Lecture 4 (1/4) Patterns of inheritance (autosomal dominant, recessive,psuedo dominant)
What are some autosomal dominant disorders?
--Familial hypercholesterolemia --Huntington disease --Myotonic dystrophy --Marfan syndrome --OI --Achondroplasia --Neurofibromatosis type I --Acute intermittent porphyria
What are monozygotic twins?
--Fertilization of a single zygote --Have identical genes
What are dizygotic twins?
--Fertilization of two ova --Shave ~50% of genes (similar to siblings)
Describe haplo-insufficiency
--Half normal levels of gene product result in phenotypic effects
What are explanations for pseudo-autosomal dominance?
--High carrier frequency (IE sickle cell in africa) --High incidence of consanguinity (isolation)
Describe the autosomal recessive inheritance pattern
--Homozygous --Both parents are carriers (phenotypically normal) --Horizontal inheritance (generational skipping) --Males/females equal
What are examples of gain-of-function mutations?
--Huntington disease --Achondroplasia
Describe are gain-of-function mutations?
--Increased level of gene expression or development of new function of gene product
What's the difference btw X-linked dominant and autosomal dominant?
--Male to male transmission seen in autosomal dominant, not X-linked
How can you tell autosomal recessive from X-linked recessive?
--Males/females affect almost equally in autosomal recessive --Males predominantly affected in X-linked
What mode of inheritance is non-mendelian?
--Mitochondrial
What is a polymorphism?
--Multiple alleles of a gene in a population
Describe dominant-negative mutations
--Mutant gene product interferes with function of normal gene
Describe myotonic dystrophy
--Mutation in DMPK --Pleiotropic phenotype --Triple repeat disorder --Symptoms: ????
Describe neurofibromatosis
--Mutation in NF1 gene --Cafe-au-lait spots, lisch nodules in eyes --Exhibit allelic heterogeneity, variable expressivity
What is allelic heterogeneity?
--Mutation varies in different families (ex single gene, entire region)
Do carries for autosomal recessive disorders have phenotypic manifestions?
--No
What are examples of dominant-negative mutations?
--OI 2-4 --Marfan syndrome
Describe the autosomal dominant inheritance pattern
--One mutant allele sufficient --Heterzygous state --Vertical inheritance --Males/females affected equally --Affected children get gene from affected parent --Male to male transmission seen --Recurrent risk: 50% affected
What's important about AIP?
--Only enzyme which isn't autosomal recessive
Who is a consultand?
--Person who approaches physician for consultation
What disease is an example of locus heterogeneity?
--SCIDS due to ADA
What is a pleiotropic phenotype?
--Single mutation but affects multiple organ systems
What does FGFR3 code for?
--Transmembrane receptor involved in differentiation of cartilage to bone
What does NF1 gene code for?
--Tumor suppressor protein
What is suggestive of autosomal dominant inheritance?
--Vertical inheritance + male to male
What is the probability that a person who is NOT affected with autosomal recessive symptoms is a carrier, if they have affected siblings?
--2/3
What is the recurrence risk for autosomal recessive inheritance?
--25% Homozygous normal --25% Homozygous affected --50% Heterozygous carrier
What are the recurrence risks for achondroplasia?
--25% homozygote normal --25% homozygote mutation (lethal) --50% heterozygote
What is the recurrence risk for autosomal dominant disorders?
--50% affected
For autosomal recessive, what percent of children are phenotypically normal?
--75%
What happens in autosomal recessive SCIDS?
--ADA deficient so dATP toxic to B-cell and T-cell development
Who is a proband?
--Affected individual who gains attention of physician
What mode of inheritance exhibits vertical inheritance?
--Autosomal dominant
What is pseudo-autosomal dominance?
--Condition has vertical transmission (looks like dominant) + 1/2 transmission risk --BUT, recessive disorder (heterzygote + homozygote have affected children)
Name some autosomal recessive disorders
--Cystic fibrosis --Sickle cell anemia --PKU --Tay-sachs --Congenital deafness --Hemochromatosis (delayed onset) --Alkaptonuria (delayed onset) --Homocystinuria --Galactosemia --SCID (ADA)
Describe achondroplasia
--FGFR3 mutation --Severe stunting of growth
What are examples of haplo-insufficiency mutations?
--Familial hypercholesterolemia --AIP --OI type 1