human and molecular genetics

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tumor suppressor genes

"Gatekeepers" regulate the cell cycle and initiate apoptosis both copies must be mutated ex- APC, RB, TP53

Monosomies

(1 copy of a chromosome)

Trisomies

(3 copies of a chromosome)

Tetrasomies

(4 copies of a chromosome)

When mutations occur in germline cells, there is a risk to pass on a genetic condition to offspring.

- Appears as if the child has a de novo (new) mutation, but the family has an increased risk to have additional children with the same condition

Cancer can occur when there are somatic or germline mutations in genes that control:

- DNA repair - Cell cycle check points - Growth promotion - Apoptosis

Molecular Genetics:

- Discuss what are variants and the different types of variants that occur in cells. - Discuss the different types of polymorphisms.- Discuss the different types of DNA repair mechanisms. - Describe what are oncogenes and tumor suppressor genes. - Discuss current molecular testing methods for detecting variants.

Whole exome sequencing (WES)

-uses similar technology as WGS, but targets only protein-coding regions of DNA that are most likely to have a functional role -these sequencing changes are the cause of many well-known genetic diseases

how do gene mutations occur?

1. DNA replication errors -proofreading mechanisms error 2. DNA repair errors -caused by chemical mutagens, radiation

Structural Rearrangements

1. Microdeletions annd Microduplications 2. Translocations 3. Inversions

DNA repair mechanisms in ssDNA

1. base excision repair (BER) 2. Nucleotide excision repair (NER) 3. Mismatch repair (MMR)

types of variants (mutations)

1. base pair substitution 2. deletion 3. insertion 4. inversion 5. duplication 6. trinucleotide repeat expansion

DNA repair mechanisms in dsDNA

1. homologous recombination 2. non-homologous end joining (NHEJ)

Most aneuploidy conceptions are not compatible with life. *Exception for chromosomes

13, 18, 21, X, and Y

Meiosis

2 rounds of cell division result in egg or sperm (germ cells) Each germ cell has half the genetic information that the parent cell had Crossing-over leads to germ cells that are genetically unique = increase in biodiversity

Microdeletions and duplications mediated by segmental duplications are recurrent due to their underlying mechanism. Which of the following disorders is the most common recurrent microdeletion syndrome? A. Aniridia-Wilms tumor B. Retinoblastoma C. Prader-Willi syndrome D. VCF/DiGeorge syndrome E. Cri-du-chat syndrome

22q11 deletion syndrome--including DiGeorge syndrome and VCF (velocardiofacial syndrome) is the most common deletion syndrome in humans, occurring in ~1/4000 births. This is a common, recurrent microdeletion mediated by NAHR of flanking low-copy repeats (LCRs). Other LCR genomic disorders (PWS, AS, Williams, Smith-Magenis, Sotos) occur at ~1/10,000- 1/20,000. Random deletion syndromes such as cri du chat, Wolf-Hirschhorn, Miller-Dieker syndrome, retinoblastoma, aniridia-Wilms tumor are less common (1/50,000-1/100,000 or less). The correct answer is D.

A balanced reciprocal translocation is observed in cells from an amniotic fluid sample. What should your next step be? A. Chromosome analysis on the parents to see if one has the same translocation B. High resolution banding to better determine the chromosome breakpoints C. Microarray studies to determine which genes are affected by the rearrangement D. No additional studies since the translocation appears balanced. E. Prenatal screening test for alpha-fetoprotein and human chorionic gonadotrophin

A couple has a child with Down syndrome who has a karyotype of 47,XY,+21. The probability for their next child to have Down syndrome is closest to: A. 1% B. 5% C. 10% D. 15% E. 33.30%

A patient has mosaic Down syndrome. Which one of the following is least likely to result in this phenotype? A. Dispermy B. Fusion of a zygote with a karyotype of 46,XX with another zygote with a karyotype of 47,XX,+21 C. Fusion of a zygote with a karyotype of 46,XX with another zygote with a karyotype of of 46,XX,-21,=rob(21q21q) D. Meiotic non-disjunction with anaphase rescue during mitosis after fertilization E. Mitotic non-disjunction after fertilization

A patient with the karyotype 46,XX,t(1;5) has A. A balanced translocation between chromosomes 1 and 5 B. An unbalanced translocation between chromosomes 1 and 5 C. A chromosomal aneuploidy D. A ring chromosome E. A Robertsonian translocation

About 90% of trisomy 21 Down conceptions are due to nondisjunction during a) meiosis I in the female. b) meiosis II in the female. c) meiosis I in the male. d) meiosis II in the male.

Comparative genomic hybridization (CGH) is one method that can be used for copy number variation (CNV) detection. Which of the following issues is a limitation of this methodology compared to a G-banded karyotype? A. Cannot detect polyploidies B. Cannot detect single copy differences C. Cannot detect unbalanced translocations D. Lower resolution than G-banded karyotype E. Requires cells to be cultured

During your time in the Genetics clinic you are asked to call the cytogenetics lab for results of a peripheral blood analysis for a healthy 34-year old man with a history of infertility. The lab faxes over the report which reads: 46,XY,t(9;22)(p22;q13) What is the most likely interpretation of these results? A. He has a balanced translocation between 9p and 22q B. He has an unbalanced translocation between 9p and 22q C. He has the Philadelphia translocation and should see an oncologist immediately D. He has a balanced translocation between 9q and 22q E. He has an unbalanced translocation between 9q and 22q

FISH testing is not used in routine diagnosis of cystic fibrosis (CF). The reason is that A. FISH is better for detecting large deletions and most CF mutations are point mutations or small deletions B. FISH is better for detecting point mutations and most CF mutations are large deletions C. FISH is better for detecting translocations and most CF mutations are not caused by translocation D. FISH is not appropriate for detecting homozygous mutations E. Other genes related to the CF gene may make the background too high for FISH

In a (an)____, the short arm of two acrocentric chromosomes break, and the long arms join, forming an unusual, long chromosome. a) Robertsonian translocation b) reciprocal translocation c) inversion d) duplication

In a cytogenetics laboratory, the prometaphase preparation differs from the metaphase preparation in that in the prometaphase preparation: A. The chromosomes appear longer and banding resolution is higher B. The chromosomes appear longer and the banding resolution is lower C. The chromosomes appear shorter and the banding resolution is higher D. The chromosomes appear shorter and the banding resolution is lower E. the chromosomes are the same length as is the banding resolution

Microarray-based comparative genomic hybridization studies are well suited for the detection of all of the following except: A. Balanced chromosomal translocations B. Deletion C. Duplication D. Monosomy E. Trisomy

Mosaicism differs from chimerism in which one of the following ways? A. Mosaics are derived from one zygote while chimeras arise from the fusion of two (or more) different zygotes or embryonic stem cells B. Chimeras are genetically identical from cell to cell, except for one locus, while mosaics differ at multiple alleles at many loci C. All females (with a randomly inactivated X chromosome in every nucleated cell) are mosaic while all males (X chromosome from their mother and Y chromosomE from their father) are chimeras D. Mosaics have heterogeneous germ cells only while chimeras have heterogeneous somatic cells only E. While one can be mosaic to varying degrees one cannot be chimeric to varying degrees

The short arms of chromosomes 13, 14, 15, 21 and 22 contain multiple copies of ribosomal RNA genes. Deletion of one or more of these short arms is generally inconsequential. Because of the almost negligible length of the short arms, these chromosomes are called A. acrocentric chromosomes B. isochromosomes C. metacentric chromosomes D. ring chromosomes E. submetacentric chromosomes

The technique in which equal amounts of patient DNA and control DNA is used to compete for binding to a large number of DNA templates is called A. comparative genomic hybridization B. DNA library screening C. in situ hybridization D. real-time polymerase chain reaction E. Southern hybridization

Using a probe that detects the telomeres of all chromosomes during interphase in a fluorescence in situ hybridization study, you observed 90 dots of light per cell nucleus. Which one of the following karyotypes is most compatible with the study results? A. 45, -21,-22,+t(21;22) B. 46, XY C. 46, XY,-7,+der(7)t(7;15) D. 46, XY,-22,+t(21;22) E. 46, XY,t(7;15)

Which of the following individuals has the LOWEST risk of generating abnormal offspring? A. A carrier of a paracentric inversion B. A carrier of a Robertsonian translocation C. A carrier of a balanced reciprocal translocation D. A carrier of a pericentric inversion

Which one of the following DNA elements ensures correct segregation of homologous chromosomes during meiosis and mitosis? A. Centromeres B. Nucleosomes C. Origins of replication D. Satellites E. Telomeres

Which one of the following cytogenetic abnormalities found in a first trimester fetus results in the highest rate of spontaneous fetal loss? A. 45,X B. 47,XX,+18 C. 47,XX,+21 D. 47,XXX E. 47,XXY

Which one of the following cytogenetic abnormalities is expected to yield abnormal results when fluorescence in situ hybridization (FISH) using probes for the sub-telomeric regions of all 24 chromosomes (22 autosomes, X and Y) is performed? (Note: all probes are labeled with the same fluorochrome) A. 45,X/47,XXX B. 46,XY,t(4;8)(p22;q32) C. 46,XY,del(15)(q11-q12) D. 46,XY,dup(15)(q11-q12) E. 46,XY,inv(9)(q21q31)

Your fellow medical student confided in you that she has not attained menarche yet, and became worried after an endocrinology lecture that the class attended recently. Her past medical history is unremarkable except for an inguinal hernia repair in infancy. Family history was unremarkable, except for an aunt who could not bear children. She also revealed that her primary care physician was puzzled at her recent school physical that she had no pubic hair, but has fully developed breasts. You suspect a genetic cause for her primary amenorrhea. What is the most likely result of her chromosome analysis? a. 46,XY b. 45,X c. 46,XY/46,XX d. 47,XYY e. 45,X/46,XX

Your patient is a 4-year old boy with developmental delay. You order a whole genome comparative hybridization array (array CGH), and it comes back normal. Which of the following underlying explanations for developmental delay would this test be least likely to detect? a. Fragile X syndrome b. Down syndrome c. 22q11 deletion syndrome d. A de novo 1 Mb deletion on chromosome 15q e. A subtelomere rearrangement

tetraploidy

A condition in which there are 92 complete pairs of chromosomes in humans.

