Unit 2 Flashcards

Question

When should cytogenic studies be ordered?

Answer 1

- Multiple congenital abnormalities - Developmental delay + minor abnormalities - History of a familial chromosomal abnormality - Intrauterine growth reduction or failure to thrive - History of multiple spontaneous abortions

Answer 2

Two or more different karyotypes from same individual. Most commonly caused by nondisjunction in early embryonic development.

Answer 3

allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences. p + q = 1 p2 + 2pq + q2 = 1

Answer 4

- Alu family (Short INterspersed repetitive Elements - SINE) ~300bp; 500k copies in genome - L1 family (Long INterspersed repetitive Elements - LINE) ~6kbp; 100k copies in genome - Facilitate aberrant recombination (non-allelic homologous recombination)

Answer 5

Minisatellites - Tandem repeated 10-100bp blocks of DNA (VNTR) Microsatellites - di-, tri-, tetra-nucleotide repeats ~5 x 10^4 per genome

Answer 6

1/1,000 bps

Answer 7

Variation in segments of genome from 200bp - 2Mb Can range from one additional copy to many Array comparative genomic hybridization (array CGH)

Answer 8

Gene's duplicated and modified to prevent loss of function of essential genes.

Answer 9

Microarray for cDNA - Fluorescence ratios are dependent on the prevalence of comparable genes. One color means unique gene - hybrid color means shared gene.

Answer 10

-> Evolutionary advantage -> Increased 1q21.1 instability -> Increased DUF1220 copy number ->

Answer 11

Duplications -> Macrocephaly; autism | Deletion -> Microcephaly; Schizophrenia

Answer 12

Congenital aberrations. Can be de novo or familial

Answer 13

Developed after conception

Answer 14

Centromere is in center of chromosome

Answer 15

Centromere is asymmetric along chromosome

Answer 16

Centromere is on one side of centromere with a small nub on otherside

Answer 17

of individual chromosomes, sex chromosomes, abnormalities. 46,XY - normal male 47,XY,+21 - Trisomy 21 male 45,X - Turner syndrome

Answer 18

of homologous chromosome sets - Diploid: having two sets (46 chromosomes) - Haploid: having one set (23 chromosomes)

Answer 19

Full set of chromosomes (46)

Answer 20

Chromosome number more than double - Triploidy: having three sets (69 chromosomes) - Tetraploidy: having four sets (92 chromosomes)

Answer 21

Incomplete sets - Trisomy: 47 - Monosomy: 45 Arises during meiosis

Answer 22

the point where two homologous non-sister chromatids exchange genetic material during chromosomal crossover during meiosis

Answer 23

2-3: reason for genetic variability

Answer 24

Spontaneous Abortions: 50-60% Stillbirth: 4-6% Newborns: 0.6%

Answer 25

Area where the density of genes is high

Answer 26

Area where the density of genes is low

Answer 27

Majority of chromosome where genomic variation is depressed

Answer 28

Disease associated regions of chromosome where mutations are more frequent

Answer 29

38% of genome | 54% of genome

Answer 30

Looser bound parts of DNA containing transcribed genes

Answer 31

Tighter bound parts of DNA containing telomeres and centromeres

Answer 32

The "missing heritability" problem can be defined as the fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on "the combined effect of all the genes in the background than on the disease genes in the foreground".

Answer 33

5mb of DNA | Required Double Strand Breaks

Answer 34

Balanced: Normal complement of chromosomal material Unbalanced: Abnormal complement of chromosomal material

Answer 35

A reciprocal, interchromosomal exchange. A break in an arm of each of two chromosomes and an exchange of material.

Answer 36

No apparent gain or loss of genetic material | No phenotypic effect (exception when the breakpoint is in a gene)

Answer 37

Balanced: Alternate splicing Unbalanced: Adjacent splicing

Answer 38

In a reciprocal translocation, two non-homologous chromosomes break and exchange fragments.

Answer 39

Centromeres of homologues go to opposite poles | Only mode of segregation that leads to gamete with full and balanced chromosome complement

Answer 40

Adjacent centromeres go to same pole | Results in trisomy and monosomy for translocated segments

Answer 41

The larger the translocation the greater the chance of additional translocations. This is because there are additional sequences that can bind to homologue chromosome in incorrect spot.

Answer 42

0-30%. Maternal carriers have a greater chance than paternal.

Answer 43

Structural chromosomal rearrangement between acrocentric chromosomes at the centromere. Short arm lost. Risks to having offspring with unbalanced karyotypes

Answer 44

α (centromeric area – some, not all) β satelites I-IV rRNA encoding genes

Answer 45

13;14 - 75% 14;21 21;21

Answer 46

Usually no phenotype Risk to having offspring with unbalanced karyotype Increased infertility in balanced RT men

Answer 47

46 chromosomes Normal homologue PLUS RT homologue - usually leads to trisomy 21 (or 13)

Answer 48

Inverted segment in chromosome Normal phenotype (usually) Familial ~1% of population Can be pericentric or paracentric

Answer 49

Inverted segment including centromere Break in both p and q arm

Answer 50

9 qh, 16qh, 1qh, Yqh Not associated with SAB, infertility or recombinant offspring

