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For fragile X, how is the diagnosis made in culture? By molecular studies? What is the mutation? When does expansion of repeats occur from pre- to full mutation? How many repeats is associated with the syndrome?
Chromosome fragility enhanced by thymidine deprivation culture; Southern blot or methylation analysis; during maternal meiosis; expansion of FMR1 gene on Xq27.3 → methylation & inactivation; >200
What are the genes for TCR gamma, beta, alpha, and delta?
- TCRG - 7p13
- TCRB - 7q25
- TCRA/D - 14q11
What are the genes for IgH, IgK, and IgL?
- IgH: 14q32
- IgK: 2p12
- IgL: 22q11
How can spontaneous/increased sister chromatid exchange (SCE) be demonstrated in culture? Name two diseases that have spontaneous/increased SCE. What are the mutated genes for these two diseases?
- Cytogenetic cultures with bromodeoxyuridine (BUDR)
- 1) XP: XPC (3p) and XPA (9q22) - DNA repair proteins
- 2) Bloom Syndrome: BLM on 15q26.1, a DNA helicase
What serum proteins are elevated in Ataxia Telangiectasia? What is the mutation? What are the hematologic effects? Other abnormalities?
AFP & CEA; classically two truncated ATM (11q22-23) mutation with t(7;14) in 10%, causing loss of ATM protein kinase activity, which protects from degeneration; variable immunodeficiency of T and B-cells with ↓IgA and ↓T-cells, and no response to live or attenuated vaccines, thymic hypoplasia, greater tendency to hematolymphoid neoplasms; cerebellar ataxia, oculocutaneous telangiectasia, recurrent sinopulm infxns, malignancies
Cafe au lait spots without neurofibromas, short stature, chronic infections, susceptibility to acute leukemia, and hypopigmentation are part of what syndrome? What is the mutation amongst the Ashkenazi Jewish population?
Bloom syndrome; BLMASH
What disease leads to triradial and quadriradial chromosomes after treatment with cross-linking agents? What is the mutation?
Friedreich's ataxia; GAA trinuc. expansion in FRDA gene (9q13) - length directly correlates with thickness of interventricular septum, age of onset, dz severity
What is the genetic mutation for this syndrome? What constitutes the vast majority of malignancies? What does lab testing show?
(Nijmegen breakage syndrome) - NBS1 gene (8q21 encoding nibrin - involved in repair of double stranded breaks), B-cell lymphomas; hypo- or agammaglobulinemia and and decreased CD3+/4+ subsets
Name 5 chromosomal breakage syndromes.
- Mnemonic: Even FAT BlCX (sounds like blacks) Can break
- Fanconi anemia
- Ataxia Telangiectasia
- Bloom syndrome
- Cockayne syndrome
- Xeroderma Pigmentosum
- chromosomal breaks
VHL mutation & associated tumors?
AD, chrom 3p25.3 mutation; clear cell RCC, hemangioblastomas, papillary cystadenomas of ovary and epididymis, papillary endolymphatic sac tumors, pancreatic neuroendocrine tumors, pheochromocytomas
What types of chromosomal abnormalities are detected by microarray? What can't they detect?
Chromosomal imbalances - gain or loss of genetic material; translocations or inversions
What types of chromosomes (metacentric, acrocentric, submetacentric) are these: 1, 3, 16, 19, 20?
Metacentric (centromere nr center)
What types of chromosomes (metacentric, acrocentric, submetacentric) are these: 13, 14, 15, 21, 22?
Acrocentric (in Robersonian translocations)
Primary cause of aneuploidy (ex. trisomies)?
Non-disjunction, mostly in Meiosis I
Most common cause of spontaneous abortions? Which trisomies most commonly involved? What other abnormalities are most common?
chromosomal anomalies (50%) and 25% of spontaneous abortions are trisomies; trisomy 16; monosomy X (most common), triploidy (eg 69, XXY)
How do tetraploidies arise? Triploidies - most common cause?
Fused diploid zygotes or failure of nuclear mem formation after 1st zygotic div; 2 haploid sperm (fused) + haploid egg (70-80% of cases)
What % of Down syndrome is due to Robertsonian translocations? patau syndrome? What is a robertsonian translocation?
3-4% (most d/t Trisomy 21) of Down syndrome patients have 46 chromosomes w/one mixed chromosome from a parent with Robertsonian translocation; 20% in patau; acrocentric chromosomes (13-15, 21-22) fuse at the centromeres and lose the stalks
What is the microdeletion/microduplication and clinical manifestations for the following syndromes:
- 1) Kallman - Xp22.3, anosmia, hypogonadism
- 2) Smith-Magenis - 17p11.2, prominent forehead, broad midface, self-mutilating
- 3) Williams - 7q11.23, elfin faces, weird teeth, infantile hyperCa, heart malformation
- 4) Wolf - 4p del, microcephaly, cleft lip & palate, broad nasal root, heart malformations
- 5) Miller-Dieker - 17p13, type I lissencephaly, vertical furrowing of brow, heart & renal malform, seizures
What is the microdeletion of CHARGE sequence and clinical manifestations?
22q11.2: coloboma, choanal atresia, genital hypoplasia, deaf, mental retardation, heart malform
What is the most common supernumerary chromosomal marker (small extra chromosomes of unknown chrom origin) in FISH studies?
What is a telomere?
End of chromosome with repetitive DNA that protects it from deterioration
What is the mutation in cystinosis and what are clinical symptoms?