Huntington's disease

A human genetic disease caused by a dominant allele; characterized by uncontrollable body movements and degeneration of the nervous system; usually fatal 10 to 20 years after the onset of symptoms.

triploidy

A rare chromosomal abnormality in which fetuses are born with an extra set of chromosomes in their cells.

Nondisjunction of chromosome 21 during meiosis II in human females can result in all of the following chromosome complements in a zygote except (assume the oocyte is fertilized by a sperm with a normal chromosome set) a) no chromosome 21. b) euploid for chromosome 21. c) monosomic for chromosome 21. d) trisomic for chromosome 21.

A. Nondisjunction of chromosome 21 during meiosis II in human females cannot result in no chromosome 21 in the zygote

gene therapy vectors

AdV, AAV, Retroviruses, HSV, Liposomes, and naked DNA are examples of _______________________.

68 billion

After 30-35 cycles of PCR, you should be left with about __________________ copies of DNA.

balanced translocation

All genetic material is present, just rearranged Robertsonian - occurs in the 5 acrocentric chromosomes (13, 14,15, 21, 22)

A young woman is found to have a balanced translocation after a family history and pedigree analysis, during a preconception counseling visit, raised a red flag for a chromosomal abnormality. Based on this clinical finding, which of the following statements about chromosomal segregation and possible offspring is the most likely clinical outcome? A. Offspring resulting from alternate segregation will be chromosomally normal. B. Offspring resulting from alternate segregation are likely to be phenotypically normal. C. Offspring resulting from adjacent-1 segregation will be chromosomally normal. D. Offspring resulting from adjacent-1 segregation are likely to be phenotypically normal. E. Offspring resulting from adjacent-2 segregation are likely to be phenotypically normal.

Alternate segregation results in normal gametes and in gametes with balanced chromosomal translocation. Thus the offspring are phenotypically normal but not chromosomally normal in all cases. Offspring from adjacent-1 or adjacent-2 segregation will all be unbalanced and all will be chromosomally abnormal. They would also be phenotypically abnormal, except in very unusual circumstances. Adjacent segregation-1 is when homologous centromeres segregate, in contrast to adjacent-2 where the homologous centrmorees go to the same cell. Adjacent-2 is rare compared to adjacent-1. The correct answer is B.

Aneuploidy

Any deviation from the haploid number (n = 2) of a specific chromosome. One or more extra or missing chromosomes.

chromosomal karyotyping

Applications: - Aneuploidy - gross/large structural changes of entire genomes (trisomies, turner, etc) - Dx of specific anomalies (Philedelphia chromosome in CML) - Deletions w/varying sizes in a given chromosome (multiple myeloma) What cytogenetic technique does this describe?

metaphase

At which stage of mitosis are chromosomes usually photographed in the preparation of a karyotype?

A couple (both chromosomally normal) has a child with trisomy 21. Assuming the Down syndrome was caused by nondisjunction in maternal meiosis I, use the genotypes given to predict the mother's genotype. Genotypes for a chromosome 21 marker with two possible alleles: Father: [2,2] Down syndrome child: [1,2,2] Based on the information given, the mother's genotype is: A. 1,1 B. 1,2 C. 2,2 D. Uninformative; cannot be predicted

A man, Donald, with X-linked hemophilia, and a healthy woman, Shirley, whose father had X-linked hemophilia, have a healthy son, Kiefer, with Klinefelter syndrome (47, XXY). The son undergoes testing and is shown not to be a carrier of hemophilia. When was non-disjunction most likely to occur? A. maternal meiosis I B. maternal meiosis II C. paternal meiosis I D. paternal meiosis II E. Cannot tell from the information provided

An 18-year-old woman presents with primary amenorrhea and short stature. Physical exam reveals neck webbing, a low posterior hairline, a broad chest with widely spaced nipples. Which of the following is the most appropriate method for confirming her genetic disorder? A. Biochemical Testing B. Cytogenetic analysis C. Linkage analysis D. DNA methylation analysis E. PCR multiplex deletion test

An individual with the chromosomal description 45, X would be a: a) normal female. b) female with Turner syndrome. c) male with Klinefelter syndrome. d) cannot be determined.

Array CGH (array comparative genomic hybridization) is a microarray based technology that can be used alone or in addition to more traditional cytogenetic testing. Of the following options, which abnormality is most likely to be detected by array CGH? A.Balanced rearrangements including pericentric and paracentric inversions B.Small terminal deletions and duplications C.Partial loss of acrocentric short arm material D.Most Robertsonian translocations (except those involving homologous chromosomes) E.All categories of inherited (familial) chromosome rearrangements

Exchange of genetic material (crossing-over) between homologous chromosomes occurs during which phase and which division of meiosis? A. Interphase B. Prophase I C. Prophase II D. Metaphase I E. Metaphase II

In G-banding, the non-centromeric dark bands represent: A. α-satellite repeats B. AT-rich regions of chromatin C. euchromatin D. GC-rich regions of chromatin E. gene-rich regions of the chromosome

In nondisjunction, which parent leads to the sex chromosome aneuploid XYY? a) mother b) father c) either parent d) both parents

Klinefelter syndrome (47,XXY) is most often caused by meiotic nondisjunction. Of the following options, which error can be EXCLUDED as a potential cause of this chromosome abnormality? A.Male meiosis I nondisjunction B.Male meiosis II nondisjunction C.Female meiosis I nondisjunction D.Female meiosis II nondisjunction

Microdeletion syndromes are relatively rare, yet are a clinically important class of genetic disorders. Of the following statements, which provides the most likely etiology giving rise to microdeletions? A. Nondisjunction is more likely in older mothers. B. Low-copy repeats increase the chance of unequal crossovers. C. Linkage disequilibrium gives rise to haplotype blocks. D. Homologous chromosomes should segregate during meiosis I. E. SNPs are abundant and located throughout the genome.

Telomerase contains A. a single-stranded DNA template for elongation of the 3' overhang at the end of a chromosome. B. a single-stranded RNA template for elongation of the 3' overhang at the end of a chromosome. C. a single-stranded DNA template that makes Okazaki fragments for lagging strand synthesis unnecessary during telomeric extension. D. a single-stranded RNA template that makes Okazaki fragments for lagging strand synthesis unnecessary during telomeric extension. E. no nucleic acid component.

The photographic arrangement of chromosomes is called a (an) a) karyotype. b) idiogram. c) anagram. d) chromogram.

When you study the chromosomes of a patient using a fluorescence in situ hybridization (FISH) probe that detects all centromeres, you detect 46 dots of light. However, when instead you use a FISH probe that detects a gene of the long arm of the X chromosome, you see 3 dots of light. Which one of the following karyotypes is consistent with these findings? A. 45,X B. 46,X,i(Xq) C. 46,XX/47,XXX D. 47,XXX E. 47,XXY

Which one of the following represents an unbalanced translocation? A. 45, XY,-15,-22, +rob(15q;22q) B. 46, XY,-8,+der(8)t(8;20)(p12;q13) C. 46, XY,t(8;20)(p12;q13) D. 47, XXX E. 69, XXX

You see a 4-year-old in clinic with delayed milestones, cleft palate, history of a ventricular septal defect (VSD) repair, and lack of a thymus. The most appropriate genetic test to order is: A. Chromosome analysis to look for an extra chromosome B. FISH analysis to look for a deletion C. Whole genome sequencing as the specific mutation is not known D. Microarray testing to assess for a gene duplication

____ contains protein-encoding genes. a) heterochromatin b) euchromatin c) pericentric inversions d) aneuploids

Structural chromosome abnormalities result from an assortment of molecular mechanisms. Our knowledge is most complete for which of the following specific molecular mechanisms? A. terminal deletion B. interstitial deletion C. isochromosome D. reciprocal translocation E. ring chromosome

B is correct. Common, recurrent micodeletions (22q11, 17p11, 15q11-q13, etc.) are interstitial deletions with flanking low-copy repeats (LCRs) with very high sequence homology. In meiosis, mispairing of proximal and distal copies (non-allelic homologous recombination, NAHR), leads to unequal cross-over producing deletion or duplication. Specific mechanisms at a sequence level are not known for other classes of structural chromosome rearrangements. The correct answer is B

base excision repair (BER)

Base is removed from DNA backbone (deoxyribose) Then replaced with correct base

repair mechanisms that correct errors in DNA sequences

Base, Nucleotide excision and mismatch

differential methylation

Beckwith-Wiedmann Syndrome - Deletion of the __________________ region will result in overexpression of genes on chromosome 11.

Beckwith-Wiedmann syndrome - Chromosome ______ - 20-30% uniparental paternal disomy - 50-60% improper methylation

Chorionic villus sampling is performed on a 38-year-old woman who is concerned about having a child with a chromosomal disorder. Which one of the following karyotypes carries the highest risk for this woman to deliver a chromosomally abnormal livebom? A. 45,XX,der(13;14)(q10;q10) B. 45,XY,der (14;21)(q10;q10) C. 46,XY,inv(2)(p11.2q13) D. 46,XX,inv(2)(q31q35) E. 46,XX,t(11;22)(q23;q11.2)

Both maternal and paternal carriers of rob(13q14q) have about a 1% chance of having a child with translocation trisomy 13. Fathers who carry rob(14q21q) have less than a 1% chance of having a child with translocation Down syndrome. Both types of inversions, regardless of the parental origin, have almost no chance of abnormal offspring. The pericentric inversion (C) is a common inversion found in the population and the paracentric inversion (D) would result in nonviable dicentric and acentric products. Mothers who carry the t(11;22) are at a 6% risk for an abnormal offspring typically have 47 chromosomes with a small extra der(22) and have mental retardation and other anomalies. The correct answer is E.