Answer 51

Form loops to maximize pairing Potential to form recombinant chromosomes which result in deletions and duplications (~50%) (can result in trisomy phenotype)

Answer 52

Normal fetal development VSD (Ventricular Septal Defect) Hypertelorism, thin upper lip, wide face Recurrent risk of 6.7% in families

Answer 53

Inversions NOT including centromere Two breaks within the same arm

Answer 54

Aniridia Turner Syndrome Chromosomes with either two or zero centromeres which are highly unstable

Answer 55

Critical protein TBX-1 involved in neural crest cells into pharyngeal arches and pouches resulting in cleft lip/palate and heart defects. Thymus defects: T cell dysfunction Parathyroid defects: hypocalcemia

Answer 56

Mitotic and meiotically heritable variations in gene expressions that are not caused by changes in DNA. They are reversible, post-translatable modifications of histones and DNA methylation.

Answer 57

DNA gets methylated in CpG islands MeCP2 recognizes methylated regions and deacetylates histones which causes them to tighten their binding with DNA. This silences the genes... except when it doesn't...

Answer 58

Genes are methylated depending on if they are paternal or maternal. This ensures the proper modulation of genetic material so the proper number of proteins are produced.

Answer 59

In the gamete It is reversible and reestablished during gametogenesis to transmit the appropriate sex-specific imprint to progeny

Answer 60

It isn't. It is stable once the embryo is fertilized.

Answer 61

Prader-Willi Syndrome: Deletion of paternal 15q11-13 Angelman Syndrome: Deletion of maternal 15q11-13

Answer 62

The region on a chromosome proximal to the genes which determine what genes will be expressed.

Answer 63

Mitotic disjunction early in gestation which kicks out an extra chromosome, rescuing it from lethality. Can lead to Prader-Willi or Angelman syndromes

Answer 64

Hypodiploid: Poor Hyperdiploid: Favorable

Answer 65

B-lymphoblastic leukemia

Answer 66

Fluorescence In Situ Hybridization: Used to identify specific chromosomal abnormalities by annealing fluorescent probes to known sequences.

Answer 67

Translocations Determining products of gene fusion (BCR/ABL) Marking chromosomes and then marking specific genes

Answer 68

PML-PAR(alpha) | ABL1-BCR

Answer 69

Acute Promyelocytic Leukemia 46, XY,t(15;17)

Answer 70

Chronic Myeloid Leukemia 46, XY, t(9;22) Treat with Gleevec

Answer 71

Targets DNA on a slide | Detects gains and losses

Answer 72

``` Genome Screen Mitotic Cells Selected Cells Gain/Loss Balanced Rearrangements Technologist Expertise ```

Answer 73

``` Genome Screen Interphase DNA Analyze all cells Gain/Loss only Technology-dependent Detects runs of homozygosity ```

Answer 74

Detects chromosomal gains/losses of tiny mutations. Detects abnormalities in known hot spots Detects abnormalities in backbone

Answer 75

DiGeorge Syndrome

Answer 76

- Deletions: >200kb - Duplications: > 400kb - ROH: > 5Mb - 10Mb

Answer 77

enumeration - ALL panel; prenatal dx

Answer 78

Trisomy 21: 95% Unbalanced Translocation involving chromosome 21: 3-4% Mosaic trisomy 21: 1-2%

Answer 79

- Normal growth - Midfacial hypoplasia - Upslantng palpebral fissures - Small Ears - Protruding tongue - Low muscle tone, increased joint mobility - Short fingers, transverse palmar crease, 5th finger incurving, increased space between 1st and 2nd toes

Answer 80

- Cardiac (50%): Atrioventricular Canal is most common to DS. - Gastrointestinal (10-15%): Esophageal atresia, duodenal atresia, Hirschprung's (missing ganglion cells in colon) - Functional GI issues: Feeding problems, constipation, GERD, Celiac Dz - Ophthalmologic: Blocked tear ducts, myopia, lazy eye, nystagmus, cataracts - ENT: Chronic ear infections, deafness, chronic nasal congestion, enlarged tonsils and adenoids - Endocrine: Thyroid Dz, insulin dependent diabetes, alopecia areata, reduced fertility - Orthopedic: hips, joint subluxation, atlantoaxial subluxation - Hematologic Issues: Myeloproliferative disorder, increased risk of leukemia, iron deficiency anemia

Answer 81

- Hypotonia effects gross motor development - Spectrum of intellectual disability - average is mild-moderate disabilities - Speech problems - Neurologic problems: hypotonia, seizures - Psychiatric issues: depression, early onset Alzheimer's, Autism

Answer 82

1st Trimester - Ultrasound measurements of nuchal folds - β-hCG - PAPP-A 2nd Trimester - αFP - Unconjugated estriol and inhibin levels

Answer 83

Genetic information missing from paternal allele of 15q11-q13. Can occur by uniparental disomy or imprinting error. Tested by using FISH or microarray

Answer 84

Prader-Willi Syndrome - errors or deletions in paternal imprinted regions of chromosome 15. Angelman Syndrome - errors or deletions in maternal imprinted regions of chromosome 15.

