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