deletion of short arm

Deletion – Terminal deletion of long arm

Deletion –Deletion of long arm

Can you give one best example for deletion resulting in disease?

Alfa-Thalassemia

Structural abnormalities

Ring chromosome: When both ends of a chromosomes are lost and the damaged ends join together, they form Ring chromosomes

Deletion – Ring

chromosome

Diseases in which ring chromosomes are seen

include:

Some tumors of adipose tissueFanconi’s anemia

Structural abnormalitiesDuplications: Ex: Fragile X syndrome The most common form of mental

retardationThe X chromosome have over 700

repeats due to duplications (Normal upto 29)

Affects 1:1500 males, 1:2500 females

Structural abnormalitiesDuplications: Ex: Fragile X syndrome

Structural abnormalities

Isochromosome formation result when the centromere divides in a tranverse plane rather than in a normal long axis of the chromosomeEx. One with 2 short arms & one with 2 long arms

Isochromosome

Structural abnormalities

Inversion: Rearrangement that involves two breaks within a single chromosome with reincorporation of inverted segment Paracentric Pericentric

Inversion – (long arm)

Paracentric Pericentric

Mutation

Permanent change in the DNA Mutation in germ cell –

Inherited diseases Mutation in somatic cells –

Cancer, congenital malformation

Mutation

Genomic Mutation – Monosomy/ trisomy

Chromosomal Mutation – rearrangement of genetic material with visible structural changes in chr.

Gene Mutation – Submicroscopic1. Point mutation2. Frame shift mutation

Mutation

Point mutation – single nucleotide base is substituted by different base.

e.g. sickle cell disease – glutamic acid replaced by valine at 6th position from the aminoterminal of beta globin chain of Hemoglobin

Mutation

Frame shift mutation One or two base pairs may be

inserted/ deleted from the DNA, leading to alterations in the reading frame of the DNA strand

Frameshift Mutation

(1-2 bp(s) deletion) (1-2 bp(s) insertion)

Insertion

Duplication

Down’s Syndrome

Down’s Syndrome

Trisomy 21, 47 XY + 21 Most common chromosomal

disorder 1 in 700 live births Due to non disjunction Or

Robertsonian translocation Parents – Normal karyotype Risk factor Mother over 35 years

The fertilization of a genetically abnormal egg carrying an extra chromosome 21 (orange) by a normal sperm (green) produces an embryo

with Down syndrome (purple).

Trisomy 21 -- Down’s syndome

Click to see animation on Non-Disjunction

Down’s Syndrome

Clinical Features Major cause of mental retardation IQ 25-

50 Very gentle, shy & friendly Diagnosed at birth by “mongol” look –

Flat facial profile, oblique palpebral fissure, epicanthic folds

40 % of patients – CHD ASD, Ostium primum, A-V valve

malformation, VSD

Down’s syndromeDown’s syndrome

Normal Mongols Down’s baby

With Mongoloid look

Down’s syndrome

Down’s syndromeDown’s syndrome

Normal hand Simian crease

Down’s syndromeDown’s syndrome

Simian creaseSimian crease

Down’s syndromeDown’s syndrome

Simian crease

Down’s syndrome

Down’s syndrome

Umbilical hernia

Down’s syndromeDown’s syndrome

Down’s Syndrome

Acute Leukemia – 10 to 20 fold ^ risk Alzheimer’s disease < 40 years of age Abnormal immune response – Infection Simian crease, Hypotonia, Umbilical

hernia

Down’s Syndrome

Acute Leukemia – 10 to 20 fold increased risk

Transient Myeloproliferative Transient Myeloproliferative SyndromeSyndrome

END

KlinefelterKlinefelter’s ’s

SyndromeSyndromeChromosomes

In sperms:

X (green)

Y (red) &

18 (aqua)

END

Marfan’s syndrome

Normal

: Tricuspid valve : Pulmonary valve : Aortic valve : Mitral valve

Marfan’s

Marfan’s syndrome

Aortic aneurysm and Aortic dissection

Chromosomes 23

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y

first meiotic division: prophase: leptotene

normal trisomy 21

chromosome 21

other chromosomes

© 2003 H. NUMABE M.D.

second meiotic division: second polar bodies

normal trisomy 21

chromosome 21

other chromosomes

© 2003 H. NUMABE M.D.

Marfan’s syndrome

Autosomal dominant fibrillin-1(FBN1) gene mutation