| MENDELIAN INHERITANCE- OBJECTIVES | |
| POPULATION GENETICS AND MULTIFACTORIAL INHERITANCE- OBJECTIVES | |
| CYTOGENETICS---- OBJECTIVES |
updated 10/24/01
MENDELIAN INHERITANCE---- OBJECTIVES
1. Understand the meaning of, and be able to define:
| * genotype | * homozygous |
| * phenotype | * heterozygous |
| * locus | * compound heterozygote |
| * allele | * double heterozygote |
| * haplotype |
2. Know the standard pedigree symbols and how they are used.
3. Know the characteristics of the different Mendelian patterns of inheritance and be able to identify the following patterns in pedigrees:
| * autosomal dominant | * X-linked dominant |
| * autosomal recessive | * mitochondrial |
| * X-linked recessive |
4. Be able to define and recognize examples of:
| * allelic heterogeneity | * incomplete penetrance |
| * locus heterogeneity | * germline mosaicism |
| * variable expressivity |
5. Understand the concept of, and the molecular basis for, anticipation.
6. Understand and be able to define the following kinds of mutations:
| * missense | * insertion |
| * nonsense | * null |
| * frame shift | * triplet repeat expansion |
| * deletion |
1. Understand the Hardy Weinberg equilibrium and how to apply it to determine allele frequencies and heterozygote carrier frequencies.
2. Understand and be able to define:
| * mutation rate | * founder effect |
| * consanguinity | * genetic drift |
| * biological fitness | * polymorphism |
| * selection | * balanced polymorphism |
3. Understand the difference between Mendelian and multifactorial/polygenic traits.
4. Know the kinds of evidence that suggest genetic factors in the etiology of a disease.
5. Understand the threshold model of polygenic/multifactorial disease and its implications for genetic counseling.
1. Know the basic anatomy of human chromosomes.
2. Understand the techniques used to visualize chromosomes, including FISH.
3. Know the basic nomenclature used to describe chromosomes and karyotypes.
4. Be able to define euploid, aneuploid, trisomy, monosomy.
5. Know the consequences of meiotic nondisjunction.
6. Be able to define reciprocal, balanced, and Robertsonian translocation, and understand the risks to offspring of translocation carriers.
7. Know the major clinical consequences of chromosomal disorders.
8. Know the chromosomal basis for Down syndrome.
9. Be able to define microdeletion/contiguous gene syndromes, genetic imprinting, uniparental disomy.
10. Understand the chromosomal basis for sex determination.
11. Understand the basis for and consequences of X-inactivation (Lyonization).
12. Know the major phenotypic features of X-chromosome aneuploidy.
13. Understand the molecular pathogenesis of Fragile X syndrome.
Incidence: 1/3500 males; 1/6000 females; all ethnic groups
Phenotype: 1. Abnormal facies
2. macroorchidism
3. MR
Karyotype: FRAXA at Xq27.3 in 50% of mitoses
INHERITANCE PATTERN:
X-linked...BUT
1. 20% of obligatory carrier males are phenotypically and chromosomally normal (Normal
Transmitting Males).
2. 1/3 of heterozygous females are clinicaly affected; MR only if mutation inherited from a
carrier mother, not from the father.
3. Penetrance (risk of MR) is a function of position in the pedigree, and appears to increase
in successive generations (anticipation),------the SHERMAN PARADOX
FMR1
Polymorphic CGG repeat in first exon
Normal: 6 to 52; mode 30; transcriptionally active
Premutation: 50 to 230; transcriptionally active expands when transmitted by the mother; prob. proportional to size
Full mutation: >230; hypermethylated; transcriptionally off
References
Warren ST, Nelson DL: Advances in molecular analysis of fragile X syndrome. JAMA 1994; 271:536-542.
Kooy RF, Willemsen R, Oostra BA: Fragile X syndrome at the turn of the century. Mol Med Today 2000; 6:193-198.
Jin P, Warren ST: Understanding the molecular basis of fragile X syndrome. Hum Mol Genet 2000; 9:901-908.