Answer 85

Infancy: hypotonic, almond shaped eyes, undescended testicles (males), feeding problems, lighter pigmentation Toddler/Preschooler: feeding problems reverse - overeat

Answer 86

Eyes: Strabismus Orthopedics: scoliosis Respiratory: Obstructive sleep apnea

Answer 87

Developmentally: Mild-moderate cognitive disabilities, and behavioral issues are common

Answer 88

Autism | Polymorphisms is GABA locus (important neurotransmitter)

Answer 89

Mildly dismorphic facial features which evolve with age. Hypotonia in infancy which leads to spasticity. Intellectual disability, seizures, Autism

Answer 90

Phenotypical only from mom. Autism. NOT dysmorphic, seizures, hypotonia during infancy

Answer 91

Pharmacogenetics: Study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity (variable response due to individual genes) Pharmacogenomics: Genomic approach to pharmacogenetics, concerned with the assessment of common genetic variants in the aggregate (variable response due to multiple loci across the genome)

Answer 92

Pharmacokinetics: describes Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs. Pharmacodynamics: describes the relationship between the concentration of a drug at its site of action and the observed biological effects.

Answer 93

CYP450 complex are detoxifying proteins active in liver and intestinal epithelium. Most CYPs function to inactivate drugs but rarely are needed for activation (CYP2D6: codeine -> morphine)

Answer 94

Metabolizes cyclosporine, ketoconazole, rifampin, grapefruit juice inhibits

Answer 95

Metabolizes codeine (activation into morphine)

Answer 96

Metabolizes Warfarin

Answer 97

Metablozies Isoniazid

Answer 98

Metabolizes 6-mercaptopurine/ 6-thiguanine prescribed for childhood ALL

Answer 99

Deficiency causes hemolytic anemia Given after sulfa drugs

Answer 100

The study of allele frequencies and changes in allele frequencies in populations

Answer 101

- Population is large - Matings are random - Allele frequencies remain constant over time . no appreciable rate of mutation . all genotypes are equally fit . no significant immigration/ emigration

Answer 102

Introduction of genetic variation to propagate fitness and new genetic traits

Answer 103

No matter how many X chromosomes there are, there is still only one that is fully active. The remainders probably have little function which leads to genetic disorder when there is aneuploidy

Answer 104

Generally the presence of a normal Y chromosome results in a male individual. Presence of a normal X chromosome and absence of a Y chromosome results in a female individual

Answer 105

7th wk: Male genital ridge Sertoli ; Leydig Cells 8th wk: Male --> Leydig produce testosterone; Sertoli produce Anti Mullerian Hormone; primitive sex cords --> testis cords; rete testis Female --> Primitive sex cords dissociate. cortical cords are formed Genital ducts: Mesonephric (Wolffian) duct: Male (under influence of testosterone) Paramesonephric (Mullerian) duct: Female

Answer 106

Based on Prader Scale from "no virilization" to stage 5 "full virilization"

Answer 107

``` Day 1: FISH studies for sex chromosomes and karyotype Hormone studies Ultrasound study (evaluate for gonads; uterus) Surgical consult with urology, endocrinology, genetics, psychology ```

Answer 108

``` 45, XO - Signs at birth . prenatal cystic hygroma . webbed neck . puffy hands and feet . heart defects - Short stature - Normal intelligence - Infertility - Hormone dysfunction - low set ears and broad chest - 1/2500 newborn girls ```

Answer 109

``` 47, XXY - Can be seen in childhood . learning disabilities . Delayed speech . tendency toward being quiet - Tall stature - Small testes - Reduced facial and body hair - Infertility - Hypospadias - Gynecomastia - 1/500 - 1/1000 newborn boys ```

Answer 110

47, XYY - Learning disabilities - Speech delays - Developmental delays - Behavioral and emotional difficulties - Autism spectrum disorders - Tall stature - 1/1000 newborn boys

Answer 111

``` 47, XXX - Tall stature - Increased risk of . Learning disabilities . Delayed speech . delayed motor milestones . Seizures . Kidney abnormalities - 1/1000 newborn girls ```

Answer 112

46, XY Causes abnormality of androgen receptor Phenotypes range from mild under-virilization to full sex reversal

Answer 113

46, XY Causes decreased ability of the body to convert testosterone to dihydrotestosterone Phenotype: undervirilized male with increased virilization at puberty

