Genetics Flashcards
What are the four classified genetic disorder categories
- Mendelian disorders
- Multifactorial disorders
- Chromosomal (cytogenetic) disorders
- Single-gene disorders with non-classic inheritance
Define penetrance
The amount of people that carry an autosomal dominant gene and expressing the trait.
Penetrance refers to the probability of a gene or trait being expressed.
e.g 50% penetrance means that 50% of people who carry the gene also express the trait
Define variable expressivity
Variability in the effect caused by the mutation
(e.g manifestations of neurofibromatosis type 1 ranges from macules on skint to tumours)
Define co-dominance
full expression of both alleles of a given gene pair in a heterozygote e.g HLA
Define polymorphism
Multiple allelic forms of a single gene
Each varient confers increased disease risk, no single gene is necessary or sufficient to produce disease
Define pleiotropism
multiple end effects of a single mutant gene
e.g sickle cell disease - can cause haemolysis, bone necrosis)
Define genetic heterogeneity
Multiple different mutations resulting in the same outcome
In what way ways can our genetic code mutate (list 4)
Point mutations in coding sequences
Mutations in non-coding regions
Deletions and insertions
Trinucleotide repeat mutations
What do point mutations usually result in
An abnormally short protein chain
What causes familial hypercholesterolemia, how is it inhereted
mutation in the gene for a membrane receptor (chromosome 19)
Autosomal dominant
How are mutations in structural genes normally transmitted
Autosomal dominant
Characteristic features of autosomal dominant disorders (4)
- in many patients, structural proteins, rather than enzymes, are affected, so it’s a problem of STRUCTURE
- Age of onset usually delayed, clinical features variable, so high variable expressibility, low penetrance
- Affects both men & women, and both can transmit to their kids
- Risk to child of affected person is 50%
Examples of autosomal dominant disorders (10)
- CNS
- neurofibromatosis
- Huntington’s disease - Urinary
- polycystic kidney disease - GIT
- Familial polyposis coli - Skeletal
- Marfan’s syndrome
- Elhers-Danlos syndrome
- osteogenesis imperfecta - Metabolic
- familial hypercholesterolemia - blood
- von Willebrand disease
- hereditary spherocytosis
Examples of autosomal recessive disorders (11)
Metabolic
- cystic fibrosis, - phenylketonuria
- alpha1-antitrypsin deficiency
- Storage problems
- Wilson disease,
- Haemochromatosis
- Glycogen storage disease
- lysosomal storage disease - endo
- congenital adrenal hyperplasia - blood
- thalassemias
- sickle cell anaemia - CNS
- Friedreich ataxia
- spinal muscular atrophy
Characteristics of autosomal recessive disorders
- in many patients, enzyme proteins, rather than structural proteins, are affected, So the problem is now FUNCTION
- age of onset usually at birth or early in life, clinical features more uniform, so low variable expressibility, high penetrance (complete penetrance is common)
Points to note
- Affected person usually has unaffected parents, these parents are usually carriers, so usually appear normal
- all children of affected parent will be carriers
- the birth of an affected child is usually the first indication of the disease in a family
- both the parents have transmitted the disease
- affects either sex
- 25% risk if a prior child is affected
- 2/3 of healthy offspring will be carriers
A sickle cell trait heterozygote will have what
- An abnormal Hb
- Mild likelihood of vascular occlusions
Key characteristics of X linked recessive disorders
- affects almost exclusively males
- affected males born to unaffected parents, mother is asymptomatic carrier
- females may be affected if father is affected and mother is carrier, or if X-inactivation if female is skewed
- no male-to-male transmission
Key characteristics of X linked dominant disorders
- affects either sex
- females often more mildly and more variably affected (males hemizygous, females heterozygous)
- child of affected female has a 50% risk, regardless of sex
- for affected male, all his daughters will be affected, but non of his sons will
Examples of X linked recessive disorders
Skeletal
- Duchenne muscular dystrophy
Blood
- haemophilia A and B, chronic granulomatous disease
G6P dehydrogenase deficiency
Immune
- agammaglobulinemia
Metabolic
- diabetes insipidus
CNS
- fragile X syndrome
Clinical expression of a female who is heterozygous for a recessive x linked disorder
The disorder may be partially expressed
Is an extra X chromosome more or less harmful than the possession of an extra autosomal chromosome and why
The possession of an X chromosome in excess of the normal complement is less harmful than the possession of an extra autosome BECAUSE
Only one X chromosome in a cell is functional
Inheritance patterns of multifactorial inheritance
- Mutations may be present in more than one gene
- The risk of recurrence in subsequent pregnancies is less than 10%
- Identical twins will show 20-40% concordance
4.The risk of recurrence of the disorder in first degree relatives is 2-7%
Characteristics suggesting a disorder is inherited as a multifactorial trait
- The disease occurs more frequently in the children of an affected person than among the grandchildren
- The risk of developing the disease is greater if both parents are affected than if only one parent is affected
- The disease occurs more frequently in women than in men
Malignant conditions usually associated with chromosomal translocation include
- chronic myeloid leukemia
- Burkitt’s lymphoma
Outline chromosomal number changes in cytogenic disorder
- Monosomy
- Trisomy
- Mosaicism > a/w a group of cells, some with which is normal, others express extra or missing chromosomes
5 abnormal structures of chromosomes
May be caused by alterations in the number or in the structure of chromosomes.
