In pedigree drawings how are males and females identified?
Males are squares
Females are circles
How are relationships stated on pedigree drawings?
Partners have a line between them
Siblings have a line above them
Line down for children
On pedigree drawings how are genetic diseases shown?
Affected people are shaded
Carriers have dots in
What does consanguineous mean?
relating to or denoting people descended from the same ancestor.
“consanguineous marriages may give rise to recessive syndromes”
How are consanguineous couples denoted in pedigree drawings?
Double line between the partners
Describe autosomal dominant inheritance
Manifest in HETEROZYGOUS form Multiple generations affected Both sexes affected Male to female & female to male transmission Most will have an affected parent 50% risk to offspring
What are the characteristics of autosomal dominant inheritance?
Most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance)
Males and females are equally likely to inherit allele and be affected
Risk for each child of an affected parent is ½
If an affected individual’s siblings/children are not affected, and they don’t carry the mutation they can’t pass it on to their offspring
What is penetrance?
Percentage of individuals who carry the mutation AND develop symptoms of the disorder
Where is age dependent penetrance most likely seen?
many dominant disorders show age-dependant penetrance
What is variable expressivity?
The variation in severity / symptoms of disorder between individuals with same mutation
E.g. Neurofibromatosis
What is meant by mosaicism?
the state of being composed of cells of two genetically different types.
Outline the new mutation rate of neurofibromatosis
de novo mutation rate varies considerably between AD conditions
Describe the somatic mosaicism seen in neurofibromatosis
new mutation arising at early stage in embryogenesis
Present in only some tissues/cells
When does germline mosaicism occur in neurofibromatosis patients?
(gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis
mutn present in variable proportion of gametes; can be transmitted to offspring
What can we anticipate about neurofibromatosis?
worsening of disease severity in successive generations
characteristically occurs in triplet repeat disorders
Describe autosomal recessive inheritance
Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
Carriers (heterozygote) not affected
Both sexes affected
Male to female and female to male transmission
Usually one generation affected
May be consanguinity
e.g. cousin marriages
What is compound heterozygosity?
Medical condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state
2 mutns in same gene
Mutns are different
Give an example of a compound heterozygous condition
E.g. Cystic fibrosis
∆F508
G542X
What is compound homozygosity?
Homozygous mutation is the presence of the identical mutation on both alleles of a specific gene
2 mutns in same gene
Identical mutns
Give an example of compound homozygous disease
E.g Cystic fibrosis
∆F508
∆F508
May suggest consanguinity
Within families where are autosomal recessive disorders usually seen?
Trait often found in clusters of siblings but not in parents & offspring.
What is the recurrence risk of autosomal recessive inheritance?
Recurrence risk = 1/4 for each sibling of affected person
What is the carrier probability of autosomal recessive disorders?
Carrier probability =2/3 for unaffected siblings of affected person.
All offspring of affected person are obligate carriers
How does X-linked inheritance work within women
Women have two X chromosomes
Two copies of X-linked genes
Can be homozygous or heterozygous
Explain how X-linked inheritance works within men
Men have one X and a Y
Only a single copy of X-linked genes
Hemizygous
Describe recessive X-linked inheritance
Recessive
Women are carriers + unaffected
No male to male transmission
Describe dominant X-linked inheritance
Women are affected
Males more severely affected/lethal
What are the rules of x-linked inheritance
X-linked genes never passed from father to son
All daughters of affected males are obligate carriers
Children of carrier females have a 50% chance of inheriting mutant allele
What is skewed X-inactivation?
normally the majority of genes on one of a woman’s X-chromosomes are inactivated
generally random but ~10% of women have uneven or skewed X-inactivation
What is meant by manifesting carriers?
some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD
What is Y-linked inheritance?
Always and only passed from fathers to sons
What is a mutation?
> a change in the genetic material
A pathogenic mutation (pathogenic variant) results in an alteration of the function of the gene product and can cause a disease phenotype
What types of mutations are there?
Substitutions (point mutations)
Deletions
Insertions
Where in DNA are mutations found?
Found in:
Coding DNA
Non-coding DNA (such as promoters and introns)
What is a silent mutation?
nucleotide change w/o amino acid change: synonymous substitution
What is a missense point mutation?
Replacement of a single nucleotide -> forms incorrect amino acid which may produce a malfunctioning protein
What are the impacts of amino acid substitution?
Physicochemical similarity between the two amino acids
Functional role of the specific domain of the protein
Phylogenetic conservation of original amino acid amongst diverse species
What is a nonsense mutation?
Incorrect sequence causes the shortening of a protein sequence
What are the consequences of base insertions and deletions?
For both insertions and deletions:
In-frame (multiple of three)
Frameshift (not a multiple of three)
Summarise the classic modes of Mendelian Inheritance
Autosomal dominant
Autosomal recessive
X-linked
Y-linked
Within the classic modes of inheritance what other factors can alter gene inheritance?
Pleiotropy, mosaicism, expressivity, penetrance
How do we estimate the mode of inheritance?
We estimate a mode of inheritance by examining pedigrees