Answer 114

``` Both originate from urogenital sinus Male structures: Androgen exposure leads to - penis - scrotum - urethral opening at tip of penis Female structure: Estrogen exposure leads to - clitoris - labia majora and minora - lower 2/3 of vagina ```

Answer 115

maintenance methylation

Answer 116

Maternal chromosome 15, silencing transcription

Answer 117

Phenotype depends on whether the mutation is maternal or paternal in origin

Answer 118

reversible modification to chromatin structure

Answer 119

Modification must remain stable after fertilization

Answer 120

AML - acute myelogenous leukemia

Answer 121

acute lymphoblastic (ALL)

Answer 122

enumeration leukemias (ALL)

Answer 123

acute promyelocytic (APL)

Answer 124

identification of markers and translocations

Answer 125

indiscriminate eating and obesity

Answer 126

47, XX, +21 / 46, XX

Answer 127

amniocentesis followed by FISH

Answer 128

Alpha satellites

Answer 129

They are non-functional genes that can be synthesized through reverse transcription

Answer 130

54% AT, 38% CG may occur in clusters or be distributive

Answer 131

They are often enriched with sequence gaps Copy number variations are often enriched with specific duplications, sequence gaps and are associated with recurrent disease. CNV's are a primary structural variation in DNA. CNV's are not highly conserved, rather they have been associated with rapid evolutionary and genetic change. CNV's cover 12% of the genome, and can range from one additional copy to many.

Answer 132

Duplication rich regions are associated with non-allelic homologous recombination

Answer 133

X-linked dominant

Answer 134

13 4 siblings 2 parents 7 children

Answer 135

Carriers do not have the phenotype

Answer 136

Two 30 year old individuals have the same single-gene disease that affects muscle tone. One must use a wheelchair and the other is able to walk

Answer 137

Only males are affected and all sons must have an affected father

Answer 138

2q estimates 2pq

Answer 139

trisomy 13 (Patau Syndrome)

Answer 140

46, XX der(14;18)(p12;p12)+18 (Edwards Syndrome) Usually due to translocation not UPD (also, mother is young so UPD not likely) so A and B are incorrect. D would be the phenotype for a Patau syndrome caused by translocation.

Answer 141

anaphase During mitosis, sister chromatids segregate from each other during anaphase. Mitosis = one round of DNA replication + one round of chromosome segregation. Daughter cells are identical to the parent cells.

Answer 142

prophase I

Answer 143

DNA replication during prophase

Answer 144

46XY, del (4)(p13.3) represents a terminal deletion

Answer 145

15q11-q13 paternal deletion (detected by FISH), normal karyotype

Answer 146

the patient will be phenotypically normal 15q duplications that are paternally derived will show a normal phenotype. 15q duplications that are maternally derived will have partial trisomy as the phenotype and increased likelihood of autism It must be a paternal DELETION to be Prader-Willi; Angelman's is associated with a maternal deletion.

Answer 147

at onset of excessive eating symptoms onset

Answer 148

increase height, alleviate excessive eating.

Answer 149

IDIC 15 (Supernumerary marker chromosome) IDIC is the most common marker for autism. These patients are hypotonic but not dysmorphic, seizures common (Supernumerary marker chromosome)

Answer 150

100% Since the first baby has a normal Y you can assume that the mom is the carrier of iXq. Though her phenotype is normal, this is the only X she can pass on. All offspring will have the isochromosome for X.

Answer 151

diminished recombination cause by a lack of chiasmata or mislocated chiasmata, faulty segregation of chromosomes by oocytes

Answer 152

Cell 1: 47, XXY infertile, Cell 2: 47, XYY fertile Paternal error in meiosis 1 results in 47XXY, Klinefelter. Patients are usually infertile with tall stature, hypogonadism, gynecomastia and language impairment. Paternal error in meiosis 2 results in XYY (XYY syndrome). Patients are phenotypically normal and usually fertile. Increased risk of behavior and educational/speech problems, but not associated with criminality. Both are 1/1000 live births

Answer 153

a female with isochromosome for the long arm of X

Answer 154

46, Y fra(X)(q27.3)

Answer 155

balanced pericentric

Answer 156

disjunction during anaphase, recombination during prophase disjunction (segregation) during anaphases 1 and 2, recombination (crossover) during prophase 1 Nondisjunction most frequently occurs during anaphase 1 but can happen during anaphase 2.

Answer 157

develop as males but have gonadal dysgenesis

Answer 158

external female genitalia with male gonads

Answer 159

genetic presence or absence of Y, development of gonads, development of internal and external organs

Answer 160

involves cis formation of XIST RNA/Barr body complex

Answer 161

pharmacogenetics

Answer 162

rifampicin induces CYP3A to metabolize cyclosporin more quickly rifampicin induces CYP3A to metabolize cyclosporin so the patient will need more cyclosporin so that he will not reject his new kidney

Answer 163

the examination of individual alleles and their differences Pharmacokinetics = how much/if a drug reaches its target Pharmacogenetics = examines a few genes/individual allele differences Pharmacogenomics = examines polymorphic loci at large Pharmacodynamics = what happens once the drug reaches its target

Answer 164

it is involved in the conversion of codeine into morphine

Answer 165

increased copy number

Answer 166

acute lymphoblastic leukemia patients Mercaptopurines will cure ALL in patients who have a normal active TMPT gene to break it down. If they don't, it will put them at risk for myelosuppression because they will break down ~0.5% of the drug and end up with no bone marrow and most likely die of immunosuppression. In patients with minimal TMPT activity, use 10% of normal dose

Answer 167

narrow therapeutic window in populations with wide therapeutic window in individual patients

Answer 168

a higher than standard dose a higher than standard dose is necessary because the patient will metabolize the drug more rapidly than patients with normal CYP3A4 levels

Answer 169

warfarin warfarin is metabolized by CYP2C9 and VKORC1 CYP2D6 metabolized: beta blockers, tricyclic antidepressants, opioids (codeine)

Answer 170

inhibition of CYP3A metabolism making the patient hypotensive the patient will be hypotensive because CYP3A metabolism is inhibited by grapefruit juice. The drug will have amplified effects because it will not get broken down.

Answer 171

Complex traits aggregate in families Do not follow simple Mendelian modes of inheritance Need to be teased out from environmental factors

Answer 172