A (an)____ chromosome has its centromere near a tip so that it has one long arm and one very short arm. a) metacentric b) submetacentric c) acrocentric d) none of the above

A 12 week fetus is noted to have a significantly increased nuchal translucency on ultrasound scanning. CVS is performed. What is the most likely karyotype finding? A. 47,XX,+13 B. 47,XX,+18 C. 47,XX,+21 D. 47,XXX

A 15-year-old boy is evaluated by a clinician for failure to develop normal male secondary sexual characteristics. Physical examination reveals small testes, a small penis, and gynecomastia. The boy has had some difficulties in school, but cognitive development is within normal limits. The child's condition is most likely due to which of the following? A. Deletion B. Nondisjunction of an autosome C. Nondisjunction of a sex chromosome D. Reciprocal translocation E. Robertsonian translocation

A 3-year-old female presents with short stature and her chromosome study shows a 45,X/46,X,+mar mosaic karyotype with a small marker chromosome of unknown origin. What is your major concern for this child? A. delayed onset of puberty B. developmental delays C. increased risk for gonadoblastoma D. increased risk for leukemia E. stigmatization due to stature

A man is found to have 45 chromosomes because his two chromosome 21s are joined at the centromere to form a single chromosome (i.e. 21/21 Robertsonian translocation). Which statement is true about his gametes? A. He has 23 chromosomes in each of his sperm. B. He has 22 chromosomes in each of his sperm. C. He has a mixture of sperms, some of which have 22 chromosomes and some have 23 chromosomes. D. He has 45 chromosomes in each of his sperm

A triploid human karyotype has how many chromosomes? a) 23. b) 46. c) 69. d) 92.

A two year old boy exhibits cognitive impairment, low set ears, Brushfield spots (speckled iris), a depressed nasal bridge and epicanthic folds. He is diagnosed with Down syndrome based on the results of a karyotype analysis. Which of the following events was the most likely cause of his condition? A. Fertilization of an ovum by two sperm B. Genomic imprinting C. Nondisjunction during meiosis D. Mitotic loss E. Reciprocal translocation

Alagille syndrome results from a (an) a) inversion. b) duplication. c) translocation. d) isochromosome

An individual with two normal sets of autosomes and a single X chromosome has a) Down syndrome. b) Patau syndrome. c) Turner syndrome. d) Klinefelter syndrome.

Approximately ____ percentage of spontaneous abortions result from extra or missing chromosomes. a) 10 b) 25 c) 50 d) 75

Consider the following normal sequence of genes: a b c d e f g h. The sequence a b f e d c g h represents a (an) a) deletion. b) duplication. c) inversion. d) translocation.

Heterochromatic regions at the ends of chromosomes are called a) centromeres. b) euchromatin. c) telomeres. d) satellites.

How many chromosomes does a person with Edward syndrome have? a) 45 b) 46 c) 47 d) 48

In a chromosomal analysis using G-banding ("routine" chromosomal analysis), a chromosome is noted to be dicentric (having two centromeres). Based on what you know about centromeric behavior, which one of the following is most likely to be true? A. An isochromosome will form in the next cell division. B. A ring chromosome will form in the next cell division. C. One of the two centromeres will be functionally suppressed because each chromosome can only "tolerate" one centromere. The mechanism of this suppression is unknown. D. The cell will die in the next cell division because this chromosome will break into multiple fragments which will be degraded. E. This dicentric chromosome will be entirely deleted from the genome.

In the following cytogenetic descriptions, which one suggests the highest dosage of genes from chromosome region 3q21-3q23? A. 46,XY,-3,+der(3)t(3;5)(q21;q23) B. 46,XY,del(3)(q21q23) C. 46,XY,dup(3)(q21q23) D. 46,XY,inv(3)(q21q23) E. 46,XY, t(3;5)(q21;q23)

Males with balanced translocations are at increased risk for which of the following conditions? A. coronary artery disease B. diabetes C. infertility D. prostate cancer

Of the following options, which ONE occurs in BOTH mitosis and meiosis? A. Homologs pair B. The ploidy level changes C. Sister chromatids segregate D. Two cell divisions occur E. Crossing-over occurs

The most common cytogenetic mechanism leading to Down syndrome is: A. Post-fertilization mitotic error B. Robertsonain translocation C. Maternal meiosis I nondisjunction D. Paternal meiosis II nondisjunction

The use of whole genome analysis of all gene coding regions has recently become technically feasible for clinical testing. What technology has allowed for simultaneous, rapid assessment of the entire genome at a low cost? A. DNA microarray B. Genome wide association study C. Next generation sequencing D. Polymerase chain reaction (PCR) E. Single nucleotide polymorphism (SNP) genotyping

When chromatids divide along the wrong plane, structures with identical arms called ____ are formed. a) ring chromosomes b) translocations c) isochromosomes d) satellites

Which of the following cell types is not used to examine chromosomes? a) white blood cells b) bone marrow cells c) red blood cells d) all of the above can be used

Which of the following individuals is MOST likely to be phenotypically normal? A. A person with the karyotype 45, X B. A person with a deletion of a single band on chromosome 4. C. A person with a pericentric inversion of chromosome 6. D. A person with the karyotype 47, XX +21 E. A person with the karyotype 46, XX,rob(14;21),+21

Which of the following provides the best explanation of the reproductive risk observed in carriers of a balanced reciprocal translocation? A.The translocation leads to structural abnormalities in other (previously normal) chromosomes, followed by clonal expansion. B.Nondisjunction causes the majority of gametes to have too much genetic material. C.During meiosis, unbalanced gametes may be produced. D.There is increased risk of unequal crossing over between low copy repeats. E.The translocation tends to be mitotically unstable causing it to be lost from some cells.

Which one of the following cytogenetic abnormalities is least likely to yield abnormal results when chromosomal microarray analysis using comparative genomic hybridization (CMA-CGH) is performed? A. 45,X/47,XXX B. 46,XY,-21,+rob(21q21q) C. 46,XY,t(3;15)(p21;q21) D. 46,XY,del(13)(q12-q22) E. 46,XY,dup(13)(q12-q22)

Which one of the following cytogenetic designations describes a trisomy? A. 45,X B. 46,i(Xq) C. 47,XX,+13 D. 47,XXY E. 69,XXX

Your pediatric patient has trisomy 13, and his parents are concerned that they might have another child with this condition. Which of the following aspects of their family history would suggest an increased recurrence risk compared to most families with a child with trisomy 13? a. Your patient is very severely affected by trisomy 13 b. There is a family history of Down syndrome c. The couple had four miscarriages before their child was conceived d. The mother is 35 years old

Which of the following prenatal testing methods can detect confined placental mosaicism? A. amniocentesis B. chorionic villus sampling C. fetal cells in maternal blood D. maternal blood E. percutaneous umbilical blood sampling

CVS samples chorionic villi from the placenta and can detect the mosaicism. The other tissues sampled do not include placental cells and will not allow for detection of mosaicism confined to the placenta. The correct answer is B.

Telomere

Caps the ends of chromosomes, consists of non-coding repetitive sequences

gene therapy

Challenges: - unwanted immune system reaction - targeting the wrong cells - infection caused by the virus - possibility of causing a tumor - cost This challenges describe what?

trisomy 18

Characteristics: - distinctive facial features - overlapping fingers, rocker-bottom feet - 90% have congenital heart defects (VSD) - severe cognitive impairment and developmental delay

trisomy 21

Characteristics: - dysmorphic features - hypotonia - 30-40% structural heart defects - 15-20X increased risk for leukemia - respiratory infections more common - variable intellectural disability (moderate to mild) What is the diagnosis?

duplication 17

Charcot-Marie-Tooth disease - PNS condition-progressive atrophy of distal limb muscles - Small _______________ on chromosome ___ - includes PMP22 gene-component of myelin - gene deletion results in hereditary neuropathy with liability to pressure palsies

number morphology

Chromosomal karyotyping is a cytogenetic technique whereby ________________ and ________________ of nuclear chromosomes of any cell type can be analyzed.

beckwith wiedemann syndrome

Clinical Features: - overgrowth - macrosomia - growth asymmetry - Organomegaly - kidney, spleen, liver, pancreas - Increased tumor incidence What is the diagnosis

Turner Syndrome

Clinical Findings: - Short stature, webbed neck - infertile, ovarian dysgenesis, lack secondary sex characteristics - congenital heart defects - Normal Intelligence - spatial perception diminished

Klinefelter syndrome

Clinical Findings: - Taller, hypotonia - Mild learning difficulties - 30% gynecomastia - sterile, hypogonadism - Increased risk for: Osteoporosis, breast cancer - Treatment - testosterone to enhance secondary sex characteristics

trisomy 18

Clinical Presentation: - Hypertonia - Prenatal growth deficiency - characteristic fist clench - rocker-bottom feet Whats the DX?

trisomy 21

Clinical Presentation: - Hypotonia - short stature - loose skin on nape - palmar crease - clinodactylyl Whats the Dx?

trisomy 13

Clinical Presentation: - Microcephaly - sloping forehead - characteristic fist clench - rocker-bottom feet - polydactyly Whats the DX?

Cri-du-chat is a chromosomal deletion in chromosome ______ that results in children who are mentally retarded, microcephaly, and have a cry that sounds like a loud cat; they die at a young age.

A baby is born with clinical features of Down syndrome. Karyotype analysis reveals an unbalanced Robertsonian translocation. Which of the following karyotypes is consistent with this diagnosis? A. 47,XY,+21 B. 47,XX,der(13;21)(q10;q10),+21 C. 45,XY,der(14;21)(q10;q10),+21 D. 46,XX,der(21;21)(q10;q10),+21

A blood sample from a dysmorphic infant is sent to the cytogenetics laboratory for karyotype analysis. The laboratory report states that the child's karyotype is "46,XY,4p-". Given these results, should the laboratory perform karyotype analysis on the parents? If yes why, and if no, why not? A. No, because this karyotype is a normal variant and karyotyping the parents will give you little useful additional information B. No, because this karyotype is abnormal, and you require no additional information to make the diagnosis. C. Yes, because this karyotype may be a normal variant, and if one of the parents has the same karyotype it allows you to determine whether it is a normal variant or not. D. Yes, because this karyotype is abnormal, and karyotyping the parents will allow you to determine whether the abnormality arose de novo (is the result of a new mutation). E. Yes, because this karyotype is abnormal and karyotyping the parents will allow you to determine which parent is the carrier for a partial chromosomal deletion.

