Patterns of Single Gene Inheritance
Clinical genetics
• Single-gene traits caused by mutations in genes in the nuclear
genome are often called Mendelian.
• Types of Mendelian genetic disorders (single-gene disorders):
1. Autosomal recessive
2. Autosomal dominant
3. X-linked dominant
4. X-linked recessive
5. Mitochondrial
Pedigrees
• A graphical representation of the family tree, with use of:
standard symbols.
• The patterns shown by single-gene disorders in
pedigrees depend on two factors:
1. Whether the phenotype is dominant (expressed when
only one chromosome of a pair carries the mutant allele
and the other chromosome has a wild-type allele at that
locus) or recessive (expressed only when both
chromosomes of a pair carry mutant alleles at a locus)
2. The chromosomal location of the gene locus, which may
be on an autosome (chromosomes 1 to 22) or on a sex
chromosome (chromosomes X and Y).
Factors affecting the pedigree
• Penetrance: the probability that a gene will have any
phenotypic expression at all.
• Reduced penetrance: when individual with the genotype
completely fail to express it.
• Expressivity: the degree to which phenotype is
expressed by individual having a particular genotype.
• Variable expressivity: when the severity of disease
differs in people who have the same genotype.
Age at Onset:
1. Early onset:
Affecting a fetus early in pregnancy (intrauterine
development), lead to multiple miscarriages.
Pattern of disease occurrence may be obscure.
2. Late onset: post reproductive years.
Autosomal Recessive Inheritance
• Occurs only when the mutant gene present in
homozygotes state.
• Occur when parent are both heterozygous and have one
copy of mutant gene and one copy of normal gene.
• Heterozygous parent have a chance of 25% of producing
affected offspring.
• The possibility that an individual carrying the gene will
pass it into children is 50%.
• Three types of mating can lead to homozygous offspring
affected with an autosomal recessive disease.
• The mutant recessive allele is symbolized as r and its
normal dominant allele as R.
Clues of autosomal recessive disease:
• The mutation skip the generation (clue for recessive).
• Unaffected parent can have affected children (clue for
autosomal).
• Male and female are equally affected.
• The chance that both parents are carriers of a mutant
allele at the same locus is increased if the parents are
related (Consanguinity) and could each have inherited
the mutant allele from a single common ancestor.
• Inbreeding describes the situation in which individuals
from a small population tend to choose their mates
from within the same population for cultural,
geographical, or religious reasons.
• The frequency of recessive genes in genetic isolates
groups is greater than that in the general population.
Note:
New Mutation in Autosomal Recessive:
• An individual have two mutant alleles inheriting one
mutant allele from a carrier parent while the other
mutant allele arose de novo in a gamete that came from
a parent who was not a carrier.
Examples of autosomal recessive conditions:
• Sickle cell anemia
• Cystic fibrosis
• PKU
Autosomal Dominant Inheritance
• More than half of all mendelian disorders are inherited as
autosomal dominant traits.
• Dominant Inheritance: a phenotype expressed in both
homozygotes and heterozygotes for a mutant allele.
• Dominant disorders are more severe in homozygotes than
in heterozygotes.
Clues of autosomal dominant condition:
• Don’t skip the generations (clues its dominant)
• Affected parent can have unaffected children (clues its
autosomal).
• Both male and female are equally affected.
• Co-dominant: two different alleles (mix phenotypes) are
expressed.
• example: ABO blood group system.
• Incompletely dominant (or semi-dominant): 2 different
alleles are blended together to give one phenotype.
• The homozygous show sever condition in comparison to the
heterozygous .
• example: Achondroplasia:
(homozygous for achondroplasia are much more severely
affected than are heterozygotes and commonly do not
survive the immediate postnatal period).
Example of autosomal dominant conditions:
• Achondroplasia
• Huntington’t disease
• Osteogenesis imperfecta
X- linked dominant
• Disease always transfer from affected father to all daughters.
(clue its X-linked)
• Father never give the disease to son.
• Do not skip the generation (clue its dominant)
• Males and females are not equally affected.
Example of X- linked dominant conditions:
• Vit D resistant Rickets
• Rett syndrome
X-linked recessive disease
• Disease transfer from mother to son and never transfer
from mother to daughter (clue its X-linked).
• Disease never transmitted from father to son.
• Skipping generations (clue its recessive).
• Males are more affected than females.
Example of X- linked recessive conditions:
• Haemophilia A and B
• Duchenne muscular dystrophy
Mitochonderial inheretance
Maternal Inheritance of mtDNA:
• The genetics of mtDNA is its maternal inheritance.
• More than 100 different point mutations have been identified
in mtDNA that can cause disease, often involving the central
nervous and musculoskeletal systems.
• All the children of a female who has mutation in mtDNA will
inherit the mutation, whereas none of the offspring of a male
carrying the same mutation will inherit the defective gene.
Non- Mendelian inheritance
• Is any pattern of inheritance in which traits do not
segregate in accordance with Mendel’s laws.
• For example:
Genetic linkage: when gene are located on the same
chromosome and no crossing over took place, hence the
genetic traits will be inherited as connection because of
genetic linkage. This case is exception of mendelian rule of
independent assortment.
• Play a role in several disease process.
Mosaicism
• Is the presence in individual or a tissue of at least two cell
lines that differ genetically but are derived from a single
zygote.
• Mutations arising in a single cell can give rise to clones of
cells genetically different from the original zygote because
once the mutation occurs, it could persist in all the clonal
descendants of that cell.
Mosaic individual could be:
• Somatic mosaicism present in some tissues of the body but
not in the gametes.
• Germline mosaicism restricted to the gamete lineage only.
Multifactorial disorders
• Although multifactorial disorders are often found
gathered in families, they do not show any distinct
pattern of inheritance.
• Are caused by a combination of the effect of multiple
genes or interaction between genes and environment.
Example of multifactorial diseases:
• Autism, Schizopherenia, Depression, Obesity, High blood
pressure, Alzheimer’s, epilepsy, heart disease, Diabetes
mellitus,…