``` Some cancers Type 1 diabetes Type 2 diabetes Alzheimer disease Inflammatory bowel disease Schizophrenia Cleft lip/palate Hypertension Rheumatoid arthritis Asthma ```

Answer 173

Twin studies using monozygotic and dizygotic twins are the favored designs for teasing out whether a disease is genetic or environmental.

Answer 174

Overlap in disease prevalence between target and control groups makes it difficult to determine the contribution of factors leading to disease.

Answer 175

the presence of the same trait in both members of a pair of twins.

Answer 176

Genetic Factors

Answer 177

Genetic Factors

Answer 178

λs = (risk of disease in siblings of affected)/(risk of disease in general population)

Answer 179

The proportion of variance in a trait that is due to genetic variation.

Answer 180

``` Incomplete penetrance (not all will show signs of disease) Variable expressivity (not all will have same effect of disease) Allelic Heterogenteity (different alleles may express as same disease or different diseases) Presence of phenocopies (environment may cause phenotype that mimics genetic version of trait) ```

Answer 181

Genes play a major role in disease. Genes can be systematically discovered Gene discovery provides clues to disease pathogenesis which may lead to new treatments/prevention May lead to testing of high risk individuals

Answer 182

Association studies occur where the disease allele frequency is relatively high but the effect size (odds ratio) is relatively small Genetic linkage studies occur with rarer allele frequency but high effect size (think Mendelian single-gene diseases).

Answer 183

Microsatellites Single nucleotide polymorphisms Copy number variants

Answer 184

Exome sequencing good for use in Mendelian diseases . Exome is only approximately ~1% of genome so cheaper to sequence only a portion that is necessary for identifying disease. This doesn't help for more complex diseases that are diseases of regulation segments of DNA.

Answer 185

Requires polymorphic DNA markers Genotype polymorphic DNA markers at known positions Sometimes they are surrogates for gene mutations (i.e. they don't necessarily cause disease but they indicate a gene that does). This occurs due to linkage disequilibrium. Identified using microsatellites, SNPs, CNVs, physical/genetic maps

Answer 186

``` Karyotype of 45, XO Abnormalities of CVS - Bicuspid Aortic Valve - Coarctation of aorta - Hypertension - Prolonged QTc Syndrome - Partial anomalous pulmonary venous connection - Persistant left SVC Abnormalities of the eye - inner canthal folds - Ptosis - Blue Sclera Skeletal System - Cubitus Valgus - Short 4th metacarpal - Short Stature ```

Answer 187

Infertility Stature Sexual development Concerns regarding health and aging

Answer 188

Secret keeping Difficulty in communicating the infertility diagnosis Perceived negative experiences with physicians

Answer 189

Phenotype expressed only in homozygotes Males and females affected equally Horizontal inheritance pattern Parents of affected children are obligate carriers The recurrence risk for each child is 1/4 Chance an unaffected child is a carrier is 2/3

Answer 190

Allelic heterogeneity: The presence of multiple common mutant alleles of the same gene in a population Compound heterozygote: An individual who carries two different mutant alleles of the same gene Parental consanguinity: Blood related parents High-risk groups: Small populations with higher than expected mutant allele prevalence.

Answer 191

High levels of phenylalanine in blood High levels of phenylalanine metabolite in urine Hyperactivity and epilepsy Mental retardation and microcephaly

Answer 192

Defects either in PAH (phenylalanine hydroxylase >98%) or its cofactor, BH4 (tetrahydrobiopterin Tyr requires PAH The pathways to convert Tyr -> dopamine and Trp -> serotonin require BH4

Answer 193

PKU women need to maintain low-Phe diet. If they stray, you increase the risk of miscarriage and congenital malformations.

Answer 194

Tandem Mass Spectrometry sorts molecules by size and charge. Needs to occur soon (but not right after) birth to determine the phenylalanine concentrations of the child once they are on their own.

