****4Th Year --> Clinical Genetics

Front 1

Apert syndrome (other name, inheritance, gene, sx)

Back 1

Acromegalosyndactyly, AD, FGFR2, sx- clover shaped head (craniosynostosis), increased ICP, variable mental retard, syndactyly, visceral abnorm (congenital heart defects)

Front 2

Screening for metabolic disorders (which disorder, what test is used)

Back 2

1. Galactosemia (GPU def) - Beutler/Baludaa, GPU-transferase enzyme test). 2. PKU- phen alanine hydroxylase def, Guthrie test. 3. Organic acid-uria (Maple syrup disease), analysis of organic acids or DNA testing of Amniotic fluid. 4. Biotinidase def(inhibition of C-3 organic acids carboxy), enzyme assay (pink is good). 5. Congenital Hypothyroid (T4, TSH).
NOTE - these are the commonly done tests. Other ones include G6PD def (newborn erythrocytes), MPS, Glycogenoses, Sickle-cell, and CAH

Front 3

DMD/BMD (inheritance, gene)

Back 3

X-linked recessive. Xp21.2. Dystrophin gene (largest human gene)

Front 4

Frequency of chromosomal abberations

Back 4

Total: 6.5%. Autosomal --> 4.5% of which 1.7% numerical (Down 1.2, Patau+Edwards 0.5), 1.9 structural. 2.5% are structural of which numerical 2% (Turner 1%, Klienfelter 1%), structural 0.5%

Front 5

Down syndrome (Dates, clinical)

Back 5

1868- Langdown down discovers as first mental retard disease. 1956- first chr. abnormal.
Clinical- epichantus, hypertelorism, macroglossia, low-set ears, mental retard, duodenal atresia, congenital heart defects, leukemia, infections, alzhemier, gap between toes, semean criss.

Front 6

Down syndrome (cytogenetics, molecular genetics)

Back 6

95% +21, 3-5% acrocentric translocations of 14;21, 22;21 or -21 due to t(13;14). Molecular- 22q21.1, 16 genes known. AD1 alzheimer, APP alzheimer, ETS2 (protonco-leukeimia), SOD1- early aging, GART (purine syn, mental retard)

Front 7

Patau syn(genetics, prevalance, clinical, prognosis)

Back 7

+13, 1/5000, 99% die in utero, 50% within a week, all within 6m. Clinical- holoprosoncephaly sequence --> hypotelorism, cleft palate, malformed forebrain, larged hooked nose, low ears, polydactyly, long narrow fingernails, heart/kidney defects

Front 8

Edwards syn(genetics, prevalance, clinical, prognosis)

Back 8

+18, 1/3000, 95% die in utero, 30% die in 1m, 1% surive to 1y. Clinical- IUGR, round head, hypertelorism, small nose, low ears, micrognathia, crossed fingers, omphalocele/NTDs,

Front 9

mention 3 deletion syndromes

Back 9

Cri-du-chat --> del(5p), Anti-edwards --> del (18p)
Wolf-hirschhorn --> del (4p)

Front 10

Cri-du-chat syn (prevalance, clinical)

Back 10

1:20,000, females 3:1. clinical- hypotonia (feeding problems), low growth, severe cognitive and speech delay, behavior problems, characteristic face, congenital heart defects, cat-like cry

Front 11

Cri-du-chat syn (genetics)

Back 11

5p deletion, critical segments 5p15.2, 5p15.3. The unique cry is on 15.3, all other symptosm due to 15.2. Most mutations involve terminal deletions with 80% being of paternal chr. Two important genes --> Semanopherin and Deltacatinin

Front 12

Wolf-hirschhorn syn (clinical, genetics)

Back 12

clinical - mental retard, beaked nose, ptosis, midlife defects, delayed bone development, cryptorchidism.
Genetics- del(4p), critical region 4p16.3(WHSC 1/2 genes)

Front 13

Phenotype of a balanced translocation carrier

Back 13

-5x mental retardation risk
-congenital malformations possible
-male infertility
-oncogene activation - tumors

Front 14

Characteristics of mulifactorially inherited diseases. Name 2 isolated abnormalities which are multifactorial, and 2 systemic disorders. Also, how do you measure heritablity.

Back 14

1. interaction of environment+polygenic
2. accumulation of disease within family
3.risk of recurrence 1-5%
4. number of genes affects the severity of disease, the no. of effected siblings,

Isolated- Duodenal atresia, hip luxation. Systemic- DM, HTN.
Heritability(H)= MZ Conc. - DZ Conc. / 100-DZ conc)

Front 15

Kleinfelter (genetics, clinical), Triple X syn(prevalance, clinical)

Back 15

Kleinfelter- 47XXY to 49XXXXY, genu valgum, tall, hypogonadism, might have mental retard.
Triple x -tall, thin, menstrual irreg., increased risk for learning problems

Front 16

Prader-willi syndrome(clinical, genetics)

Back 16

clinical - feeding difficulty, growth retard, small feet, bulimia, mental retard.
Genetics- 15q11-12 SNRPN (nuclear RNA), maternally imprinted.