A couple in their late 20s who have a child with Down syndrome with a 47,XX,+21 karyotype present to you for genetic counseling. Which of the following topics should you discuss with the parents? A. Adults with Down syndrome are at risk for Huntington disease B. Parents should be karyotyped to look for Robertsonian translocations C. This disorder is tested for as part of the state newborn screening program D. The child is at risk for leukemia E. The majority of babies with Down syndrome are born to mothers over age 35

A couple seeks testing and counseling after they have a child with cystic fibrosis. Testing reveals that the mother is a carrier, but the father is not. How can these results be explained? a) the man tested is not the biological father b) a mutation altered the child's normal allele c) uniparental disomy (from the mother) d) all are possible explanations, additional testing is needed

A man is found to have 45 chromosomes because his two chromosome 21s are joined at the centromere to form a single chromosome (i.e. 21/21 Robertsonian translocation). What is the risk of a future child having Down syndrome? A. 1% B. 25% C. 50% D. 100%

A newborn infant is suspected to have Down syndrome. A chromosome analysis shows that 30% of the blood lymphocytes have the karyotype 46,XX and the remaining 70% have the karyotype 47,XX,+21. Which of the following events, occurring alone, is the can best explain this finding? A. Dispermy B. Error in oogenesis C. Error in spermatogenesis D. Meiotic non-disjunction E. Mitotic non-disjunction

A woman comes to you for counseling because of recurrent miscarriages. Which one of the following potential cytogenetic findings in her would result in the lowest likelihood of a liveborn infant with a chromosomal abnormality? A. A balanced reciprocal translocation B. A balanced 14;21 Robertsonian translocation C. A balanced 21;21 Robertsonian translocation D. A paracentric inversion E. A pericentric inversion

All of the following aneuploids result from female nondisjunction except a) Klinefelter syndrome. b) triplo-X. c) Turner syndrome. d) Jacobs syndrome.

Choose the one abnormal karyotype that is MOST likely to result from paternal meiosis II nondisjunction A. 45,X/46,XX B. 47,XXX C. 47,XXY D. 47,XYY E. 47,YYY

Cri-du-chat syndrome is associated with a) a missing chromosome number 5. b) an additional chromosome number 5. c) a deletion of the long arm of chromosome number 5. d) a deletion of the short arm of chromosome number 5.

In oogenesis, meiosis I is competed at: A. birth. B. fertilization. C. implantation. D. ovulation. E. puberty.

NOEY2 is a paternally expressed imprinted gene located on chromosome 1. Based on the information given, which of the following options would be associated with the HIGHEST level of NOEY2 gene expression? A. Microdeletion of the maternal chromosome (including the NOEY2 gene region) B. Microdeletion of the paternal chromosome (including the NOEY2 gene region) C. Maternal uniparental disomy (for chromosome 1) D. Paternal uniparental disomy (for chromosome 1) E. Chromosomally normal individual

Of the following options, which describes the location of the ribosomal RNA (rRNA) genes? A. Centromere B. Telomere C. Submetacentric long arm D. Acrocentric short arm E. Chromosome 9q21

On microarrays, what is the primary method used to distinguish sequence variants from one another? A. Reverse transcription of size fractionated RNA molecules B. Nuclease protection of the target sequence C. Mass differences measured by spectrometry D. Hybridization to sequence-specific DNA molecules E. Size fractionation by capillary electrophoresis

Our closest relative, according to karyotypes is the: a) mouse. b) domestic cat. c) gorilla. d) chimpanzee.

Prenatal diagnostic techniques that obtain fetal chromosomes include all but a) amniocentesis. b) fetal cell sorting. c) chorionic villus sampling. d) fluorescence in situ hybridization.

The most common autosomal aneuploid is a) trisomy 13. b) trisomy 15. c) trisomy 18. d) trisomy 21.

This structure emanates from the centromere and contacts the spindle fibers during mitosis: a) alpha satellite b) subtelomere c) euchromatin d) kinetochore

Which of the following karyotypes is not possible in the offspring of a translocation carrier (involving chromosomes 14 and 21) and a normal individual. a) deficient 14 or deficient 21 b) normal c) translocation Down syndrome d) all are possible outcomes

Which of the following karyotypes represents an UNBALANCED chromosome abnormality? A. 46,XX, t(5;20)(q22.2;q31.2) B. 45, XY, Rob(13;21)(q10;q10) C. 46,XX, ins(6;4)(q13.1;q12q24) D. 46,XY,del(10)(q23q25)

Which of the following pregnant women is at the MOST risk of delivering a child with Down syndrome: A. A 23 year old mother of a previous child with trisomy 21. B. A 42 year old mother of two normal children. C. A 23 year old woman who is a carrier for a 14;21 Robertsonian translocation D. A 23 year old woman who is a carrier for a 21;21 Robertsonian translocation E. A 23 year old woman whose partner carries a 13;21 Robertsonian translocation

Which of the following syndromes results from a chromosome deletion in a major proportion of cases? A. CHARGE syndrome B. Fragile X syndrome C. Mowat-Wilson syndrome D. Prader-Willi syndrome E. Charcot-Marie-Tooth syndrome

Which one of the following cytogenetc findings would be properly classified as an aneuploid state? A. 23,X B. 46,XY,inv(1)(q23q32) C. 46,XY,t(4;8) D. 48,XXYY E. 69,XXX

Which one of the following hypothetical risk factors gives a woman the highest risk of having a liveborn child with a chromosomal abnormality? A. Her age, which is 25 B. Her blood chromosome study result, which shows 46,XX/45,X C. Her blood chromosome study result, which shows a large paracentric inversion of chromosome 2 D. Her blood chromosome study result, which shows a large pericentric inversion of chromosome 2 E. Her family history, which shows that she has a brother with 47,XY,+21.

Why would one perform clustering of microarray expression data? A.To reduce the number of subjects who must be analyzed B.To minimize the number of microarrays that must be processed C.To reduce the number of statistical tests that must be performed D.To visually represent the similarities in gene expression among genes and subjects E.To group together genes that are close to one another on each chromosome

You are fascinated by cytogenetics and volunteer in the lab. A snowstorm prevents all the staff from getting to work and you are asked to help out by scoring a FISH experiment. The sample is an amniotic fluid from a woman who is 42 years old. Mix 1 contains probes for 13 (green) and 21 (red). Mix 2 contains X (red), Y (green) and 18 (aqua). You find the following pattern: Mix 1: 2 green, 3 red. Mix 2: 3 red, 1 green and 2 aqua. Assuming all other chromosomes are normal, the karyotype of the fetus is most likely to be: A. 48,XX,+13,+21 B. 49,XY,+13,+18,+21 C. 49,XXY,+13,+18 D. 49,XXXY,+21

You perform an interphase FISH analysis using a probe that detects the telomeres of all chromosomes in a cell nucleus. You see 94 fluorescent dots. Which one of the following groups of diagnoses is most compatible with this observation? A. Balanced chromosomal rearrangement states B. Monosomies C. Single gene disorders D. Trisomies E. Unbalanced chromosomal rearrangement states

After a normal meiosis I cell division, the resulting cells contain which of the following number of chromosomes and chromatids? A. Contains 23 chromosomes and 23 chromatids B. Contains 23 chromosomes and 46 chromatids C. Contains 46 chromosomes and 23 chromatids D. Contains 46 chromosomes and 46 chromatids E. Contains 46 chromosomes and 92 chromatids

D Keywords: meiosis Explanation: Meiosis is a reduction division. In meiosis I, homologous chromosomes replicate so each chromosome consists of two sister chromatids glued together by cohesins. In the final phases of meiosis I, homologous chromosomes segregate into separate daughter cells with each of the four resulting cells containing 23 chromosomes each of which consists of two sister chromatids.

A newborn presents with a cardiac defect, cleft palate and a hypoplastic thymus. Which of the following chromosome abnormalities is the most likely cytogenetic imbalance in this patient? A. A deletion of 1q.21.1 B. A deletion of 2q11.1 C. A deletion of 16p11.2 D. A deletion of 22q11.2 E. A deletion of 22q13.3

Deletion 22q11.2 causes VCF/DiGeorge syndrome. The three phenotypic characteristics listed are most consistent with a clinical diagnosis of 22q11.2 deletion. The correct answer is D.

Microdeletions and Microduplications

Deletion or duplication of a chromosomal region, not an entire chromosome. Individually these are rare, but del/dup syndromes as a group are very common. Chromosomal Microarray Analysis (CMA)- Thousands of DNA probes across the genome, on each chromosome, are used to detect deletions or duplications. Uses single nucleotide polymorphisms (SNPs) to find large regions of homozygosity Important for identifying imprinted regions, autosomal recessive conditions, or consanguinity. Results -Pathogenic/Likely Pathogenic Variant of Unknown Significance "Normal" Region of Homozygosity

Cytogenetics:

Describe nondisjunction and the consequences of nondisjunction. Discuss the various types of structural rearrangements and their effect on reproductive outcomes. Discuss current testing methods for detecting structural chromosomal changes

Consequences when DNA damage is not corrected

Disease in the individual. The earlier the mutation occurs in embryology, the more tissues can potentially be affected.

trisomy 13

Distinctive physical presentation: - Hypotonia (decreased muscle tone) - Orofacial clefts - Polydactyly (extra finger/toes) - Microcephaly (smaller head) - Microphthalmia (smaller eyes) - CNS defects, 90% have cardiac defects What is the diagnosis?

trisomy 21

Down syndrome is also known as ________________

translocations

During chromosome breakage or exposure to clastogens (radiation etc), the cell will try to repair the damage using ___________________-.

trisomy 21

Dysmorphic Features: - Microbrachycephaly with Flat Occiput - Flat Nasal Bridge with Hypoplastic Alae Nasi - Upslanting palpebrae and epicanthal folds - Brachydactyly, Wide 1st-2nd Toe Gap - Single palmar crease and clinodactylyl What is the diagnosis?

trisomy 21

Dysmorphic facial features: - flat occiput - epicanthal folds - brushfield spots Whats the DX?

trisomy 13

Dysmorphic facial features: - ocular abnormalities - cleft lip and palate Whats the DX?

trisomy 18

Dysmorphic facial features: - receding law - low-set ears Whats the DX?