Answer 195

``` Deficiency in α1-antitrypsin Northern European disease 1/2500 (1/25 carrier) Increased risk of developing emphysema Increased risk of cirrhosis and liver cancer Increased symptom severity in smokers ```

Answer 196

α1-antitrypsin (or SERPINA1) inhibits elastase. Elastase is released by activated neutrophils, destroying elastin in the connective tissues. A deficiency allows elastin to breakdown the elastin at a higher rate, leading to lung disease.

Answer 197

Z-allele is the most common allele. Individuals with the Z/Z genotype have 15% normal SERPINA1 protein. This misfolding of the protein leads to it building up in the liver causing liver damage. S allele is less common. Individuals with the S/S genotype have about 50-60% normal SERPINA1 protein.

Answer 198

A fatal genetic disorder in children that leads to rapid degeneration of the central nervous system. Death usually in 2-4 years.

Answer 199

T-S is a lysosomal storage disorder of the GM2 ganglioside in the lysosome. GM2 ganglioside is primarily synthesized in neurons of the brain. T-S patients are unable to degrade the GM2 ganglioside because of a defective hexosaminidase A gene (HEX A)

Answer 200

All lead to accumulated glycolipids. They differ in what part of the chain they affect. T-S affects the α subunit of the hexosaminidase protein (HEX A) Sandhoff disease affects the β subunit T-S AB variant affects the GM2AP gene which is an activator of the hexosamidase protein.

Answer 201

Ashkenazi jews are the high-risk population. DNA testing can detect ~95% of carriers.

Answer 202

α-like genes: ζ in embryonic stage, α2 and α1 from fetal to adult stage β-like genes: ε in embryonic stage, γ in fetal stage, δ then β in adult. LCR regulates globin transcription

Answer 203

Sickle cell anemia is caused by a mutation in the β6 Glu codon which changes to the code to a Val. This causes Hb S fibers in low-O2 states which leads to vaso-occlusion Hemoglobin C disease changes the Glu to a Lys causing similar but milder symptoms

Answer 204

Using Mst II cleaves the β RNA at three sites creating a distinct Southern blot. In sickle cell disease, the enzyme only cuts in two places causing a different Southern blot profile.

Answer 205

``` αα/αα: Normal αα/α-: Silent Carrier αα/--: α-thalasemia 1 trait (mild) α-/α-: α-thalasemia 2 trait (mild) α-/--: severe anemia (HbH) --/--: hydrops fetalis ```

Answer 206

Thalassemia Major: Severe decrease in β-globin production "Cooley's anemia" Thalassemia Minor: Decreased but sustainable production in β-globin production β0-thalassemia: Complete loss of β-globin production β+-thalassemia: Almost total loss of β-globin production β0-thal allele: Complete loss of β-globin production on an allele. β+-thal allele: Reduced production of β-globin production on an allele. simple β-thalassemias: single mutation variation complex thalassemias: multiple mutation variation

Answer 207

HPFH is a disorder in which fetal hemoglobin persists into adulthood. It usually is asymptomatic and may have potential treatment affect in sickle cell disease and β-thalassemias.

Answer 208

``` α-thal-1 (--): SE Asia --/--: hydrops fetalis α-/--: HbH disease αα/--: mild anemia α-thal-2 (α -): Africa, Mediterranean, Asia α-/α-: mild anemia αα/α-: silent carrier ```

Answer 209

``` Qualitative: - Hb S (Sickle Cell Disease) - Hb C (Hemoglobin C Disease) - Hb E (SE Asian β-Thalassemia) Quantitative: - α-thalassemia - β-thalassemia - γ-thalassemia - δ-thallassemia ```

Answer 210

269mm worldwide carriers - 15% of Africans are S carriers - 7% of SE Asians are E carriers - 4-5% of SE Asians and Mediterraneans are β-thal carriers

Answer 211

``` Homozygous SS disease: Sickle Cell Anemia S Heterozygous: AS: Sickle Cell Trait Sickle Syndromes: 1) Hemoglobin SC hemoglobinopathy 2) SB° thalassemia 3) SB+ thalassemia ```

Answer 212

Homozygous CC hemoglobinopathy Heterozygous C C-β-thalassemia

Answer 213

Homozygous EE Heterozygous AE E-β-thalassemia

Answer 214

``` Red cell transfusion Iron chelators Vitamin C Splenectomy/cholecystectomy Bone marrow transplant ```

Answer 215

Passed by either parent One allele is sufficient to transmit trait Rare homozygous when mutation causes disease

Answer 216

Reduced penetrance | Variable expresivity

Answer 217

``` Expansion of DNA consisting of three nucleotides. Slipped mispairing Anticipation Parental transmission bias AD, AR and X-linked transmission ```

Answer 218

Autosomal dominant CAG repeat disorder Anticipation - Paternal - earlier onset Progressive neuronal degeneration Onset 35-44, death 15years later Mutation in HTT gene - expansion of Glu may cause altered structure of protein

Answer 219

``` Autosomal dominant Small stature Rhizomelic limb shortening short fingers Genu varum Trident hands Large head/frontal bossing Mid facial retrusion Small foramen magnum ``` Mutation in Fibroblast Growth Factor Receptor 3 (FGBR3) - Regulates bone growth by limiting cartilage > bone formation - Missense mutation increasing the activity of the protein interfering with skeletal development

Answer 220

2 or more of the following - 6 or more cafe-au-lait spots - 2 or more neurofibromas - 1 plexiform neurofibroma - Freckling in axillary or inguinal area - Optic glioma - 2 or more Lisch Nodules - Distinctive osseous lesions - Affected first degree relative Mutation in NF1 gene - tumor suppressor Loss of function mutation Dominant but requires second NF1 mutation

Answer 221

Systemic disorder of connective tissue - Ocular - Skeletal - Cardiovascular ``` Diagnosis: - Aortic root enlargement - +1 of the following . Ectopia lentis . FBN1 mutation . Systemic score >7 ```

Answer 222

X-linked recessive: phenotype in all males and homozygous females. Heterozygote females are carriers X-linked dominant: phenotype expressed in homozygote females and all males.

