Monogenic Disorders Flashcards
outline genetic heterogeneity of disease
genetic heterogeneity: the same clinical phenotype can result from mutations at different loci, many different alleles within a given gene are associated with a certain genetic condition, and different mutations within the same geen can account for different disease phenotypes
locus heterogeneity
Locus Heterogeneity: many different genes determine the complex structures involved in hearing, such as the cochlear hair cell.
ex/ hearing loss→ complementation
deletion/aberancy of one gene may not entirely affect the complex structure
allelelic heterogeneity
Allelic Heterogeneity: affected individuals are often compound heterozygotes for different mutations and are clinically indistinguishable
ex/ cystic fibrosis: CFTR gene has over 1000 different alleles which have sequence mutations/changes that result in a non-functioning chloride channel.
example of an allelic disorder
Duchenne and Becker muscular dystorphy: both conditions are caused by deletions in the dystrophin genes, but are different. Deletions that are frame-neutral cause milder BMD
clinical heterogenetiy
: there is no one-to-one correspondence of genes and phenotypes
ex/ CFTR gene: some mutations in the gene do not cause CF, but rather cause male factor infertility due to congenital bilateral absence of the vas deferens.
Multiple generations affected
Males and females equally effected
Male to male transmission occurs
Each offspring of an affected parent has a 50% chance of being affected.
type of pedigree?
sounds like autosomal recessive
Dominant negative effect:
type of dominant confition where ther emutant allele may produce an abnormal protien product which may interfer with the dunction of the normal allele product
what is the heredity pattern for cancer syndomres?
autosomal dominant– Trait of predisposition to cancer is DOMINANT, but at the cellular level, mutation is recessive
Moderate mental retardation, behavioural problems, tall stature, mildly dysmorphic: long face, large ears, mild joint laxity.
Generally is X linked, but the mutation is dynamic! The expression depends on the size of the expansion, and has a general form of anticipation: disorder changes as the generations pass.
Some symptoms are seen in premutation carriers; like premature ovarian failure, neurological complications
X inactivation modulates the expression in females.
fragile X syndrome.
Seen in Leber Hereditary Optic Neuropathy: male presents with sudden onset, painless loss of vision in his right eye, 3 months later he loses his vision in the left eye. Over the next year, he regains some vision but remains legally blind. Many family members have had the same problem.
Type of inheritance pattern?
Cystoplasmic mitochondrial DNA has ALL FROM THE EGG!! There is maternal inheritance.
Very “non-mendelian” because thousands of mitochondira/cell each with dozens of DNA molecules and are randomly segregated during cytokinesis
General Presentation of inheritance of Mitochondrial Mutations:
all maternal offspring are affected, no paternal offspring are affected.
explain the phenotypic heterogenetiy of mitochondrial mutations
Due to: large number of genes involved (13 mitochondrial genes and hundreds of nuclear genes), heteroplasmy (single cell which has both normal and mutant mitochondrial DNA → mutant load can vary from organ to organ, cells of course can be homoplasmic and thus all mutant), energy requirements vary from tissue to tissue and also depending on the amount of stress the patient is under
Mitochondrias are complicated because it actually contains both nuclear and mitochondrial DNA. many genes and proteins come from outside the mitochondria
How much mutation in a given egg is what controls the phenotypic heterogeneity.
outline how maternal vs paternal deletions of 15q11-13 change the disease process
Deletions of 15q11-13 are identified in both Prader-Willi and Angelman Syndrome
Paternal deletion = PWS
Maternal deletion = AS
proteus syndrome is caused by ___ ___ of the AKT1 gene
Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny.
imprinting syndrome
differential expression of a gene depending on the parent of origin!!
Can be seen in 15th chromosome deletions (paternal vs maternal 15q deletion results in PraderWilli Vs AngelMan)
For certain genes, the expression depends on whether the gene was transmitted via the maternal or paternal gamete
Genes are marked or imprinted during gametogenesis
