Genetic Diseases

Genetic Diseases
Presentation by:Amrik Sahota
Dept Path & Lab Med
UMDNJ - RWJMS

What’s the Nature of This Talk?

* Review
* Preview
* Overview

Major Topics
* Mutations
* Single gene disorders
* Chromosomal disorders
* Multifactorial disorders
* Molecular diagnostics
* Pediatric disorders (not discussed)

DNA RFLPs
HLA antigens
Serum proteins
Blood groups
Structural changes
Chromosomes
Marker
Polymorphic Markers
Microsatellite markers
Single Nucleotide Polymorphisms
Causes of Mutation
* Spontaneous mutations
o Arise naturally during DNA replication
* Induced mutations
o Ionizing radiation (X-rays)
o Non-ionizing radiation (UV)
o Chemical mutagens

Types of Mutation
* Single gene mutations
o Minor structural alterations (single base changes, deletions, insertions, etc)
* Chromosomal mutations
o Major structural alterations (deletions, insertions, inversions, translocations, etc)
o Loss or gain of whole chromosomes (monosomies, trisomies, etc)

Single Gene Mutations
* Structural gene mutations
* Regulatory region mutations
* Dynamic mutations

Point Mutation (Sickle Cell)
Single Base Deletion (ABO)
Three-base Deletion (Cystic Fibrosis)
Premature Chain Termination (Beta Thalassemia)
Four-base Insertion in Hexosaminidase A Gene (Tay-Sachs)
Summary of Single Gene Mutations
Type Effect Example
Deletion Null Cystic fibrosis
Insertion Null Tay-Sachs
Inversion Null Hemophilia A
Missense Null Sickle cell
Nonsense Null Beta-globin
Frameshift Null Cystic fibrosis
Splicing Null Beta-globin
Regulatory Low exp. Beta-globin

Molecular Consequences of Single Gene Mutations
* Loss of function
* Haploinsufficiency
* Dominant negative mutation
* Gain of function

Loss of Function Mutations
Adenine Phosphoribosyltransferase (APRT) Deficiency
Adenine
DHA
Crystals in kidney
Stones in kidney
Renal injury
XDH
Precipitation/crystallization
Aggregation
Blockage of tubules
Tubular loss
Renal failure
AMP
APRT
T Insertion
Recognition Sequence by Tru9I
TCT Deletion
Recognition Sequence by Mbo II
E5-wild:
E5-mutant:
APRT Mutations
Haploinsufficiency
FH and LDL receptor
LDL Receptor Mutations
Dominant-negative Mutations
Dominant-negative Mutations: Collagen Genes
Gain of Function Mutation
Gain of Function Mutation: Oncogenes
Chromosomal Mutations
* Deletion: Loss of a piece of a chromosome
* Translocation: Breakage of two chromosomes and fusion of broken parts
* Isochromosome: Loss of one arm and duplication of the other
* Aneuploidy: Gain or loss of one or more intact chromosomes
* Mosaicism: More than one chromosomal complement in a given individual
Normal Male Karyotype
Types of Genetic Disorders

* Single gene disorders
* Chromosomal disorders
* Multifactorial disorders

Single Gene Disorders
* Thalassemia 1/50
* HNPCC 1/200 to 1/1000
* Sickle cell 1/400 to 1/600
* Cystic fibrosis 1/2,000 to 1/4,000
* Marfan syndrome 1/10,000 to 1/20,000

Inheritance Patterns For Single Gene Disorders

* Classic
* Non-classic
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
X-linked Inheritance
Mitochondrial Disorders
Mitochondrial Inheritance
Mitochondrial Inheritance (Leber Optic Neuropathy)
Other Disorders
Fragile X Syndrome
Fragile X Chromosome
Fragile X Pedigree
Nucleotide Repeat Mutations
Pathology of Single Gene Disorders
Sickle Cell Mutation
Normal and Sickle Cell Hemoglobin
Sickle cell
ORGAN/TISSUE INVOLVED
PROBLEMS CAUSED
KIDNEY
Hematuria
Urinary frequency
SPLEEN
Serious infections
Abdominal pain
LUNGS
Pneumonia
Chest problems
BONES
Infection Necrosis
BRAIN
Stroke
Headache
LIVER
Hepatomegaly
Jaundice
Complications of Sickle Cell Disease
NCBI
Chromosomal Disorders
Normal Male Karyotype
X Chromosome Idiogram
Finding Our Way Around
Sub-sub-band (q11.11)
Common Multifactorial Disorders
Frequency of Multifactorial Disorders
Multifactorial Versus Single Gene Disorders
Comparison of Single Gene and Multifactorial Diseases
Multifactorial Versus Polygenic Diseases
Interactions Between Genes and Environment
Molecular Diagnostics
Direct Gene Diagnosis (Factor V)
Allele Specific Oligo Probes
Fragile X Analysis
Summary

* Mutations
* Single gene disorders
* Chromosomal disorders
* Multifactorial disorders
* Molecular diagnostics

Genetic Disorders: Here and Now
Era of Genetic Medicine

Genetic Diseases.ppt