Deletion
- Loss of a segment of a chromosome
Translocation
- Transfer of a segment of one chromosome to another two types…
- Balanced reciprocal
- Exchange of chromosomal material between two chromosomes with no net gain or loss of genetic material - Robertsonian fusion
- Reciprocal translocation between two acrocentric chromosomes involving the short arm of one and the long arm of another. Leads to the formation of one abnormally large and one extremely small chromosome.
Iso-chromosome
- One arm is lost (short or long) and the remaining arm is duplicated.
- i.e chromosome with two short or two long arms
Inversion
- Rearrangement associated with two breaks in a chromosome followed by inversion and reincorporation of the broken segment
Ring chromosome
- deletion affecting both ends, followed by fusion of the damaged ends
Are chromosomal/karyotype abnormalities implicated in neoplasms and if so why.
Karyotype/chromosomal abnormalities are thought to be a primary event in development of many human neoplasms
BECAUSE
In certain types of human neoplasia, karyotype abnormality is non-random and common in that tumour type
What are the most common types of non-random structural abnormalities in tumour cells.
- balanced translocations
- chromosomal deletions, and
- cytogenetic manifestations of gene amplification
What is aneuploidy
- It refers to a chromosome number different from the normal or euploid number
- Aneuploid cells may have more or fewer chromosomes than normal
Common disorders associated with aneuploidy
- Most patients with Down syndrome
- All trisomy syndrome
- Turner’s syndrome
- Poly-X females
How can Aneuploidy be detected
- May be detected by karyotyping
- In tumour cells may be detected by flow cytometry
What are 2 usual cause of aneuploidy
Non-disjunction
- Occurs during gametogenesis results in the formation of gamete with one less chromosome and one extra chromosome
- Failure of homologous chromosomes to separate in anaphase 1 (both get pulled to one side)
- Failure of sister chromatids to separate at meiosis II
- Gives rise to nullisomic and disomic gametes
Anaphase lag
- Homologoous chromosome in meosis or chromatid in mitosis is left behind.
- i.e chromosomes successfully seperate during anaphase but one spindle fibre lags behind leaving a chromsome in the cytoplasm not the nucleus so it gets destroyed.
- The result is one normal gamete/cell and one gamete/ cell with monosomy.
Are all cells in the body affected by aneuploidy
Meiotic non-disjunction means an aneuploid
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Examples of trisomies and monosomy
Trisomies only survival for
> Sex chromosomes: XXY, XYY, XXXY, etc…
> 21 (down syndrome) 1/700 live births
> 13 (Patau syndrome) 1/5000 live births
> 18 (Edwards syndrome) 1/3000 live births
Monosomy X only
> Turner’s syndrome
What are complex multigenic disorders
Caused by an interplay of variant forms of genes and environmental factors.
Genetic variants with at least 2 different alleles and an incidence in the population >1% are called polymorphisms.
Occurs when several polymorphisms are present
Small effect and low penetrance
Not all polymorphisms are equally important - e.g 20-30 genes are implicated in T1DM, only 6-7 are important.
What are 2 distincttive features of mitochondrial disorders
- Matrilineal inheritance
- Heteroplasmy (some mitochondria acquire duplications, deletions etc and others don’t. Leads to variation in expression of mutations in various genomes in the mitochondria).
What tissues are affected by mitochondrial diosders
Neural
Muscular
Inheritance pattern of mitochondrial disorders
Mostly autosomal recessive (in paediatrics)
Around 25% obey mitochondrial inheritance
- Both sexes affected
- Transmission only by females (mitochondria are maternally derived only)
- No transmission by males
What is incomplete penetrance
- An individual carrying mutation who does not express the phenotype
- A feature of dominantly inherited disorders
What is variable expressivity
- Variation between affected individuals in clinical manifestation
- Most common in dominant disorders
