Chapter 5- Genetic Disorders Flashcards
What types of mutations are highly penetrant and follow classic Mendelian inheritance patterns?
Single genes with large effects
What are the most common cause of genetic disorders?
Multi-genetic disorders
What is a mutation?
Permanent change in DNA
What is the difference between a germ cell and somatic mutation?
Germ cell- transmitted to offspring
Somatic- not transmissible
What kind of mutations are there?
- Coding
- Non-coding- enhancer or promoter
- Frameshift
- Trinucleotide repeat- amplification of triplet nt sequences
What are the two kinds of point mutations?
- Missense- single nt substitution changes the triplet base code
- Nonsense- single nt substitution creates a stop codon
What are the two types of missense mutations?
- Conservative- protein structure remains
2. Nonconservative- change affects the final protein structure
What is penetrance?
The percentage of individuals that carry the gene AND express the trait
What is variable expressivity?
Variation in the effect caused by the mutation (expression varies among individuals)
What is pleiotropism?
Multiple possible end effects of a single mutation (expressions within a person varies)
What is genetic heterogeneity?
Multiple different mutations can lead to the same outcome
What are the different transmission patterns of single gene disorders?
- Autosomal dominant- LOF
- Autosomal recessive- complete penetrance, metabolism errors
- X-linked- sex linked recessive, fully expressed in men
What are the consequences of enzyme defects?
Reduced synthesis
Toxic substrate accumulation
Decreased end product
Decreased substrate metabolism
Defects in receptors and transport
Alterations in non-enzyme proteins
Adverse drug reactions
What disorders are associated with structural proteins?
Marfan syndrome
Ehlers-Danlos syndrome
What are the characteristics of Marfan syndrome?
Mutation in 15q21.1 (fibrillin-1 gene)
Affects skeletal, ocular, CV and integumentary systems
Tall, long extremities, scoliosis
What are the characteristics of Ehlers-Danilo’s syndrome?
Defect in collagen synthesis
Fragile skin and poor wound healing
Hyper mobile joints
What are the characteristics of familial hypercholesterolemia?
Mutation in LDL receptor
Loss of feedback control (increased circulating cholesterol)
What disorders are associated with enzyme defects?
Lysosomal storage diseases
Tay-Sachs disease
Niemann-Pick
Gaucher disease
Mucopolysaccharidoses
Glycogen storage diseases
Allaptonuria/ochronosis
What are the characteristics of lysosomal storage diseases?
Accumulation of partially degraded metabolites
Enlarged lysosomes
Lack of autophagy
What are the characteristics of Tay-Sachs disease?
Hexosaminidase deficiency inhibits ganglioside catabolism
Neurons most affected
Oil red O and Sudan black pos
Whorled lysosome
Cherry red spot in macula
What are the characteristics of Neimann-Pick disease?
A (infantile) and B- sphingomyelin accumulation
C- defect in nonenzymatic lipid transport
What are the characteristics of Gaucher disease?
Reduced glucocerebrosidase activity (accumulation)
PAS pos
What are the different types of Gaucher disease?
I- mononuclear phagocyte involvement
II- CNS involvement, infants
III- involves both macrophages and CNS
What are the characteristics of mucopolysaccharidoses?
Deficiency in enzymes that degrade glycosaminoglycans
Coarse facial features, mental retardation, corneal clouding valve and sub-endothelial arterial thickening
What are the two forms of mucopolysaccharidoses?
Hunter- x-linked recessive
Hurler
What are the three forms of glycogen storage diseases?
- Hepatic- catabolism deficiency
- Myopathic- glycolysis enzyme deficiency
- Miscellaneous- alpha-glucosidase deficiency, glycogen overload in many organs (Pompe=cardiac involvement)
What are the characteristics of alkaptonuria/ochronosis?
Decreased homohentisic oxidase
Blocks phenylalanine metabolism
Homogentisic acid accumulation
Blue-black pigment
What are polymorphisms?
Genes with at least two alleles (one has a frequency >1%)
What are the numerical chromosomal disorders?
Monosomy
Trisomy
Mosaicism- different cell populations
What are the structural chromosomal disorders?
Deletions
Translocation- balanced/reciprocal or Robertsonian/centric
Isochromsome- deletion and duplication
Inversion- paracentric or pericentric
Ring chromosome
What are the different types of cytogenic autosomal disorders?
Trisomy 21 (Down syndrome)
Trisomy 18 (Edward’s syndrome)
Trisomy 13 (Patau syndrome)
Chromosome 22q11.2 deletion syndrome (diGeorge and velocardiofacial)
Cri du chat (5p deletion)
What are the characteristics of Down syndrome?
Extra chromosome 21
Due to maternal age or Robertsonian translocation
Flat face, epicanthic folds, congenital heart disease
What are the characteristics of Edward’s syndrome?
Extra chromosome 18
Mental retardation
Micrognathia, overlapping fingers, congenital heart defects, renal malformation
What are the characteristics of Patau syndrome?
Extra chromosome 13
Microcephaly, mental retardation
Microphthalmia, polydactyly, cleft palate, cardiac and renal defects
What are the two forms of chromosome 22q11.2 deletion syndrome and their characteristics?
DiGeorge- thumping hypoplasia, T cell deficiency
Velocardiofacial- congenital heart disease
What is the Lyon hypothesis?
One x-chromosome is randomly selected to be inactivated
Mosaicism seen in females
What is a Barr body?
Inactive X-chromosome
What is SYR?
Sex determining region on a Y chromosome
What are the cytogenetic disorders involving sex chromosomes?
Klinefelter syndrome (2+X and 1+Y)
Turner syndrome (monosomy of X)
What are the three different types of trinucleotide repeat mutations?
Fragile X- CCG repeats during oogenesis
Huntington disease- CAG repeats during spermatogenesis
Friedreich’s ataxia- GAA repeats in FXN gene (LOF)
Why is the expression of mutations in mitochondrial genes unpredictable?
Cell can contain both normal and mutant mtDNA
Heteroplasmy- proportions during division are random
What is genomic imprinting?
Epigenetic process resulting in differential inactivation of either maternal or paternal alleles if certain genes
What are the two disorders of genomic imprinting?
- Prader Willi- q12 deletion in chromosome 15 from father
2. Angelman- q12 deletion in chromosome 15 from mother
How does gene silencing occur?
Methylation
What is gonadal mosaicism?
Mutation in gonadal cells early in embryonic development
Disease can be passed on