Front 17

Weidemann-beckwith syn(clinical, genetics)

Back 17

clinical- macrosomy, macroglossia, mental retard, creases on earlobe, Wilms tumors.
Genetics- 11p15, IGF2 gene, maternally imprinted.

Front 18

Mitochondrial DNA - characteristics

Back 18

34 genes, circular DNA, oxidative phos. related.
-high mutation rate, -many copies, -abnormal mDNA in every cell, maternal inheritance, extreme variable expressivity - heteroplasmia.

Front 19

Mitochondrial DNA -disorders

Back 19

1. Hereditary optic neuropathy (Leber)- visual loss, ND4 gene, maternal inheritance
2.MERRF - myoclonic epilepsy & regged red fibers, point mutation Lys-tRNA, sporadic/maternal.
3. Kaerns-Sayer syndrome - retinopathy, AV blcok, deafness, big deletions, SPORADIC
4. MELAS - mitochondrial Encephalopathy, Lactic acidosis, Stroke. mutation in Leu-tRNA, sporadic/maternal

Front 20

Fragile X syn (prevalance, clinical)

Back 20

Most frequent inherited mental retardation. 1:1000-4000 males, 1:6000 females
Clinical- mental retard in males (some females), big head, long face, macroorchidism, autism, hyperextendable joints.

Front 21

Fragile X syn (genetics)

Back 21

CGG triplet expansion, FMR1 gene on Xq27.3. No FMR protein causes lack of maturation and apoptosis of neurons. Triplet repeats: 25-50 normal, 50-200 permutations (unstable, carrier), 200-2000 promoter hypermethylation, no gene function.

Front 22

Name 3 diseases in the chondrodysplasias group, what is the most common mutation, and what is the difference between the 3 muations

Back 22

Achondroplasia, hypochondroplasia, tanatophor dysplasia. All defects in FGFR3 (4p). MC mutation is seen in achondroplasia --> 1138neucoleotide(most mutated nucleotide of the genome), arg-gli exchange. this is a mutation in the TM domain.
hypochondro and tanatophor have mutations in the TK domain.

Front 23

Mechanism of FGFR3 mutation and DD of chondrodysplastic diseases

Back 23

FGFR3- mutation leads to a constituate activation of the receptor and to inhibition of enchondral ossification.
DD- Cartilage-hair hypoplasia, Campomelic dysplasia (17q, AD/AR, pes equi, curvuature of tibia, hypoplasia of fibula), Pseudochondroplasia(9 pericentric, AD/AR, normal face, short extremities)

Front 24

Marfan syndrome(inheritance, clinical, similar disease)

Back 24

AD, 1:10,000, 15q15 fibrillin-1 gene, Fibrillin is a component of elastin cotaining fibers.
Clinical- long arms, long fingers, hyperextendable joitns, pectus excuvatum, scoliosis, aortic dilatation/dissection.
Similar disease- congenital arachnodactyly with contractures (fibrillin2 gene, chr 5)

Front 25

Complex inherited diseases (general, 3 diseases, 4 genetics models)

Back 25

Most orthopedic diseases show this kind of inheritance. Examples are pes equinovarus, scoliosis, hip luxation.
Models- oligogenic(major gene), polygenic, non transmitted, mixed

Front 26

Give 3 possible causes of Pes Equinovarus and Scoliosis that show their mixed origin

Back 26

Pes - 1. Multifactorial(genetic+environment), spinal origin (spina bifida sequence), deformity (oligohydroamnion).
Scoliosis - multifactorial, monogenic (chr8), popliteal pterygium syndrome

Front 27

Neurofibromatosis (two types, genetics, clinical)

Back 27

AD, Most common monogenic disorder.
Type 1- complete penetrance, 1:3500, NF1 on 17q11.2 (signal transduction role)
Type 2- high penetrance, 1:50,000 Merlin gene on chr 22.
Clinical differnce- no Lisch nodules and less Cafe au lait spots on NF2, no schwanomas on NF1.

Front 28

Name 3 syndromes that show Craniosynostosis. When does the posterior fontanell close normally ? the anterior one?

Back 28

Apert, Cruozon, Jackson-Weiss.
Posterior - 8w, anterior- 18m

Front 29

Spinal muscular atrophy - genetics

Back 29

incidence 1:6000, SMN1/2(survival motor neuron) genes on Chr 5. these genes regulate neuronal apoptosis and their mutations cause early neuronal death of the motor neurons in the spinal cord.

Front 30

Spinal muscular atrophy - 3 diseases

Back 30

Infantile, type I, Werdnig-Hoffmann - manifests soon after birth, severe hypotonia, most babies do not survive past 1 year do to pneumonia and resp. failure.
Intermediate, type II - onset between 6-18months, children are able to maintain a sitting position.
Adult, type III, Kugelberg-Walender - manifests after 18months, children are able to walk.