17p13 of CTNS gene; rickets, short, corneal deposits, renal Fanconi syn, cornea, BM, kindey, etc. shows cystine crystals (hexagones)
All of the following characterize McLeod syndrome except:
A) Xp21 (XK gene, X-linked recessive)
B) elevated serum LDH
C) neurologic dysfxn, esp basal ganglia
D) absent Kell Ag
B - they have elevated serum CPK, NOT LDH
The most common type of Charcot-Marie-Tooth dz is Type I. What is the mutation? How do they present clinically? How does Type II present?
Type I: 1.5Mb duplication of 17p12 at PMP22 gene (deletion causes hereditary neuropathy with pressure palsies/HNPP); peripheral nerve demyelination with onion bulb formation of nerves and muscle atrophy; axonal degeneration but clinically similar
In unbalanced translocations, what does partial trisomy and monosomy refer to?
After meiosis with translocated chromosomes, you have 3 copies of one portion and only one copy of the other portion that was lost in translocation, ex. If you have der(9)t(3;9)(p23;p22), you have partial monosomy for 9p22 portion and partial trisomy for 3p23 portion that translocated to chrom 9
How many chromosomes are there in a person with Robertsonian translocation? What is the incidence?
45 (count centromeres) b/c two short arms are lost; 1:1000
Pericentric vs. paracentric inversion? Which ones are more often seen clinically?
- Peri = centromere Involved (2 chrom breaks in same arm)
- Para = spares centromere (1 break in each arm)
- Peri more common b/c odd # breaks in paracentric inversions are lethal
What are the three possible mechanisms of chromosomal defect in Prader -Willi and Angelman syndrome at 15q11.2?
- 1) Microdeletion (70% in PW), 2) uniparental disomy from non-disjxn → two copies from one parent, none from the other (~25% in PW but rare in Angel), 3) methylation (imprinting)
- Prader-Willi: Prader lacks father = only maternal chrom present (MR and obesity)
- Angelman: only paternal chrom present ("Happy puppet")
All of the following are true regarding Noonan syndrome (male Turner syndrome) except:
A) Differs from Turner's in right sided heart defects (esp pulm stenosis) and more often mental retardation
B) Lymphatic malformations common
C) Physically resembles Turner's
D) Mutation in PTPN11 (12q) and KRAS (12p)
E) Renal anomalies common
E - only Turner's has renal anomalies as well as left-sided heart defects like coarctation of Ao, and intelligence usually nml
What is the defect in Krabbe disease? Clinical manifestations? What ethnicity has a high incidence of this dz?
AR inherited mutation of GALC/galactocerebrosidase gene on chrom 14q31; neurologic sxs in infancy → severe impairment including blindness, death by age 2yo; Muslims
Accumulation of ammonia due to metabolic disorders result in lethargy, vomiting, asterixis (flapping tremor), coma, and death. Name three general causes of hyperammonemia.
- 1) AR organic acidemia d/o
- 2) Ureal cycle d/o
- 3) hepatic dysfxn
Which organic acidemia(s) are associated with the following clinical findings:
1) maple syrup odor and ↑branched chain AAs
3) sweaty feet odor
5) Reye syndrome
- 1) maple syrup urine dz (branched chain ketoacid dehydrogenase deficiency)
- 2) propionyl CoA carboxylase and MM CoA mutase deficiency
- 3) Isovaleric acidemia
- 4) 3-methylcrotony-l-CoA carboxylase, ketothiolase and HMG-CoA lyase def
- 5) HMG-CoA def
A patient w/h/o CML has cytogenetic analysis showing i(17q). What does this indicate?
Transition to blast phase - additional anomalies (i(17q), 9q-, +Ph, +8, +19) are seen 3-6 mos before blast phase and poor prognostic indicator
In addition to JAK2, the following mutations are seen in myeloprolif disorders except:
E) KIT (D816V)
A - this is seen in Factor V Leiden (*remember 506 and 306 positions are in FV Leiden!)
Patients previously exposed to alkylating agents get what type of MDS mutation? Topoisomerase II agents?
5q-; MLL (11q23)
All of the following have an intermediate to bad prognosis in CLL except:
E) trisomy 12
What is the chrom mutation in DLBCL?
What is the most common cytogenetic anomaly in myeloma? Most common translocation? How many anomalies are typically found?
13q14; t(11;14)(q13;q32) (Cyclin D1-IgH) translocation; >4 anomalies in >80% of cases
Which chromosomal anomalies in multiple myeloma have the best prognosis? intermediate? worst?
- Best: t(11;14)
- Intermediate: 13q14 (also most common anomaly) deletion alone
- Worst: t(4:14), t(14;16) and 17p13.1 deletion
Benign tumor translocations?
1) Uterine leiomyoma
2) Pleomorphic salivary gland adenoma
- *All involve chromosome 12:
- 1) t(12;14)(q14;q23) involving RAD51B on chrom 14
- 2) t(9;12) involving HMGIC
- 3) t(3;12) involving LPP
Name three ways chromosomal abnormalities lead to altered gene function.
- 1) Deregulation of gene expression, ex. Burkitt
- 2) Deletion of chromosomal material
- 3) Novel protein expression, ex. CML
What are homogeneous staining regions (HSRs)?
Areas of oncogene amplification (ex. N-myc) that integrate into other chromosomes...and like stain the same color and stuff
In CML with t(9;22), what type of additional deletion is less responsive to Gleevec?
Concomitant 9q deletion that is lost with translocation
In FISH, what does a break apart probe look like with inversions?
Two probes of two different colors adjacent in a normal chromosome but "break apart" or appear separate when an inversin is present
What is a constitutional chromosomal abnmlty?
abnormality present in all cells of the body so not acquired (present in early phase of embryogenesis)