Single Gene Disorders II Flashcards
Why is diagnostic criteria important? What is an example?
Helps determine if a disorder is inherited in a dominant or a recessive pattern.
A heterozygous individual may show some loss of physiologic function and it is up to the medical community to define if reduced activity can still be considered normal
Example. Familial Hypercholesteremia, heterozygous individual will present twice the elevation of LDLs so disorder is dominant. Disorder is dominant because threshold is set low
What is heterogeneity?
One disorder can be caused by different mutations, in different chromosomal loci
What is pleiotrophy?
One mutation can cause more than one disorder
What is locus heterogeneity? Where does it often occur?
Mutations in different chromosomal loci cause the same disorder
Often observed in proteins that require processing and trafficking like extracellular matrix proteins (collagen)
Defects of the protein processing have the same outcome as defects of protein itself
What is allelic heterogeneity?
Different mutations in the same gene (same locus) cause the same disorder or different subtypes of disease
Null mutations may cause disease via haploinsufficiency
Missense mutations may cause disease via dominant negative effect
May complicate molecule disease since one does not know which mutation to look for in a large gene
In regards to pleiotropy, what needs to be taken into consideration?
Often a mutation affects more than one system and can cause seemingly separate disorders
Produces more than one trait and same mutation might present differently in different patients
Traits might overlap for different mutations
What are examples of pleiotropy?
Phenylketonuria affects the nervous system development and the integumentary system (form of albinism)
Overlaps with disorders like tyrosinase mutation which also causes albinism
What is osteogenesis imperfecta?
A disorder of type I collagen
Causes deficiency in bone formation
Caused by mutations in COL1A1 and COL1A2 collagen genes
What is osteogenesis imperfect an example of? What heterogeneity does it have?
Genetic Heterogeneity
Allele heterogeneity
Type I: Caused by null mutation in COL1A1 gene due to haploinsufficiency and will reduce amount of collagen in tissue
Type II: Caused by missense mutations in COL1A1 gene via dominant negative effect - assembly of nonfunctional fibers
Locus heterogeneity:
Type VIII: Caused by loss of function mutations in prolyl-hydroxylase (P3H1) gene via recessive inheritance - impair collagen processing
What is collagen made from? and what occurs to it to make collagen?
Collagen is made from procollagen alpha1 and alpha2 proteins
Both proteins need post-translational modifications via hydroxylation of proline and lysine and N-linked glycosylation
What mutations can occur in collagen assembly in OI?
Mutations in collagen processing enzymes cause recessive forms of OI
Mutations in collagen genes cause dominant forms of OI
Dominant negative mutations can be more severe than null mutations
What is NF1?
Neurofibromatosis type 1
Physical exam shows multiple neurofibromas and cafe au lait macules on abdomen
Eye exam shows Lisch nodules
What is penetrance?
Percentage of people with mutation who develop symptoms
Penetrance has to be factored into risk and disorder can skip generation when penetrance is low.
Reduced penetrance means individuals with mutation have no signs of disease
What is expressivity?
Differences in presentation
Disorders can present differently even in the same family
Variable expressivity means individuals with the mutations have different phenotypes and diagnosis may be missed
In relation to NF1, what is its penetrance and expressivity?
NF1 has complete penetrance (everyone with mutation shows symptoms) and variable expressivity (cafe au lait spots to severe neurofibromas)
In the pt with NF1, why were the parents not affected?
The child could have inherited a new mutation
Mutation could be present in one of the parents but diagnosis was missed
In disorders with low penetrance or variable expressivity, what is the recurrence risk?
If child inherited new mutation - recurrence risk is low
If mutation present in one of the parents as a carrier. The heterozygous individual will have a 50% chance of passing the mutation to the next generation
What is achondroplasia?
Most common form of dwarfism
Children may present with short limbs, enlarged neurocranium, and midface hypoplasia
Caused by gain of function mutation in FGFR3 receptor
Fully penetrance and narrow variation in expressivity
In the case of achondroplasia, why might the parents not be affected when the disease is fully penetrant with little variation in expressivity?
New mutation in child!
When do new mutations often occurs?
Occur in diseases where affected individuals have low fitness
Often occur in large genes and genes with mutation hotspots (CpG repeats, mC de-aminates to thymine)
Correlated with advanced paternal age
What is fitness?
Probability an individual will reproduce
Correlates with probability of new mutations
If fitness is 0, all cases must be due to new mutations
What is Huntington Disease?
Disease that causes involuntary muscle movements and increase in moody and depressive disorders.
Has 100% penetrance and narrow variation of expressivity
Autosomal dominant neurodegenerative disorder
In the example of HD where the grandparents are not affected and 2 siblings are affected, what explains this inconsistency?
The grandparents not being affected makes it appear to be a new mutation but than it should not affect two siblings.
Explanation is in the mechanism by which new HD mutations arise
How does a new HD mutation arise?
Gene responsible for HD has a triplet repeat and the repeat number can increase during gametogenesis and HD will develop if there are more than 40 repeats. Full mutation shows dominant mode of inheritance
An individual with 35-40 repeats carry a premutation and have a risk of having multiple affected children. They do not develop HD but are at high risk of creating fully penetrant mutant alleles
Once a mutant alleles has been created by triplet expansion, it will be transmitted in an autosomal dominant mode
How does severity work in HD?
Severity of disease increases upon transmission.
Severity in HD measured as age of onset and disorder affects successive generations at an even younger age
This phenomenon is called anticipation
Children will have longer trinucleotide repeat regions than their parents and longer repeats mean earlier age of onset
What are other human disorders similar to the way HD is inherited?
Fragile X syndrome - mytotonic dystrophy
Repeats can be located in UTR, exons or introns