A baby with several dysmorphic features and a congenital heart defect has a chromosomal microarray analysis (CMA) by comparative genomic hybridization (CGH) done to search for the cause of the patient's phenotype. In this case, the patient's DNA is labeled with a red fluorochrome, and DNA from a normal individual is labeled with a green fluorochrome. When the CMA-CGH is completed, all dots on the chip show a yellow color under fluorescence scanning, except for one dot which shows a significant green shift from the yellow. Without knowing which probe was on that dot on the chip, which one among the following diagnoses is the most likely? A. Down syndrome B. Fragile X syndrome C. Klinefelter syndrome D. Trisomy 18 E. Williams syndrome

A woman is a balanced carrier of a Robertsonian translocation involving chromosomes 14 and 21. Her husband is chromosomally normal. They have two children: a daughter who is a balanced translocation carrier and a son with translocation Down syndrome. Given below are genotypes for a polymorphic marker on the long arm of chromosome 21. Based on the genotypes given for three family members, predict the genotype of the translocation Down syndrome son. Mother: [1,2] Father: [2,2] Balanced carrier daughter: [1,2] Translocation Down syndrome son: ? A. 1,1 B. 1,2 C. 2,2 D. 1,1,2 E. 1,2,2

An infant with multiple congenital anomalies is found to carry one structurally abnormal chromosome, conferring both partial trisomy and partial monosomy. In order to provide the parents with information on the risk of recurrence in a future pregnancy, what additional testing should be considered? Choose the single best choice from the options provided. A. Gene scanning in the parents to rule out a chromosome breakage syndrome B. Gene scanning in the parents to rule out partial trisomy and/or partial monosomy C. Array CGH (comparative genome hybridization) in the parents to rule out partial trisomy and/or partial monosomy D. Routine chromosome analysis of both parents to rule out partial trisomy and/or partial monosomy E. Routine chromosome analysis of both parents to rule out a balanced chromosome translocation

If a proper biopsy of the inguinal mass was obtained prior to "hernia" repair in infancy, what would you most likely expect to find? a. gonadoblastoma b. intestinal tissue c. ovarian tissue d. ovotesticular tissue e. testicular tissue

Only a few specific autosomal trisomies are seen in live born infants. Of the following options, the best explanation for this is: A.Only a few specific chromosomes are at risk to undergo nondisjunction during meiosis. B.Nondisjunction occurs primarily in spermatogenesis, and the sperm produced are unlikely to fertilize the egg. C.The autosomal trisomies are largely underdiagnosed, since most affected infants are phenotypically normal. D.Since autosomal monosomy is so much more common, the autosomal trisomies are rare. E.Although nondisjunction may involve any chromosome, most autosomal trisomies are lethal.

Using a probe specific for the centromere of chromosome 21, a fluorescence in situ hybridization (FISH) study was performed on a patient sample. 3 dots of fluorescence were seen in each of 100 interphase chromosome spreads. Other than Down syndrome due to trisomy 21, which one of the following diagnoses is also compatible with this finding? A. Down syndrome due to Robertsonian translocation between chromosomes 14 and 21 B. Down syndrome due to trisomy 21 mosaicism C. Monosomy 21 D. Paracentric inversion of chromosome 21 E. Triploidy

Using a probe that detects the centromeres of all chromosomes in a fluorescence in situ hybridization study, how many dots of light would you expect to see in most patients with Down syndrome? A. 2 B. 3 C. 45 D. 46 E. 47

Which of the following is the most common cause of triploidy? A. Nondisjunction in maternal meiosis I B. Nondisjunction in maternal meiosis II C. Fertilization of an aneuploid egg by a normal sperm D. Fertilization of a normal egg by an aneuploid sperm E. Fertilization of a normal egg by two normal sperm

Which of the following would not routinely be detected by comparative genomic hybridization analysis performed on a patient's blood sample? A. Down syndrome B. Trisomy 18 C. Williams syndrome D. Klinefelter syndrome E. Balanced translocation

Which one of the following DNA repeat elements protects a chromosome from being inserted into another chromosome through random recombination? A. a-satellites B. Centromeres C. Microsatellites D. Minisatellites E. Telomeres

Which one of the following cytogenetic abnormalities is most readily detected by comparative genomic hybridization using chromosomal microarray? A. 45,-21,-21,+rob(21;21) B. 46,XX/46,XY (ratio of 95:5) C. 46,XX,inv(8) D. 46,XX,t(5;7)(q12;p22) E. 48,XXYY

Which one of the following denotes a pericentric inversion? A. 46, -X, +i(Xq) B. 46, XX, del(5)(p11) C. 46, XX, dup(5)(p13;p22) D. 46, XY, inv(1)(p21;p36) E. 46, XY, inv(1)(p21;q21)

Which one of the following is most likely to be a consequence of dispermy? A. 45,X/46,XY B. 46,XX/47,XX,+21 C. 46,XY,t(7;15) D. 47,XY,+21 E. 69,XXX

trisomy 18

Edwards syndrome is also known as ________________-

Nucleotide Excision repair(NER)

Entire nucleotide, including DNA backbone must be removed XPA-XPG and ERCC1 genes are important in NER

Nondisjunction

Failure of two homologous chromosomes or two sister chromatids to separate leading to imbalance Can occur during meiosis or mitosis Can occur in meiosis I or meiosis II

normal karyotype

Female: 46, XX Male: 46, XY

trisomy 21

Gene Imbalance: - 90% from nondisjunction of maternal chromsomes What Trisomy does this describe?

RNase

In order to obtain a cDNA library from RNA, _____________ (enzyme) partially degrades the RNA after the RNA/DNA double helix is formed.

DNA polymerase

In order to obtain a cDNA library from RNA, ________________ (enzyme) is needed to synthesize a complimentary DNA strand after the RNA is partially degraded.

reverse transcriptase

In order to obtain a cDNA library from RNA, ___________________(enzyme) must be used to make a DNA copy from the original mRNA.

monosomy

In regards to aneuploideis, _________________, especially the autosomal type, are mostly incompatible with life.

trisomy

In regards to aneuploidies, _________________ are sometimes viable and relatively common.

Main source of mutations

Insertion and deletion of nucleotides splicing errors

Inversions

Inversion (flipping) of material within a chromosome

Genetic testing to identify these chromosomal abnormalities includes

Karyotyping, FISH and chromosomal microarray analysis

unbalanced translocation

Loss and/or gain of chromosomal material in the rearrangment

restriction enzymes

Molecular cloning uses ___________________ to cleave DNA and specific sites.

Polyploidy

Multiple sets of all the chromosome Triploidy - 69, XXX or XXY or XYY Multiple anomalies Severe intrauterine growth deficiency Typically miscarry (~1-3% of all miscarriages) Tetraploidy - 92, XXXX or XXYY or XXXY Polyploidy is NOT compatible with life

Familial Adenomatous Polyposis (FAP)

Mutations in the APC gene• Oncogene 100s -1,000s of polyps present - carpeting colon cancer presents

Retinoblastoma

Mutations in the RB1 gene - Tumor suppressor

how do we identify mutations?

NGS WES WGS

meiosis I

Nondisjunction during __________________ can be very severe due to resulting in two trisomy gametes and two monosomy gametes.

meiosis II

Nondisjunction during ___________________ is not as severe due to resulting in two normal gametes but one trisomy gamate and one monosomy.

Roberstonian Translocation

Occurs when two acrocentric chromosomes lose their short arms/satellites and fuse together Chromosomes 13, 14, 15, 21, and 22

Uniparental Disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

inactivating

One X-chromosome is responsible for _________________ the other X-chromosomes

single nucleotide polymorphism (SNP)

One base-pair variation in the genome sequence

Which of the following microarray confirmation methods can allow the cytogeneticist to determine the mechanism of an imbalance detected on comparative genome hybridization studies? A. Fluorescence In Situ Hybridization (FISH) B. Junction fragment PCR C. Multiplex ligation-dependent probe amplification (MLPA) D. Quantitative PCR E. Targeted microarray for the abnormal region

Only FISH can show the localization of the signal on chromosomes and allow for a determination of the mechanism for the imbalance. The correct answer is A

During meiosis, homologs must pair in order for recombination to occur. Which of the following events allows optimal pairing and normal segregation: A. One or more chiasma per chromosome B. Two or more chiasma per chromosome arm C. Distal position of chiasma on chromosome arm D. Medial position of chiasma on chromosome arm E. Centromere pairing of chromosomes

Optimal pairing includes one chiasma per chromosome arm, or two per chromosome. The correct answer is A.

Meiotic recombination is necessary for genetic diversity and rates of genetic recombination are different in males than females and for different chromosomal regions. The highest rate of recombination is observed in which of the following situations? A. in females compared to males near centromeres B. in males compared to females near centromeres C. in males compared to females in the middle of each chromosome arm D. near centromeres compared to near telomeres E. near telomeres compared to near centromeres

Overall, recombination rates in human females are significantly higher (~50%) than males, except near telomeres, where male recombination rates are higher than female. Human recombination is about twice as high as that in mouse, perhaps due to our biarmed chromosomes compared to all telocentric chromosomes in mice (remember the obligatory 1 crossover per chromosome arm for stable pairing and segregation). Recombination is suppressed near centromeres, and increases greatly near telomeres in both males and females (but more so in males). The correct answer is E..

viral

PCR can be used to detect ___________ genome in the blood (e.g. HIV or COVID-19).

trisomy 13

Patau syndrome is also known as _________.

chromosomal abnormalities

Ploidy, translocations/rearrangements, deletions/duplications, and genomic imprinting are all examples of ______________________.

An MRI shows lissencephaly in your patient, however the patient does not have any dysmorphic facial features. Which of the following is the most likely mutation? A. Point mutation within the LIS1 gene coding region. B. Terminal deletion of 17p which includes the LIS1 gene C. Terminal deletion of 17q which includes the LIS1 gene D. Terminal duplication of 17p which includes the LIS1 gene E. Triplet repeat expansion involving the LIS1 gene

Point mutations within the LIS1 gene cause Isolated Lissencephaly syndrome. These individuals can only exhibit lissencephaly without the more dysmorphic features that are associated with Miller-Dieker syndrome, which is caused by larger deletions of 17p. The correct answer is A

Triploidy is the result of three copies of each human chromosome and is one of the most common causes of spontaneous miscarriage. Which of the following occurrences is the most common mechanism by which triploidy arises? A. chimerism B. duplication of an entire maternal haploid chromosome set C. one egg fertilized by two sperm D. tetraploid conception with loss of one copy of each chromosome E. two eggs fertilized by one sperm

Polyspermy is the most common cause of triploidy. Chimerism may caused by the fusion of two embryos and differs from mosaicism. The other options are not likely to be observed. The correct answer is C.

deletion 15

Prader-Willi and Angelman Syndromes result from a small _______ on chromosome ____.

