Human Genetics Lec 2

LEC.2
Dr. Liqaa M. Al sharifi
Classifications of genetic disorders:
Human diseases in general can roughly be classified in to:
1- Those that are genetically determined.
2- Those that are almost entirely environmentally determined.
3- Diseases with multifactorial (polygenic inheritance) implies that both genetic and environmental
role in the expression of diseases such as hypertension and diabetes mellitus.
Classification of Genetic disorders:
1. Classical Genetic Diseases:
A- Single gene (or unifactorial) disorders (Mandelian disorders).
B- Chromosomal (cytogenetic) disorders.
C- Multifactorial disorders.
2. Non- Classical diseases (or the single gene disorders with atypical pattern of inheritance)
A. Diseases caused by mutation in mitochondrial genes.
B. Triplet repeat mutations.
C. Genomic imprinting.
D. Gonadal mosaism.
Disorders caused by single gene defects (mednelian disorders)or (unifactorial)
These are divided in (Autosomal Recessive (AR), Autosomal Dominant (AD), X-Linked Recessive
(XLR), X-Linked Dominant (XLD).
-Autosomal : The gene responsible for the phenotype is located on one of the 22 pairs of autosomes (nonsex
determining chromosomes).
-X-linked : the gene that encodes for the trait is located on the X chromosome.
-Dominant: conditions that are manifest in heterozygotes (individuals with just one copy of the mutant
allele).
-Recessive: conditions are only manifest in individuals who have two copies of the mutant allele (are
homozygous).
(a) Autosomal Recessive Disease: -It involves mutations in both copies of a gene.
It is characterized by: -
1) ? & ? affected equally, though some traits exhibit different expression in males and
females ( ovarian cancer and hypospades).
2) The affected individual should be homozygous for the affected gene.
3) If both parents are heterozygous the chance of having affected child is 25%.
4) If the affected person married from normal person, all the children will be
heterozygous.
5) If affected person married from a heterozygous person the children will be: -
• 50% affected.
• 50% heterozygous (carrier).
It is called Pseudodominant inheritance, which refers to the observation of apparent
dominant ( parent to child) transmission of a known AR disorder. It is most likely to
occur for relatively common traits, such as sickle cell anemia.
6) The affected cases are almost always born in only one generation (sister, brother or
cousins…), this is called horizontal inheritance.
7) Increased frequency of consanguinity, particularly for rare traits. The risk of a genetic
disorder for the offspring of a first-cousin marriage (6-8%) is about double the risk in
general population (3-4%)
examples of autosomal recessive disorder:
Haemopoitic : sickle cells anaemia and thalassemias.
Metabolic : cystic fibrosis , phenyle ketonuria ,galactosemia,homocystenuria,lysosomal storage disease,
Wilson disease, haemochromatosis, glycogen storage disease.
Endocrine : congenital adrenal hyperplasia.
Nervous: spinal muscular atrophy.
(b) Autosomal Dominant Disease: -It is characterized by: -
1) The transmission occurs from one parent to the child .
2) The responsible mutant gene can arise by spontaneous mutant gene.
3) The affected cases in multiple generation, which is called vertical or perpendicular
inheritance (grand parent-parent-child).
4) ? & ? affected equally.
5) The recurrence risk is 50%.
6) The finding of male-to-male transmission essentially confirms AD inheritance.
7) For many patients with AD disorder there is no history of an affected family member,
which could be explained by:
a- New mutation.
b- Incomplete penetrance:- not all the individuals who carry the mutation have
phenotypic manifestations, which may appear as skipped generation in such family we
see that affected grand parent-normal (Skipped) parent-affected child.
c- Variable expression: manifestations of the disorder in different degrees.
d- Somatic mutations: the mutation occur not in the egg or sperm that forms a child but
in the cell of an developing embryo. The phenotypic manifestations are usually milder
than if all cells contain the mutation .
Examples of autosomal dominant disease :
Nervous: tuberous sclerosis .
Urinary : polycystic kidney .
Gastrointestinal : familial polyposis .
Haemopoitic : hereditary spherocytosis, von willebrand disease.
Skeletal : marfan syndrome ,achondroplasia.
Metabolic : familial hypercholestrolemia