Lecture 14-Medical Genetics: Consequences of Genomic alteration Flashcards
4 categories for genetically determined diseases
single gene disorders- beta thalassaemia
chromosomal disorders-trisomy 21
multifactorial genetic disorders- diabetes mellitus, hypertension. result from interaction of multiple genes
somatic cell disorders- cancer. appear only in specific somatic cells unlike the others which appear in the DNA of all cells.
mutation
any permanent heritable change in the sequence of genomic DNA. any alteration in DNA from its natural state: may be disease causing or a benign normal variant.
polymorphism
occurrence together in a population of two or more alternative genotypes, each at a frequency greater than that which could be maintained by recurrent mutation alone. natural variation in genomic DNA sequence, that usually have no obvious adverse effects on the individual and occur with fairly high frequency in general.
silent mutation
single base change that does not result in an amino acid change
missense mutation
single base change that does result in an amino acid change; may or may not cause abnormal phenotype. e.g.. sickle cell anaemia
nonsense mutation
single base change that changes an amino acid to a stop codon
frame shift mutation
insertion or deletion of bases in anything other a multiple of 3
spice donor/acceptor mutation
alteration of sequences for accurate splicing of introns. introns removed, exons spliced together.
deciding when a DNA change is pathogenic
if a missions attention, is it at a functionally important site?
is the encoded protein truncated? shorter? non functional
Is RNA splicing affected?
does the change segregate with disease in the family?
loss of function mutations
produce a reduced amount of function of the gene product. have minimal effect on phenotype unless both alleles are affected. haploinsufficiency sometimes occurs where 50% product level results in an altered phenotype
some heterozygous loss of function mutations produce a dominant negative effect (abnormal product interferes with product of normal allele)
null allele
results because of an absence of a normal gene product or absence of normal function.
dominant negative effect
(abnormal product interferes with product of normal allele)
gain of function mutations
produce either an increased amount or increased activity of the product. not always good, i.e.. melanoma B-raf is unregulated. stem cells divide out of control
autosomal
chromosomes 1-22
a character is dominant if
it manifests in the heterozygote and not if it doesn’t and recessive it doesn’t
autosomal dominance
transmitted from generation to generation irrespective of gene. an affected person with an autosomal dominant disorder (eg. huntingtons) has one normal and one mutant allele. 50:50 of passing down the mutant.
affected person usually has one affected parent
affects either sex
transmitted by either sex
child of affected and unaffected mating has 50% chance of being affected
autosomal recessive
if an autosomal recessive gene exists in the heterozygous form the person will be a carrier. its only the homozygous form which will manifest disease.
affected person usually born to unaffected parents
affects either sex
increased incidence of parental consanguinity
after birth of affected child each subsequent child has 25% chance of being affected.
Lyonisation
random inactivition of one of the copies of the X chromosome. Because of this in a sex linked recessive condition a heterozygote may express phenotypic mutation known as a manifesting hetozygote
X linked recessive
affects mainly males
affected males usually born to unaffected parents (mothers asymptomatic carrier)
no male to male transmission
all daughters of affected males are obligate carriers
manifesting heterozygote explained by lionisation:mild manifestations of the disorder in carrier females
X linked dominant
affects both sexes, more female than male
females often more mildly and variably affected due to lionisation
child of affected female, regardless of sex will have 50:50 chance of being affected
child of affected male will have all affected females and no males.
Y linked
also known as holandric inheritance
affects only males
affected males always have an affected father
all sones of an affected man are affected
complications to basic mendelian pedigree patterns
common recessive conditions can give pseudo dominant pattern (eg. blood group O)
nonpenetrance
variable penetrance-eg. autosomal dominant with variable penetrance gives ectodactyly- split hand, split foot
variable expression- eg. autosomal dominant with variable expression gives waardenburg syndrome-various different facial features
new mutations/germline mosaicism- eg. osteogenesis imperfecta
causes of trisomy 21
- error in cell division, the longer the gap between metaphase 1 being reactivated the more likely that non disjunction will occur.
- translocation; cutting and rejoining of asymmetrical chromosomes.
