Introduction to Medical Genetics Fadel A. Sharif

Contact details  Medical Technology Department  Genetics lab 

 Textbook: Genetics in Medicine, 7 th edition. Nussbaum, McInnes & Willard. W.B. Saunders Co. (2007). Genetics in Medicine, 7 th edition. Nussbaum, McInnes & Willard. W.B. Saunders Co. (2007).  Reference Emery’s Elements of Medical Genetics, 13 th edition, Turnpenny & Ellard. Churchill Livingstone. (2007). Emery’s Elements of Medical Genetics, 13 th edition, Turnpenny & Ellard. Churchill Livingstone. (2007).

Grades  Midterm exam30%  Assignments, participation & quizzes10%  Final exam60%

Topics   1: Introduction   2: Patterns of Single-Gene Inheritance   3: Genetic Variation in Individuals   4: Genetic Variation in Populations   5: Gene Mapping   6: Principles of Clinical Cytogenetics   7: Clinical Cytogenetics: Disorders of the Autosomes and the Sex Chromosomes   8: Treatment of Genetic Diseases   9: Genetics and Cancer   10: Prenatal Diagnosis

Glossary & Definitions   Genetics is concerned with variation and heredity in all living organisms   Human genetics is the science of variation and heredity in humans   Medical genetics deals with human genetic variation of significance in medical practice and research   Cytogenetics: the study of chromosomes

Glossary & Definitions   Genomics: the study of genome, its organization and functions   Population genetics: genetic variation in human populations and factors that affect allele frequencies   Clinical genetics: application of genetics to diagnosis and patient care   Genetic counseling: risk information, psychological and educational support to patients and/or their families

Glossary & Definitions  Genotype - the genetic constitution of the organism  Phenotype - the observable expression of genotype

Glossary & Definitions  Locus - a chromosomal location  Alleles - alternative forms of the same locus  Mutation - a change in the genetic material, usually rare and pathological  Polymorphism - a change in the genetic material, usually common and not necessarily pathological

Glossary and Definitions  Homozygote - an organism with two identical alleles  Heterozygote - an organism with two different alleles  Hemizygote -having only one copy of a gene  Hemizygote - having only one copy of a gene Males are hemizygous for most genes on the sex chromosomes Males are hemizygous for most genes on the sex chromosomes

 Dominant trait - a trait that shows in a heterozygote  Recessive trait - a trait that is hidden in a heterozygote Glossary and Definitions

Family history is important  It can be critical in diagnosis  Can provide info about natural history of the disease & variation in its expression  Can clarify pattern of inheritance  Note: Diagnosis of a hereditary condition allows risk estimation in other family members so that proper management, prevention, & counseling can be offered to patient & family

Role of Genes in Human Disease   Most diseases / phenotypes result from the interaction between genes and the environment   Some phenotypes are primarily genetically determined Achondroplasia   Other phenotypes require genetic and environmental factors Mental retardation in persons with PKU   Some phenotypes result primarily from the environment or chance Lead poisoning

Major types of genetic disease  Chromosomal disorders  Single gene disorders  Polygenic diseases

Chromosomal disorders  Addition or deletion of entire chromosomes or parts of chromosomes. Rearrangement of chromosomal segments  Typically more than 1 gene involved  Classic example is trisomy 21 - Down syndrome

Down Syndrome

Single gene disorders  Single mutant gene has a large effect on the patient  Transmitted in a Mendelian fashion  Autosomal dominant, autosomal recessive, X-linked, Y-linked  Osteogenesis imperfecta - autosomal dominant  Sickle cell anemia - autosomal recessive  Haemophilia - X-linked

Autosomal dominant pedigree

Polygenic diseases  The most common yet still the least understood of human genetic diseases  Result from an interaction of multiple genes, each with a minor effect  The susceptibility alleles are common  Type I and type II diabetes, autism, multiple sclerosis

Polygenic disease pedigree

Identifying disease genes has been revolutionized by the sequencing of the Human Genome

The sequence  3.3 billion base pairs  Gene prediction ~ 25,000  This is likely to be an underestimation due to the occurrence of regulatory RNAs

Accessing the sequence  Public databases  Freely available  Continuously modified and updated

Searching for FRZB

FRZB is located on chromosome 2

FRZB transcript sequence

Two common amino acid substitutions in FRZB