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

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Accelerate CGL phase (WHO criteria, cytogenetics)

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

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

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

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

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1. interaction of environment+polygenic2. accumulation of disease within family3.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)

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Chromosomal aberrations in AML - prognostic values

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

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Classification of ALL according to genetic changes

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

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

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

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Cri-du-chat syn (genetics)

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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

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Cri-du-chat syn (prevalance, clinical)

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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

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DMD/BMD (inheritance, gene)

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

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DNA-index

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

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Down syndrome (cytogenetics, molecular genetics)

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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)

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Down syndrome (Dates, clinical)

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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.

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Edwards syn(genetics, prevalance, clinical, prognosis)

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+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,

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FAB AML classification

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M0 - minimal differentiation, shows Auer rodsM1 - Myeloblastic, no maturationM2 - myeloblastic, with maturation (t(8;21) common), Auer rodsm3- APL (t(15;17), DIC common.m4- myelomonocytic (inv16)m5- monoblastic (m5b mature monocytes also, m5a only immature cells)m6 - erythrocyticm7 - megakaryocytic

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Fragile X syn (genetics)

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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.

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Fragile X syn (prevalance, clinical)

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

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Frequency of chromosomal abberations

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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%

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Genes involved in Colorectal CA progression ?

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

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

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

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

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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)

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

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

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

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

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

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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.

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List 4 B-cell specific aberrations

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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

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

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

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Marfan syndrome(inheritance, clinical, similar disease)

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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)

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Mechanism of FGFR3 mutation and DD of chondrodysplastic diseases

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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)

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mention 3 deletion syndromes

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

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Mitochondrial DNA - characteristics

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

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Mitochondrial DNA -disorders

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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

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

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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.

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

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

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Neurofibromatosis (two types, genetics, clinical)

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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.

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Patau syn(genetics, prevalance, clinical, prognosis)

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+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

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Ph chromosome

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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.

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Phenotype of a balanced translocation carrier

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

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Prader-willi syndrome(clinical, genetics)

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

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

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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

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Spinal muscular atrophy - 3 diseases

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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.

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Spinal muscular atrophy - genetics

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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.

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Two genomic imprinting causes of Wilms tumor

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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.

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Weidemann-beckwith syn(clinical, genetics)

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

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

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

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

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

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

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

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

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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/Abl2. 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

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WHO AML classification

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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

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Wolf-hirschhorn syn (clinical, genetics)

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