Mosaicism

Presence of more than one cell line in an individual

G-banding has been the preferred method for cytogenetic analysis since the late 1960s. The underlying DNA content corresponds to the staining pattern observed by G-banding. Which of the following descriptions details the difference(s) between G-negative bands and G-positive bands? A. G-negative bands are more gene rich than G-positive bands B. G-positive bands are GC rich regions and are early replicating C. G-negative bands are AT rich and are late replicating D. G-negative bands are GC rich and are late replicating E. G-positive bands are more gene rich than G-negative bands

R-bands are the reverse of G-bands, so there are the same number of each. G-positive bands are AT-rich and relatively later replicating. The correct answer is A

Frameshift

Reading frame altered Entire sequence after insertion/deletion is abnormal

In-frame insertions and deletions

Reading frame not altered Only specific amino acids are added/missing

Translocations

Rearrangement of chromosomal material between different chromosomes. Balanced & unbalanced

Proto-oncogenes

Regulates cell proliferation, growth transcript factors, and apoptosis Once mutated, is called an "oncogene" Only one copy needs to be mutated to cause problems Examples: HER2, RET, RAS

Polymorphisms are

STRPs, VNTRs, CNPs, SNPs

acrocentric chromosomes (13, 14, 15, 21, 22)

Satellites and stalks composed of repetitive non-coding DNA Short arm/stalk/satellite region is a common area of chromosome breakage and fusion

autosomal

Sex chromosome aneuploidies are less severe than autosomal aneuploidies because they carry less genetic material.

cryptic splice sites

Some base-pair substitution mutations produce new splice sites that replace or compete with authentic splice sites during mRNA processing

Mutations in both copies of tumor suppressor genes leads to cancer, whereas only one copy needs to mutated in a proto-oncogene to cause cancer.

Some chromosome abnormalities can be inherited, while others occur sporadically during cell division

If you were a T-lymphocyte destined for cytogenetic analysis, some of the treatments you would experience along the way (in correct order) are: A. Hypotonic solution, acetic acid, Giemsa, trypsin B. Hypotonic solution, lysis buffer, trypsin, Giemsa C. Phytohemagglutinin, hypotonic solution, fixative, Colcemid, Giemsa D. Phytohemagglutinin, Colcemid, hypotonic solution, fixative, trypsin E. Trypsin, acetic acid, hypotonic solution, Giemsa

T-lymphocytes are stimulated to a blast phase with the red kidney bean extract phytohemagglutinin (PHA). After 48-72 hours, a mitotic poison such as Colcemid or colchicine is used to block spindle formation and attachment to "arrest" cells in mitosis, a hypotonic treatment is used to swell the cells, they are fixed in 3:1 methanol:acetic acid, put onto slides, and then most often treated with trypsin prior to Giemsa staining to produce G-banding patterns. The correct answer is D.

maternal paternal

The Angelman syndromes region is active on the _________________ chromosome and inactive(methylated) on the ______________ chromosome.

9 22

The Philadelphia chromosome, commonly found in chronic myeloid leukemia and acute lymphoblastic leukemia, is a result of reciprocal translocation between chromosomes ____ and ____.

paternal maternal

The Prader-Willi syndrome region is active on the ________________ chromosome and inactive(methylated) on the ______________ chromosome.

A young woman with severe mental retardation, short stature, and other malformations has a karyotype of 45,X/46,X,r(X). Which of the following explanations is most likely to account for the constellation of clinical features noted above? A. Both X chromosomes are likely to be active in the cells with 46 chromosomes. B. The normal X is likely to be inactive in most or all of the cells with 46 chromosomes. C. The ring X is likely to be acentric explaining its absence in the 45,X cell line. D. The ring X is likely to be inactive in most or all of the cells with 46 chromosomes. E. The XIST gene will almost certainly be present on the ring X chromosome.

The abnormal phenotypes seen in association with mosaic karyotypes of the type indicated are associated with failure of X inactivation. This is usually also associated with lack of expression of the XIST gene. This means that both the normal X and the ring X are likely to be active. The XIST gene is considerably more likely to be deleted than to be present on the ring X, although deletion of the X inactivation center may be more pertinent than deletion of the XIST gene. As mentioned above, both X chromosomes are likely to be active. The ring is not likely to be acentric. The correct answer is A.

Chromosomal rearrangements can result from a variety of mechanisms during meiosis or mitosis. Which of the chromosome rearrangements listed below always involves at least two chromosomes? A. Balanced Translocation B. Duplication C. Interstitial deletion D. Isochromosome E. Pericentric inversion

The correct answer is A. Keywords: structural chromosomal abnormalities Explanation: A balanced translocation in the only structural chromosomal abnormality in the list provided to involve at least two chromosomes. All other listed abnormalities involve only one chromosome.

Aneuploidies typically result from meiotic errors but the specific missing or additional chromosome is not necessarily derived from the maternal or paternal gametes at an equal rate. Which of the following aneuploidies virtually always arises as a result of maternal meiotic error? A. 45,X B. 47,XY,+16 C. 47,XX,+21 D. 47,XXX E. 47,XXY

The correct answer is B. Keywords: aneuploidy, nondisjunction Explanation: Trisomy 16 is a prenatal lethal aneuploidy due to a maternal meiosis I nondisjunction in 100% of cases. Turner syndrome (45,X) is 70% paternal and 30% maternal in origin. Trisomy 21 is 92% maternal and 8% paternal in origin. 47,XXX is 90% maternal and 10% paternal in origin. Klinefelter syndrome (47,XXY) is 54% maternal and 46% paternal in origin.

41. A phenotypically normal person carries a reciprocal balanced translocation between two autosomes. When segregation occurs in this individual during meiosis I, which of the following statements regarding the eventual offspring appropriately associates the genotype with the expected phenotype? A. Alternate segregation always leads to a normal karyotype with a normal phenotype B. Alternate segregation can lead to an abnormal karyotype with a likely normal phenotype C. Adjacent-1 segregation leads to a normal karyotype with an abnormal phenotype D. Adjacent-1 segregation leads to an abnormal karyotype with a likely normal phenotype E. Adjacent-2 segregation leads to a normal karyotype with a likely normal phenotype

The correct answer is B. Keywords: segregation of a balanced translocation Explanation: Alternate segregation can produce either normal or balanced translocation in the offspring. If the carrier is phenotypically normal, then the offspring carrying the same balanced translocation will most likely be phenotypically normal. Adjacent-1 segregation can only produce the unbalanced versions of the translocation in the offspring with an abnormal phenotype. Adjacent-2 segregation is very rare and will also produce unbalanced products that are phenotypically abnormal.

Imprinting plays a role in determining the phenotype of many different conditions. In which of the following groups of disorders can all of the diagnoses be associated with imprinting as a major determinant of phenotype? A. Angelman syndrome, Prader-Willi syndrome, DiGeorge syndrome B. Ovarian teratoma, Trisomy 13 mosaicism, Beckwith-Wiedemann syndrome C. Triploidy, Prader-Willi syndrome, ovarian teratoma D. Triploidy, Williams syndrome, Beckwith-Wiedemann syndrome E. Prader-Willi syndrome, Trisomy 8 mosaicism, Russell-Silver syndrome

The correct answer is C. Keywords: imprinting Explanation: Imprinting plays a major role in the phenotype of Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedmann syndrome, Russell-Silver syndrome, ovarian teratoma, and triploidy. Imprinting does not play any role in the phenotype of Trisomy 13 and Trisomy 8 mosaicisms, DiGeorge syndrome, and Williams syndrome.

Recurrent microdeletions and their reciprocal microduplications are the result of which molecular mechanism? A. Allelic homologous recombination (AHR) B. Fork stalling and template switching (FoSTeS) C. Non-allelic homologous recombination (NAHR) D. Non-homologous end joining (NHEJ) E. Replication slippage

The correct answer is C. Keywords: molecular mechanisms, recurrent CNVs Explanation: Recurrent microdeletions/microduplications are caused by NAHR, which is mediated by the homologous flanking segmental duplications. FoSTeS, NHEJ, and replication slippage, all result in non-recurrent copy number changes. AHR is a normal recombination mechanism that does not result in copy number changes.

A patient carries an interstitial deletion in the proximal region of the long (q) arm of the paternal homologue of chromosome 15 [del(15)(q11.2q13.1)]. This patient is expected to present with which of the following disorders? A. Angelman syndrome B. DiGeorge syndrome C. Miller-Dieker syndrome D. Prader-Willi syndrome E. Williams syndrome

The correct answer is D. Keywords: microdeletion, genomic disorders Explanation: 15q11.2q13.1 deletion on the paternal chromosome 15 causes Prader-Willi syndrome, whereas the same deletion on the maternal chromosome 15 causes Angelman syndrome. DiGeorge syndrome is due to a 22q11.2 deletion. Miller-Dieker syndrome is due to a 17p13.3 deletion. Williams syndrome is due to a 7q11.23 deletion.

The mammalian somatic cell cycle is approximately 24 hours in length. Which of the following phases of the cell cycle requires the most time? A. G1 B. S C. G2 D. Interphase E. Mitosis

The correct answer is D. All of the phases of mitosis take approximately one hour.

Which of the following recurrent translocations is diagnostic of chronic myeloid leukemia (CML)? A. t(8;21)(q22;q22) B. t(15;17)(q22;q21) C. t(12;21)(p13;q22) D. t(4;11)(q21;q23) E. t(9;22)(q34;q11.2)

The correct answer is E. Keywords: cancer cytogenetics, leukemia Explanation: The t(9;22)(q34;q11.2) is diagnostic of CML and a subset of B-precursor ALL. The t(8;21)(q22;q22) is diagnostic of AML-M2. The t(15;17)(q22;q21) is diagnostic of acute promyelocytic leukemia (AML-M3). The t(12;21)(p13;q22) is diagnostic of a subset of B-precursor ALL. The t(4;11(q21;q23) is diagnostic of a subset of B-precursor ALL observed mostly in infants.

