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What causes Fragile X?

-A portion of X chromosome dangles by a thread and leads to the MC form of mental retardation (1/1000 males)- most widespread single gene cause of autism.
- Unstable CGG repeat at Xq27.
-Expansion from pre to full mutation only occurs thru FEMALE meiosis.
-Severity of dz correlates with # of CGG repeats.
-Expansion of CGG affects the FMR1 (Fragile X mental retardation 1) gene on X chromosome—> failure to express a protein required for normal neural development


Results from XYY?

-Taller than average men.
-“Aliens 3 Syndrome” Clinical phenotype is normal (other than tall stature). NOT excessively violent. (An error in chromosome separation during anaphase II of meiosis II resulting from a process known as nondisjunction leaves sperm cells with an extra copy of the Y-chromosome). This = XYY which occurs in 1/1000 MALE births.


What is Klinefelters?

-47,XXY: “Hermaphrodite disorder”
-Highly misunderstood, predominantly male phenotype, actual presence of both sex organs is exceedingly rare. Hypogonadism = Low testosterone and LH/FSH (not so much testicular atrophy). Weaker muscles and reduced strength, taller than average later. Less muscle, less facial and body hair, broader hips, larger breasts, weaker bones, lower energy. By adulthood males are similar to XY people, mb taller. Mb infertile.


3 places in the cell that proto-oncogenes can become oncogenes?

receptors, messenger systems and nuclear transcription


What can go wrong with receptor synthesis?

amplification and point mutation


Know the 5 points of control

1) Chromatin: Histone methylation. Target sites of histone methylation are cytidines which exist as CG (CpG. Areas with lots of them are CpG islands) Methylation of CpG down regs transcription. Histone acetylation- add an acetyl group, stop further condensing of DNA- encourages active transcription. Generally, methylation upregs transcription and demethylation inhibits. Methyl, Acetyl and Phosphate groups are ones that modify histones.
2) Transcription- Promoters CCATT and TATA boxes. Are in all protein coding genes. Exon shuffling, enhancers (transcription factors bind to enhancer regions)
3) Translation- RNA transport (exportins). Importins and exportins are regulated by GTPases called Ran
4) Post-translation into cytoplasm- Cap/ tail communication
5) Post-translation modification


Trisomy 21

Down syndrome – extra chromosome
40% with congenital heart defects, increased risk of ALL, reduced infertility


Trisomy 18 Edward Syndrome

Very poor prognosis, AVSD, PDA, hand and foot malformations, low set ears, micrognathia


Trisomy 13 – Patau syndrome

Polydactyly, cleft palate, microphthalmia (small eyes), microcephaly, cardiac and renal defects, very poor prognosis


Turner syndrome

45,X - 46, XX-47, XXX
Only monosomy consistent with life (bc it’s autosomal)
50% are 45,X. The rest are mosaics with 46, XX and 47, XXX occurring in different cells. Arising from X-chromosome monosomy, Turners’s syndrome results in marked short stature, ovarian dysgenesis and neurocognitive problems. Significantly greater adult height treated with growth hormone injections


What can go wrong with the cells messenger system

point mutation and translocation


Translocation of chromosome 9,22 on tumor suppressor gene causes Philadelphia chromosome leads to?



Translocation of 15,17 leads to?



Translocation of 14,18 leads to?

follicular lymphomas


Translocation of 8,14 leads to?

Burkitt’s lymphoma


Translocation of 11,14 leads to?

mantle cell lymphoma


Contrast and compare oncogenes and tumor suppressors. i.e. which provide gain of function and which loss of function. Which process requires just one allele to be bad and which requires the two hit process?

Oncogenes = gain of function; needs mutation in one copy of allele
Tumor suppression = loss of function; needs mutation in both copies allele


Are tumor markers usually used to diagnose cancer? If not what are they used for?

We use tumor markers to detect the presence of certain types of cancer in the body, and to monitor the progress of cancer treatment.


What is the difference between Northern Blot, Southern, Western and Dot Blots?

-Southern blot: analyzes DNA fragments on a gel electrophoresis using a probe
-Northern blot: analyzes RNA fragments on a gel electrophoresis using a probe
-Western blot analyzes proteins on gel electrophoresis using enzyme linked antibody
-Dot blot is used in medical genetics to analyze RNA, DNA, or proteins and DOES NOT use electrophoresis


What is gene linkage? How is it used for mapping?

-Linkage maps: distance is measured in the frequency of recombination of coupling arrangements of alleles on linked genes
-If the gene of interest and the marker are on different chromosomes, the alleles will remain together in an egg or sperm only about 50% of the time and thus are unlinked.
-If the gene and marker are on the same chromosome but are far apart, the allesles will remain together about 50% of the time, and are also said to be unlinked.
-If the gene and marker are close together on the same chromosome, a crossover between the two alleles is much less likely to occur and show less than 50% recombination and thus are said to be linked.