Answer 223

Always from maternal side mitochondrial DNA sorts randomly so depending on the amount of mtDNA in each egg, disease could be more severe. Group of diseases center around tissues that require heavy oxidative phosphorylation: brain, retina, skeletal muscle and heart.

Answer 224

Half of female cells express the maternally-inherited X and half express the paternal-inherited X.

Answer 225

XIST - gene located on X chromosome expressed only from the inactivated X. Majority of genes on inactive X chromosomes are methylated, inactivating them. Nonrandom X chromosome inactivation occurs when there are structural abnormalities. Skewed X inactivation observed when a female shows signs of symptoms of an X-linked recessive condition such as Duchene Muscular Dystrophy

Answer 226

X-linked dominant - Hypophosphatemia - Short stature - Bone deformity Gene: PHEX - Regulates fibroblast growth factor - Inhibits kidneys ability to reabsorb phosphate

Answer 227

``` X-linked dominant Gene: FMR1 Trinucleotide repeat: CGG Most common inherited cause of inherited development delay Anticipation Maternal transmission bias (transmitte on X-chromosome) - Intellectual diabilities - Dysmorphic features (large ears, long face, macroorchidism) - Autistic behavior - Social anxiety - Hand flapping/biting - Aggression ```

Answer 228

``` X-linked recessive disorders Spectrum of muscle diseases - Duchenne Muscular Dystrophy - Becker Muscular Dystrophy - DMD-associated dilated cardiomyopathy Mutation in DMD gene (largest human gene) ```

Answer 229

Progressive muscular weakness: proximal > distal Calf hypertrophy Dilated cardiomyopathy Elevated creatine kinase levels Onset prior to 5yo, wheelchair bound before 13, death by 30

Answer 230

X-linked recessive - Blood disorder where blood fails to clot (deficiency in Factor VIII) - Spontaneous bleeds into joints, muscles, intracranial - Excessive bruising - Prolonged bleeding after injury Mutation in F8 gene

Answer 231

1) Different gene expression pattern/phenotype, identical genome 2) Inheritance through cell division, even through generations 3) Like a switch: on/off 4) Erase-able (inter-convertible)

Answer 232

Cell states start as pluripotent cells but finally rest in a "lower energy state" of differntiation

Answer 233

Cells differentiating into discrete organs Ancestral behavior affects methylation Disease can occur from methylation reversing and having the cell turn into an undifferentiated cell (cancer)

Answer 234

Methylation occurs on CpG islands. When cells reproduce the reciprocal strand will have the same sequence. New strand is methylated based on parental strand

Answer 235

DNA Methylation Histone Modification Chromatin State

Answer 236

Protein structures that can form (prion disease) | Cytoplasmic epigenetic cycle

Answer 237

Silencing of a tumor suppressor gene can lead to cancer. Treatment can include using a DNA methyltransferase and histone deacetylase to "open up" the tumor suppressor.

Answer 238

Caused by genetic mutations (deletions, insertions or rearrangements) that eliminate or reduce the function of a protein. Duchenne Muscular Dystophy Alpha-thalassemia Turner Syndrome Hereditary neuropathy w/ liability to pressure palsies Osteogenesis Imperfecta Type I (trimer collagen disease)

Answer 239

Caused by genetic mutations that increase the function (or quantity) of a protein. Hemoglobin Kempsey Charcot Marie Tooth

Answer 240

Caused by a genetic mutation that alters the behavior of a protein Sickle cell anemia Osteogenesis Imperfecta Types II, III, IV

Answer 241

Caused by altered promotors/silencer mechanism which fails to alter gene expression Hereditary Persistence of Fetal Hemoglobin

Answer 242

Transcription: Thalassemias, Hereditary Persistence of Fetal Hemoglobin Translation: Thalassemias Polypeptide folding: More than 70 hemoglobinopathies Post-translational Modification: I-cell disease Assembly of monomers into a holomeric protein: Osteogenesis imperfecta Subcellular localization of the polypeptide or the holomer: Familial hypercholesterolemia Cofactor or prosthetic group binding to the polypeptide: homocystinuria Function of a correctly folded, assembled, and localized protein produced in normal amounts: Hb Kempsey

Answer 243

Disease severity worsening in subsequent generations. Genetic anticipation is explained by the mechanism of tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster.

Answer 244

Diseases that are genetically related (due to the same gene) ex: Duchenne, Becker 1 and Becker 2 Muscular Dystophy (Dystrophin Gene) ex2: CMT1A and HNPP (PMP22 Gene)

Answer 245

Examining biochemical or genetic material that indicate the presence or absence of genetic disease.

Answer 246

Allelic heterogeneity refers to multiple mutations of the same allele, each able to contribute to a disease. Genetic heterogeneity refers to multiple genes, each able to contribute to a disease. Negative genetic results don't always mean the patient doesn't carry the disorder. Will need to be confirmed by testing affected individuals in same family.