Carriers of balanced structural chromosomal rearrangements are at risk of having offspring with an unbalanced chromosome complement. Which of the following statements is true regarding the risk of unbalanced offspring? A. Carriers of small pericentric inversions have higher risk than large pericentric inversions B. Carriers of paracentric inversions have higher risk than pericentric inversions C. Carriers of balanced autosomal translocations have a 75% risk of having unbalanced offspring D. Female carriers of the 21;21 Robertsonian translocation have a 50% risk of having trisomy 21 offspring E. Female carriers of the 14;21 Robertsonian translocation are at higher risk than male carriers

The correct answer is E. Keywords: risk in carriers of balanced chromosomal abnormalities Explanation: The risk of having a trisomy 21 offspring in female carriers of the 14;21Robertsonian translocation is ~10-15%, whereas the risk in male carriers is ~0-2%. Carriers of large pericentric inversions have higher risk than small pericentric inversions. Carriers of pericentric inversions have higher risk than paracentric inversions. Carriers of balanced autosomal translocations have a 10-15% risk of having unbalanced offspring. Carriers of the 21;21 Robertsonian translocation have a 100% risk of having trisomy 21 offspring.

A child is born with a partial deletion and partial duplication for the same chromosome. Which of the following chromosomal abnormalities represents the likely parental chromosome abnormality predisposing to this occurrence? A. Balanced insertion B. Balanced reciprocal translocation C. Balanced Robertsonian translocation D. Paracentric inversion E. Pericentric inversion

The correct answer is E. Keywords: structural chromosomal abnormalities Explanation: A pericentric inversion is the only structural chromosome abnormality that can predispose to a terminal duplication on one chromosome arm and a terminal deletion on the other chromosome arm in the offspring.

The historical milestones in cytogenetics mark exciting intervals in the development of the field of clinical genetics. Which of the following series of events follows the chronological order in which these milestones were attained? A. Hypotonic treatment of cells > Correct chromosome number is 46 > Y chromosome identified in humans > Chromosome banding techniques>Fragile sites and fragile X syndrome B. Correct chromosome number is 46 >Hypotonic treatment of cells > Y chromosome identified in humans > Chromosome banding techniques> Fragile sites and fragile X syndrome C. Y chromosome identified in humans >Hypotonic treatment of cells > Correct chromosome number is 46 > Chromosome banding techniques> Fragile sites and fragile X syndrome D. Hypotonic treatment of cells > Y chromosome identified in humans> Correct chromosome number is 46 > Chromosome banding techniques> Fragile sites and fragile X syndrome E. Y chromosome identified in humans> Hypotonic treatment of cells > Correct chromosome number is 46 > Fragile sites and fragile X syndrome> Chromosome banding techniques>

The discovery of the Y Chromosome and the XX/XY mechanism of sex determination in humans was by T. S. Painter in 1923, hypotonic treatment of cells by T. C. Hsu in 1953, the correct chromosome number by Tjio and Levan in 1956, chromosome banding techniques in 1969/70, and fragile sites and fragile X in the late 70s. The correct answer is C.

A newborn presents with microcephaly, hypotonia, and a high-pitched cat-like cry? Which of the following cytogenetic abnormalities is most likely to be found on chromosomal analysis? A. 4p deletion B. 5p deletion C. 5q deletion D. 8p deletion E. 11p deletion

The features described fit Cri du Chat syndrome which typically results from terminal deletion 5p from band 5p15.2 to 5pter. 4p- syndrome results in Wolf-Hirschorn syndrome. 5q- and 8psyndromes do not have alternative names. 11p- deletion is associated with WAGR syndrome. The correct answer is B.

Reproductive Risks

The larger the "unbalance" of genetic material, the more likely that it will be incompatible with life and the pregnancy will result in an early miscarriage. Often presents in a family as instances of multiple miscarriages (>3). Smaller unbalances are more likely to result in live births, but also more likely to result in congenital birth defects, developmental delays, and intellectual disability.

knockout knockin

The loxP sequence and cre-mediated recombination play large roles in gene _______________ and _____________.

Patau Syndrome

The name for Trisomy 13

A child is born with a partial deletion and partial duplication involving the same chromosome. Which of the following parental chromosomal abnormalities is most likely to lead to this occurrence? A. balanced reciprocal translocation B. balanced Robertsonian translocation C. isochromosome D. pericentric inversion E. paracentric inversion

The occurrence of a deletion and duplication involving the terminal portions of the same chromosome is typically the result if one parent carries a pericentric inversion. This occurs if there is a cross-over within the inversion loop at meiosis. The correct answer is D.

A 2-year-old boy presents with a history of retinoblastoma, dysmorphic features and developmental delay. Which of the following molecular abnormalities is the most likely cause of his clinical findings? A. Nonsense mutation in the RB1 gene. B. Missense mutation in the RB1 gene. C. RB2 gene mutation D. Contiguous gene deletion of 13q14 E. Contiguous gene deletion of Xq27.3

The patient has additional clinical features (dysmorphic features and developmental delay) toretinoblastoma, suggesting a larger deletion that includes more genes than just the RB1 gene. The correct answer is D.

A middle-aged couple visits prenatal clinic for preconception counseling. Based on the wife's age their risk of having a child with Down syndrome is increased. The genetic counselor explains that even if their pregnancy were to result from a trisomy 21 conception there is a reduced likelihood that the pregnancy would lead to a liveborn infant. Which of the following probabilities best represents the likelihood that a trisomy 21 conception will result in a liveborn infant? A. 1% B. 20% C. 70% D. 90% E. 100%

The probability that a trisomy 21 conception will result in live birth is approximately 20%. The correct answer is B.

molecular cloning PCR

The two types of gene amplification techniques are ________________ and _________________. - Provide larger quantities of otherwise limited genetic material with greater material with greater enrichment for a desired sequence

Unbalanced Translocation

Too much of some chromosomal material (partial trisomy) Too little of some chromosomal material (partial monosomy)

Edwards syndrome

Trisomy 18 is also known as ___________

down syndrome

Trisomy 21 is also known as ______________

age

Trisomy risk increases with ___________.

Abnormalities of chromosome number and structure can cause genetic syndromes.

True

Balanced Translocation

Typically, does not have impact on health unless an important gene is interrupted at the breakpoint

Routine banding

Unit of Resolution: Chromosome band (400-550 band stage) Typical Dx Approach: ________________________

whole genome sequencing

Unit of Resolution: Nucleotide Typical Dx Approach: _______________________-

comparative genome hybridization FISH chromosomal microarrays

Unit of Resolution: Submicroscopic Region (50-250K bp) Typical Dx Approach ___________________ ______________ ______________ (there are 3)

chromosomal Karyotyping

Unit of Resoultion: Haploid Genome to Whole Chromosome Typical Dx Approach: ____________________________

high resolution banding

Unit of resolution: Chromosome band (850-band stage) Typical Dx Approach: ________________________

FISH (fluorescent in situ hybridization)

Uses DNA probes that are specific to a targeted chromosomal region Detects areas that are known hotspots for deletions and duplications Need to know, or have an idea of, what you are looking for

13 14 15 21 22

What are the acrocentric chromosomes?

Array Based Comparative Genomic Hybridization

What cytogenetic technique does this describe?

FISH

What cytogenetic technique does this describe? 1) DNA probe specific for region of interest. DNA probe hybridizes to complemtnary sequences on the chromsomes. 2) Fluorescent antibodies recognize the DNA probe. Antibodies attach to DNA probe on the chromosomes. 3) Fluorescent dye stains the chromosomes. Signals from the probe are examined through a special microscope.

FISH

What cytogenetic technique is this?

G banded karyotype

What cytogenetic technique is this?

high resolution chromosomal banding

What cytogenetic technique is this?

Fluorescence in situ hybridization FISH

What cytogenetic technique is this? - a specific region of a chromosome is identified by a complementary DNA sequence tagged to a fluorophore

Mitosis

What happens in MI body

high resolution chromosomal banding

What is the cytogenetic technique? - Allows 550-850 band resolution - Arrested cell division in prometaphase and prophase when chromosomes are less condensed - e.g. unexplained multiple congenital anomalies, mental retardation, developmental delay, and dysmorphic features

G banded karyotype

What is the cytogenetic technique? - Need dividing cells (metaphase) - Uses trypsin and Giemsa - Heterochromatin stains darkly - Euchromatin has minimal staining - Allows 450-550 band resolution

DNA microarray

What is this called?

Meiosis

What made ME

Flow cytometry

What technique does this graph represent?

Centromere

Where the chromosome attaches to the spindle apparatus during cell division

inactivation center

X-chromosome inactivation requires X ____________________ (Xic) and is regulated by XIST gene (non-coding RNA).