What types of DNA polymorphisms are there? Which type is used for paternity testing and forensics?

-RFLP) The presence or absence of a restriction site produces DNA fragments of varying lengths, reflecting sequence variation
-VNTR) variation in fragment lengths is produced by differences in number of tandem repeats located between 2 restriction sites. ***Used for paternity testing and forensics
-STRP) variation in fragment lengths is produced by differences in the number of microsatellite repeats found between 2 PCR primer sites
-SNP) are single differences in a nucleotide sequence


Which polymorphism occurs in Huntington disease and Fragile X?



What is the difference in fetal loss rates between amniocentesis and CVS? How soon in pregnancy can each procedure be done?

-Amniocentesis at 16 weeks, risk of fetal demise is 0.5%
-Chorionic Villus sampling (CVS) done at 10-12 weeks, fetal mortality rate is 1%


When can cfDNA be taken from the mothers blood, and how does cfDNA work

9 weeks, it’s a blood test that separates fetal DNA from maternal DNA


What is the function of BRCA1 and BRCA2? What happens if it becomes mutated? Do men get cancer from these mutations? If so what types?

- BRCA1: caretaker gene, produces breast cancer type 1 susceptibility protein, responsible for repairing damaged DNA or destroying it if not repairable, expressed in mammillary cells and other tissues. If mutated -> various cancers
-BRCA2: fx similar to BRCA1 but the mutated protein is much different, binds single strand DNA (BRAC1 – double strand) an ddirectly interacts with the recombinase RAD51 to stimulate strand invasion and recombination
**Breast and ovarian cancer are risks of defective BRCA genes
** males with defective BRCA are at risk for breast CA, melanoma, GB, bile duct, pancreatic and stomach CA, males with BRCA2 -> risk of prostate CA


What is the function of RAD51?

In the nucleus of many types of normal cells the BRCA1 protein interacts with RAD51 during repair of DNA double strand breaks. BRCA2 binds single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion and recombination


What is the founder effect? In which country is virtually all breast- ovarian cancer (HBOC) a result of just 1 person?

All germ-line BRCA1,2 mutations have been inherited, suggesting a large “founder” effect in which a certain mutation is common to a well-defined population group and can, in theory, be traced back to a common ancestor.
Ashkenazi Jews


What types of DNA breaks does the BRCA1 repair?

Double strand


What types of DNA breaks does the BRCA2 repair?

Single strand


Which test is ordered if the person is of Ashkenazi Jewish decent?

a multisite 3 point BRCA analysis


If a person has a relative where the gene mutation is already known, what test is ordered?

a single site BRCA test


What does the Hardy-Weinberg Principle contend?

Provides a solution to how variation is maintained in a Mendelian population. It contends that the frequencies of alleles will remain constant in the absence of selection, mutation, migration and genetic drift.


What is Beckwith–Wiedemann Syndrome and what is its significance?

Overgrowth disorder that is usually present at birth, characterized by an increased risk of childhood cancer and certain congenital features such as abdominal wall defects as hernia, large tongues, and large bodies and or limbs, large adrenal glands, diastasis recti, ear crease or ear pits and neonatal hypoglycemia


List some good and bad points to DTC direct to consumer genetic testing

good: potentially lifesaving information
bad: inconsistent, false positives/negatives, may not be scientifically validated, result interpretation not always easy, information may be incomplete, anxiety provoking, next steps unclear, not covered by insurance, expensive, not covered by HIPAA


How has CMA testing increased the yield in genetic testing?

Microarray-based CGH to detect changes in genomic copy number, more than any other single test, has dramatically increased rate of diagnosis among individuals with unexplained developmental delay and mental retardation


How do the genetics of MTHFR work? (i.e. 667 &1298 mutations)

MTHFRR is a key regulatory enzyme in folate and homocysteine metabolism. Disruption of homocysteine influences risk of several complex disorders


Know the NCCN guidelines for people why are at increased risk of breast or ovarian cancer, but do not have the well-known BRCA1 or 2 mutations

consider comprehensive BRCA1/BRCA2 testing of patient or if unaffected, test family member with highest likelihood of mutation OR consider multi-gene testing, if appropriate.


What are the common indications for genetic testing?

Family history, personal hx of ovarian carcinoma or male breast CA, personal hx prostate CA, pancreatic CA


What type of abnormality is the CMA test looking for in terms of mutations

looks for very small deletions (<1MB)


How is GDD distinguished from other disorders causing intellectual delay?

CGH broad genomic coverage, with chromosomal microarray


What is XLID? What is its significance?

X-linked genetic testing
X-linked intellectual disability (XLID) is estimated to account for approx. 10% of all cases of intellectual delay (ID). More than 70 genes responsible for XLID in which mutations have been identified have been cloned. There are more than 100 genes that have been identified by linkage and not yet cloned.