Recessive Disease 1 Flashcards
Mendelian disease
Single-gene disorder: caused by allele at single locus
Follows classic inheritance patterns in pedigrees
Prevalence of Mendelian diseases
About 1% (much rarer than multifactorial diseases)
Age of expression of major types of single gene disease
Most show up shortly after birth
About 1% show up after reproductive period (including Mendelian forms of common diseases like blood pressure)
Probably are many unknown ones that prevent embryo implantation (show up as infertility in pedigrees)
Tool used to infer mode of inheritance of a given disorder
Pedigree/ family history
Characteristics of autosomal recessive inheritance
Usually seen only within siblings, not in parents or relatives
Males and females equally likely to be affected
Recurrent risk is 25% with each additional child
Parents of affected individual may be coming from same family, especially if disease is rare
Pleiotropy
Single mutation can cause multiple diverse symptoms, sometimes in different organ systems
Example: cystic fibrosis
Cystic fibrosis symptoms
Abnormal mucous secretions and very salty sweat Chronic obstructive lung disease Pancreatic insufficiency Biliary obstruction and fibrosis Infertility (especially in males)
Cause of cystic fibrosis
Mutation of CFTR protein (ion channel protein for Cl)
Causes reduced fluid secretion, which causes increased protein, which causes thick mucous
Carriers of autosomal recessive disorders
Still have one functional allele, which is often able to compensate for non-functioning allele
Often have slight physiological, disease-like characteristics (incomplete dominance)
Assumptions for Hardy-Weinberg Equilibrium
Random mating No inbreeding No migration No new mutations Large population No selection Assumptions are frequently violated
Molecular basis of autosomal recessive disorders
Usually caused by “loss of function” alleles, which prevent protein production (e.g. gene deletion, premature stop codon, splicing mutation, etc.) or lead to nonfunctional protein (e.g. missense mutation)
Hardy-Weinberg equation
Frequency of dominant allele: p Frequency of recessive allele: q p + q = 1 p^2 + 2pq + q^2 = 1 Genotype AA: p^2 Genotype Aa: 2pq Genotype aa: q^2
Penetrance
Probability that mutant allele will cause disease
Reduced penetrance
Not all individuals with disease genotype get disease
Expressivity
Severity of expression of phenotype