XIST

X-chromosome inactivation requires X inactivation center (Xic) and is regulated by ___________ gene (non-coding RNA).

metacentric

__________ describes a chromosome with the centromere in middle

barr body

_____________ is a dense body formed from a deactivated X chromosome.

submetacentric

______________ describes a chromosome with the centromere slightly off center

uniparental heterodisomy

______________ error in meiosis resulting in both homologs from a single parent

Klinefelter syndrome

______________ is a chromosomal disorder in which males have an extra X chromosome, making them XXY instead of XY

uniparental disomy

______________ is the inheritance of both chromosomes of a homologous pair from a single parent. - results from an error in Meiosis II

gene knockin

_______________ a gene addition in which a gene of interest has been added to a particular site in a genome

gene knockout

_______________ genetic manipulation in which one or more of an organism's genes are prevented from being expressed

trisomy

_______________ is a chromosomal abnormality in which an extra copy of a chromosome is present in the cell nuclei, causing developmental abnormalities.

polyploidy

_______________ is a chromosomal alteration in which the organism possesses more than two complete chromosome sets.

unbalanced

_______________ translocations result in a gain or loss in genetic material.

balanced

_______________ translocations result in no loss in genetic material.

whole genome sequencing

________________ - a process that determines the nucleotide sequence of an entire genome - can determine sequences that are overrepresented in patient genome - can determine translocation in patient genome

Prader Willi Syndrome

________________ - deletion in the paternal 15q-PWS

nondisjunction

________________ is an error in meiosis or mitosis in which members of a pair of homologous chromosomes or a pair of sister chromatids fail to separate properly from each other.

reciprocal translocation

________________ is the equal exchange of genetic material between non-homologous chromosomes. - Carriers are OK but the offspring can have issues

angelman syndrome

_________________ - deletion in the maternal 15q-AS

CRISPR

_________________ - guide RNA binds to target sequence - Cas9 enzyme binds to guide RNA - Cas9 enzyme cuts both strands of DNA - the cut is repaired introducing mutation

gel elecrophoresis

_________________ - technique used to used separate charged samples of interest according to size.

PCR

_________________ Applications - Genetic variations (SNP genotyping) - Detection of rare diseases (HSV in Kaposi's sarcoma) - Digital PCR (Rare allele detectin) - Forensics and paternity testing - Real-Time quantitative analysis

SKY multiplex

_________________ FISH - Not great resolution - Complete karyotyping with automated analysis - Origin of marker chromosomes, small insertions and complex rearrangements can be inferred (e.g. translocations)

polyploidy

_________________ describes a chromosomal abnormality where too many genes are being expressed for the embryo to handle.

Turner Syndrome

_________________ is a chromosomal disorder in females in which either an X chromosome is missing, making the person XO instead of XX, or part of one X chromosome is deleted.

next generation

_________________ sequencing is more useful when: - When a large number of pathogenic genes need to be screened - Dx of complex diseases - cancer screening and management - Dx of infections - Healthy people

Robertsonian

_________________ translocation - carriers are normal - offspring can have significant issues

Flow cytometry

__________________ - Laboratory technique to assess size, granularity, and protein expression of individual cell sample. - Fluorescent-labeled antibody attaches to the cell - Cell passes through a laser that makes label fluoresce - Fluorescence is detected; labeled cells are counted

Next generation sequencing

__________________ - entire genomes sequenced using multiple parallel reactions to analyze short segments of DNA and compare the results to known sequences. - uses fluorescent, reversible terminator NTPs

trisomy x

__________________ A condition of females who have three X chromosomes instead of normal two - No physical abnormalities - mild reduction in intellectual skills

Metaphase

__________________ FISH - Higher sensitivity, specificty, and resolution (2 Mb) vs banding - reliable detection of small microdeletions/microduplications not visible by G-banding. Also detects aneuploidy and presence of derivative (structurally rearranged) chromosomes - Uses dividing cells - DNA or RNA probes - detection of bacteria in clinical samples

DNA fingerprinting

__________________ analysis of sections of DNA (short-stranded repeats) that have little or no known function, but vary widely from one individual to another, in order to identify individuals.

XYY syndrome

__________________ chromosomal disorder in which the male has an extra Y chromosome - taller stature - reduced IQ - increased incidence of ADD and ADHD

aneuploidy

__________________ is a chromosomal aberration in which one or more chromosomes are present in extra copies or are deficient in number.

gene therapy

__________________ is the insertion of working copies of a gene into the cells of a person with a genetic disorder in an attempt to correct the disorder

angelman syndrome

___________________ - short stature - seizures - ataxic gate - severe speech impairment - microcephaly - severe intellectural disability - developmental delay What is the diagnosis

sex chromosome

___________________ aneuploidies are less severe than autosomal aneuploidies because they carry less genetic material.

PCR

___________________ in forensics - DNA fingerprinting

monosomy

___________________ is a chromosomal abnormality consisting of the absence of one chromosome from the normal diploid number.

Cri du chat

___________________ is a chromosomal deletion in chromosome 5 that results in children who are mentally retarded, microcephaly, and have a cry that sounds like a loud cat; they die at a young age

PCR

____________________ - relies upon thermostable DNA polymerases - carefully designed oligonucleotide primers - optimized cycling conditions (temp and time) - Steps: Denaturation, Annealing, and Extension - 5' --> 3'

Interphase

____________________ FISH - High resolution (< 1 Mb) with minimal condensation - Rapid (<24 hrs; nondividing cells; no cell culture) - can use parafinn embedded sections - Valuable in prenatal diagnosis of most frequent numeric chromosomal anomalies (e.g. trisomy 21/18/13 & alterations in X/Y alterations)

real time

____________________ PCR amplification is a continuous fluorescent measurement of PCR product during each cycle of PCR, compared to the standard PCR where quantification of visible PCR product by densitometry.

acrocentric

____________________ describes a chromosome whose centromere is placed very close to, but not at, one end.

cloning vector

____________________ is a DNA molecule capable of autonomous replication in a host cell (ex. E. coli) and selected for cloning

BCR-ABL1

____________________ is the fusion protein that results from the Philadelphia chromosome, which induces cell proliferation through the inhibition of apoptosis.

Muenke Syndrome

_____________________ - a type of craniosynostosis syndrome defined by a single mutation in the FGFR3 gene that creates a new restriction site.

sanger sequencing

_____________________ Dideoxynucleotides halt DNA polymerization at each base, generating sequences of various lengths that encompass the entire original sequence. Terminated fragments are electrophoresed and the original sequence can be deduced.

reciprocal translocation

_____________________ between chromosome 9 and 22, aka Philadelphia chromosome, results in BCR-ABL1 fusion protein ( a cancer protein that induces cell proliferation).

Charcot Marie Tooth

_____________________ disease - PNS condition-progressive atrophy of distal limb muscles - small duplication on Chromosome 17 - includes PMP22 gene - component of myelin - Gene deletion results in hereditary neuropathy with liability to pressure palsies

Robertsonian translocation

______________________ - confined to the acrocentric chromosomes (13, 14, 15, 21, 22) -short(p) arms are lost -long(q) arms are fused between 2 chromosomes

DNA microarray

______________________ - reverse transcribe mRNA to cDNA - label with fluorescent dyes - Hybridize to special exon arrays - compare relative signal to derive relative mRNA quantity

Prader Willi Syndrome

______________________ - short stature - neonatal hypertonia - small hands/feet - hypogonadism - obesity - mild/moderate intellectual disability - developmental delay What is the diagnosis

genomic imprinting

______________________ is a phenomenon in which expression of an allele in offspring depends on whether the allele is inherited from the male or female parent - Epigenetic change - DNA methylation

Philadelphia chromosome

______________________ is an abnormal chromosome produced by translocation of parts of the long arms of chromosomes 9 and 22.

gene knockout

_______________________ - To decrease gene expression by breaking mRNA using siRNA - requires Dicer to cleave dsRNA - RISC complex used to protect from viral RNA - cleaves mRNA

enzyme linked immunosorbent assay

_______________________ - immunologic technique widely used for the detection of antigens and antibodies in clinical samples Applications: - Hormones - Allergens - Viral and bacterial antigens - Antibodies in response to vaccination or infection (COVID-19, HIV, Hep B).

southern blotting

________________________ - a technique where DNA sample is separated based on fragment size (# of bp) using gel electrophoresis and is then transferred on to nitrocellulose/nylon membrane where it is fixed in place

Genotyping microarrays

________________________ Advantages: - automated, high-throughput analysis of specific mutations or polymorphisms - can study several samples for several patients simultaneously - relatively less hands-on work per sample - automation of data interpretation Disadvantages: - Expensive - microarray equipment and individual arrays - Not suitable for low-volume testing - use and throw

Array Based Comparative Genomic Hybridization

_________________________ - Patient genome is cohybridized with control reference - query the whole genome represented as an ordered array of genomic segments on a microscope slide - Only relative copy numbers are known. Needs to be confirmed by karyotyping or FISH

chromosomal karyotyping

___________________________ is a cytogenetic technique whereby number and morphology of nuclear chromosomes of any cell type can be analyzed

Fragile X Syndrome

a disorder produced by injury to a gene on the X chromosome, producing mild to moderate mental retardation

mutations in germline (egg & sperm)

are the only mutations passed on

whole genome sequencing

can see mutations even in non-coding regions, interpretation is harder

Next generation sequencing

entire genomes sequenced using multiple parallel reactions to analyze short segments of DNA and compare the results to known sequences.

Trisomy 21 (Down Syndrome)

extra 21st chromosome

pericentric inversion

includes centromere

Inversion Reproductive Risks

increases the likelihood of incorrect pairing during meiosis, leading to unbalanced gametes

non-synonymous

missense (different amino acid) and nonsense (premature stop codon)

splice site mutation

mutation at a point where coding and non-coding regions meet in a section of DNA

trinucleotide repeat expansion

mutation that results in expansion of the number of trinucleotide repeats

synonymous

no amino acid change

paracentric inversion

no centromere involvement

2 types of base pair substitutions

non-synonymous synonymous

Chromosome Arms

p (short) and q (long)

types of inversions

paracentric and pericentric

consequences of nondisjunction

polyploidy aneuploidy mosaicism uniparental disomy

Which of the following chromosome abnormalities is mostly likely constitutional? A. t(8;21)(q22;q22) B. t(11;22)(q23;q11.2) C. del(5)(q22q33) D. inv(16)(p13q22) E. t(15;17)(q22;q21)

the 11;22 translocation is the most common non-Robertsonian translocation observed in constitutional cytogenetic studies. The correct answer is B.

Mismatch Repair (MMR)

the correction of mistakes that escape the DNA polymerase proofreading activity

Karyotyping

the process of sorting chromosomes into their matched pairs. An important technique for investigating chromosomal disorders

Chromosomal microarray

to detect micro-deletions or duplications

Oncogenesis Genes

tumor supressor, proto-oncogene

small insertions and deletions

• Can be as small as a base or two BRCA1/2 mutations Smith-Lemli-Optiz syndrome

large insertions and deletions

• Can encompass the entire gene, multiple genes, or only part of a gene Duchenne muscular dystrophy 22q Deletion syndrome

The Human Genome

• ~20,000 genes • 46 chromosomes • 23 pairs of chromosomes • 1-22 = autosomes • 23 = sex chromosomes

human and molecular genetics

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