Block 7 Michigan Genetic

Not all genes on the X chromosome are inactivated during Lyonization. Two genes on the short arm of the X chromosome which are not inactivated are the Xga antigen gene and the steroid sulfatase gene. There are also genes on the long arm of the X chromosome which are not inactivated, because they are needed to maintain ovarian function until menopause.

The false negative rate is the number of affected individuals who test negative divided by the total number of negative test results. This is C/(C + D) for the table shown.

Anticipation may be defined as "increasing severity and earlier age of onset in successive generations". Anticipation is most often due to the gradual expansion of a trinucleotide repeat element in the gene whose mutation causes the disease. Myotonic muscular dystrophy is caused by the expansion of a GCT repeat in the 3' untranslated region of the gene. Normal individuals have 5-35 copies of the repeat, while patients with MMD always have greater than 50 copies, and some patients have greater than 1000 copies. Expansion of these trinucleotide repeats occurs primarily when the gene goes through female meiosis. In fact, congential MMD, caused by trinucleotide expansions containing thousands of copies, is caused only by alleles that are inherited maternally.
Other genetic disorders caused by the expansion of trinucleotide repeats include fragile X syndrome and Huntington disease.

Aneuploidy is when the chromosome number is not an exact multiple of the haploid number. Down syndrome (trisomy 21), Turner syndrome (45, X), and Klinefelter syndrome (47, XXY) are all examples of aneuploidy. In contrast, Fragile X syndrome is characterized by expansion of a CGG triplet repeat in the first exon of the FMR-1 gene on the long arm of the X chromosome, with the total chromosome number not being affected (i.e. still euploid).

Since Huntington's disease (HD) is caused by a single, known mutation, a PCR test can provide direct diagnosis without the need to test other family members. HD is caused by the expansion of a CAG repeat in the coding region of the HD gene, huntingtin. The CAG repeat ranges from 10-30 copies in length in normal chromosomes and from 36-121 copies in length on HD chromosomes.

Screening tests are aimed at identifying a subset of the population for which more specific diagnostic tests are applicable. Therefore a successful "screening" program does not need to have 100% positive predictive value.

Genetic counseling must be nondirective to respect the autonomy of the patient. Autonomy is synonymous with self-determination, self-rule, or self-governance. In genetic counseling, the patient should be given as much information as possible so that he/she can make the best decision possible for himself/herself (which will not be the same decision for all patients).

A negative LOD score of

Sensitivity if defined as the number of affected individuals who test positive for the disease out of the total number of affected individuals. For the table shown, this is equal to A/(A + C).

A way to remember this is "positive in disease" or PID, because PID (pelvic inflammatory disease) is a sensitive topic.

The false positive rate is the number of unaffected individuals who test positive out of the total number of positive test results. For the table shown, the false positive rate is equal to B/(A + B).

To work this problem draw out the family lineage, calculate the risk of having the CF gene at each branch and multiply each risk. The parent of this woman through whom she is related to her first cousin has a 1/2 chance of carrying the mutant CF, this parental sib has a 1/2 chance of carrying the allele and this person's child (the first cousin) also has a 1/2 chance of carrying the mutant allele. Cumulative risk = 1/2 x 1/2 x 1/2 = 1/8 that the first cousin has a mutant allele. Then the risk to have an affected child is 1 x 1/2 x 1/8 x 1/2 = 1/32.

Conversion of a proto-oncogene into an oncogene is characterized by activation of the gene so that it loses normal control and functions inappropriately in cell growth. Thus an event that inactivates the gene, like the action of telomerase, would not be expected to activate it.

The most likely recombination fraction (), is that which gives the highest positive lod score (). For this question, the highest lod score is when =0.10. To change this to centimorgans, use the conversion that 1 cM is equal to a 1% or 0.01 recombination frequency between the two loci. Therefore, =0.10 means that the two loci are separated by a distance of approximately 10 cM.

The father (I-1) has 2 different alleles at the RFLP analyzed, one 10kb in size and one 6kb in size. The mother (I-2) has the same 4kb allele for this RFLP on each copy of her chromosome 13. The affected daughter (II-2) received two copies of the 6kb allele from her father and one copy of the 4kb allele from her mother. The non-disjunction event must have occurred in paternal meiosis II, as this is the stage when the identical sister chromatids separate.
NOTE: If an affected daughter had received 2 copies of the maternal 4kb allele, it would be impossible to determine if the non-disjunction event had occurred during maternal meiosis I or maternal meiosis II.

B-thalassemia major is characterized by very little or no -globin. This results in the formation of  homotetramers (a4) which precipitate in the RBCs causing RBC destruction in the bone marrow and spleen. Increasing a-globin production would only exacerbate homotetramer formation and worsen the patient's condition.

Specificity is defined as the number of unaffected people who have a negative test result out of the total number of unaffected people. For the table shown, this is D/(B + D).

Specificity can be remembered as "negative in health" or NIH.