Front 31

Give 4 categories of protooncogenes (+ examples) and 3 examples for TSGs (+examples)

Back 31

Protooncogenes: Growth factors, Growth factor receptors (HER2/neu), Signal transduction (ras), Transcription factors (myc), apoptosis regulators (bcl-2).
TSGs : Cell-cycle control (Rb1), DNA repair genes, pro-apoptotic genes (p53)

Front 32

Ph chromosome

Back 32

Present in 95% of CGL (CML). t(9;22)(q34;q11), BCR/Abl. Abl stands for Abelson. It contains a TK domain and is a protooncogene. BCR/abl translocations cause a longer G0 stage, less maturatio signals and anti-apoptosis.

Front 33

Accelerate CGL phase (WHO criteria, cytogenetics)

Back 33

WHO: 10-19% myeloblasts, >20% basophils, <100,000 or >1,000,000plt, cytogenetic evolution, splenomegaly.
Cytogenetics- +8, i(17q), +19.

Front 34

List 3 differences between the Ph chromosome of CGL and that of Ph+ ALL.

Back 34

ALL --> 50-80% break is outside BCR, product is 190KDa, affects only lymphoid cell line.
CGL --> break inside BCR region, product 210KDa, affects all 3 cell lines. Also in 20-50% of Ph+ ALL.

Front 35

List the response values of Ph+ CGL to therapy (IFN, Glivec, chemo)

Back 35

Complete --> 0% Ph+
Partial --> 1-34% Ph+
Moderate --> 35-64%
Minimal --> >64%

Front 36

FAB AML classification

Back 36

M0 - minimal differentiation, shows Auer rods
M1 - Myeloblastic, no maturation
M2 - myeloblastic, with maturation (t(8;21) common), Auer rods
m3- APL (t(15;17), DIC common.
m4- myelomonocytic (inv16)
m5- monoblastic (m5b mature monocytes also, m5a only immature cells)
m6 - erythrocytic
m7 - megakaryocytic

Front 37

WHO AML classification

Back 37

AML with recurrent chromosomal translocations: AML with t(8;21), AML with inv16, AML with t(15;17), AML with t(11q23;variable).
AML with multilineage dysplasia : with prior MDS or without prior MDS.
AML - therapy related: Alkylating agent related, epodophyllotoxin related.
AML - not otherwise classified

Front 38

What are the agent-specific chromosomal aberration seen in AML related to alkylating agents?

Back 38

+8, +21, i(17q), del(20q), t(1;3)

Front 39

Chromosomal aberrations in AML - prognostic values

Back 39

Best prognosis --> Del(16q)
Good --> t(8;21), t(15;17), inv(16)
Average --> t(8;21) / -Y
Poor --> Ph+, t(11q23;variable)
Worst --> Agents related; -7, -5, +8

Front 40

Classification of ALL according to genetic changes

Back 40

Either numerical or specific-structural. correlation between aberration and cell line (T, B). Factors determining prognosis are pluidity and specific translocations.

Front 41

Give two changes of favorable prognosis in AML, and two of unfavorable.

Back 41

Favorable- hyperploidity >51, t(12;21) AML/TEL.
Unfavorable - Ph+, or MLL changes (t11)

Front 42

What are the most common translocations in AML ? what are the genes involved ?

Back 42

8;21 AML/ETO,
15;17 APL/RARalpha,
t11;variable , 11 is MLL

Front 43

List 4 B-cell specific aberrations

Back 43

t(8;14) c-myc/IgH,
t(8;22) c-myc/IgLambda
t(2;8) c-myc/IgKappa
t(14;18) bcl-2/IgH -->Follicular lymphoma
t(11;14) CyclinD1/IgH --> Mantle cell lymphoma
+12, -11, -12 --> SLL/CLL
All c-myc translocations common in Burkitt's lymphoma

Front 44

DNA-index

Back 44

By Flow cytometry:
Diploid 0.97-1.03
hypodiploid <0.97
Hypoerdiploid A 1.03-1.16
Hyperdiploid B >1.16

Front 45

Two genomic imprinting causes of Wilms tumor

Back 45

1. IGF2 overexpression. Protooncogene. 11p15 with maternal imprinted. Reactivation of maternal allelle --> Weidemann-Beckwith syndrome.
2. H19, TSG, 11p15, paternal imprinted. LOH (functional nullisomy) leads to Wilms tumor.

Front 46

Genes involved in Colorectal CA progression ?

Back 46

del(5q) - APC
del (18q) - DCC
del (17p) - p53
ras
Order is APC (two hits, TSG) --> ras (oncogene) --> p53 (TSG)

Front 47

What are the somatic abnormalities associated with the deleted form of Retinoblastoma

Back 47

del(13q) --> facial dysmorphy, mental retardation, esterase-d deficiency,

Front 48

What are the two main types of Oncogene activation via translocations ? give examples

Back 48

usually proliferation specific genes (protooncogenes) & differentiation specific genes (TCR, Igs).
Types: 1.Fusion gene --> new structure & function (qualitative change) t(9;22)(q34;q11) BCR/Abl
2. Increase in oncogene transcrpition. same features, greater amount, quantitative change, t(8;14) myc/IgH. myc will be enhanced by the enhancers of the Ig