Answer 247

Observing the visual characteristics of a chromosome. Can diagnose aneuploidy, duplications, rearrangements, insertions and deletions great in size that 5Mb Cannot diagnose single gene deletions, point mutations, small deletions, duplications, and insertions, methylation defects, trinucleotide repeat abnormalities.

Answer 248

Observing specific alterations of the chromosome (need a hybridized marker) usually beyond the resolution of chromosomal analysis. Best during interphase. Used to observe deletions, translocations and abnormal copy numbers in chromosomes, Cannot diagnos any diseases not specifically known (need a fluorescent hybridized marker that is known. Not good for point mutations.

Answer 249

Expression Arrays generally used to test the presence of RNA (expression). These test the activity of genes rather than just the presence or absence of them. Chromosomal Micro Arrays look for chromosomal deletion/duplications. Used as a higher resolution version of chromosomal analysis as you can observe changes in chromosomes with a resolution of ~200kb (del) ~400kb (dup) vs 5Mb. Used for aneuploidies, unbalanced chromosomal rearrangements, chromosome deletions and duplications Can't diagnose abnormalities less than resolution

Answer 250

When mutations in certain genes are known, can be used to identify small DNA level mutations. Advantages - very sensitive 1-100bp detection. Can detect known or novel mutations. Disadvantages - might miss whole gene deletions.

Answer 251

Trisomy 21 - Supportive care and cardiac surgery Multiple Endocrine Neoplasia - prophylactic surgery Metabolic Diseases - Enzyme Replacement Therapy

Answer 252

Alpha-1 AT (Antitrypsin) - elastases unchecked: recombinant AT1 therapy Fabry Disease - Deficiency of alpha-galactosidase A: Recombinant Alpha-Galactose therapy

Answer 253

Gene Therapy: Introduction of genetic material into human cells to treat an acquired or inherited disease Principle: Introduction of a disease should cure or slow down the progression of the disease Approaches: Non-viral, viral, in/ex vivo

Answer 254

``` Avoidance Dietary Restriction Replacement Diversion Inhibition Depletion ```

Answer 255

Achondroplasia - GOF mutation - Advanced paternal age (de novo) - Autosomal dominant - FGFR3 transmembrane TKR - inhibits bone growth Nonsyndromic Deafness - LOF mutation - Congenital deafness (recessive), Progressive deafness (dominant) - 3/4 nonsyndromic - GJB2 mutation Fragile X Syndrome - FMR1 gene - Triplet repeat expansion - LOF/GOF

Answer 256

Achondroplasia - Prenatal onset - Rhizomelic short stature - Megalencephaly - Spinal cord compression Nonsyndromic Deafness - Congenital deafness (recessive) - Progressive deafness (dominant) Fragile X Syndrome - Age at onset: childhood - Mental deficiency - Dysmorphic facies - Male postpubertal macroorchidism

Answer 257

Achondroplasia - FGFR3 mutation: PCR genetic sequencing Nonsyndromic Deafness - GJB2 mutation: PCR genetic sequencing Fragile X Syndrome - Southern Blot

Answer 258

variable expressivity Neurofibromatosis Type 1 presents with autosomal dominance, 100% penetrance, and variable expressivity. The clinical presentation includes cafe au lait spots, Lisch nodules, neurofibromas, pheochromocytomas and scoliosis. The mutation is of the NF-1 gene on chromosome 17.

Answer 259

locus heterogeneity This patient has autosomal dominant polycystic kidney disease, a genetic disorder with locus heterogeneity. Locus heterogeneity means that mutations to different genes can produce the same phenotype. PKD1 = 85% PKD2 = 14.5% Clinical features include bilateral enlarged kidneys with multiple cysts, end-stage renal disease, extrarenal cysts, intracranial aneurysms, hypertens

Answer 260

Tay-Sachs disease a cherry red spot on the eye is a characteristic feature of lipid storage disorders, such as Tay-Sachs, and in central retinal artery occlusion

Answer 261

Sandhoff Disease In Tay-Sachs, only HexA activity is affected. In AB variant, neither HexA nor HexB activity is affected in this test. In Sandhoff disease, both HexA and HexB activity are affected.

Answer 262

Z/Z Patients with this genotype produce only 10%-15% of normal levels of alpha1-antitrypsin, whose role is to inhibit elastase. Z/Z accounts for most cases of disease. M/M is normal. S/S genotypes have 50%-60% of normal levels and do not express disease symptoms S/Z are compound heterozygotes that produce 30%-35% of normal levels. These patients may develop emphysema. The Z allele makes a misfolded protein that aggregates in the ER of the liver, leading to damage to liver and lung. The S allele makes an unstable protein that is less effective in inhibiting elastase.

Answer 263

The baby has low levels of phenylalanine, and therefore does not have PKU PKU is caused by a defect in the phenylalanine hydroxylase (PAH) enzyme causing phenylalanine to accumulate in the blood. In the Guthrie bacterial inhibition assay, the infant's blood is added to an agar plate containing Bacillus subtilis and thienylalanine. Thienylalanine normally inhibits B. subtilis but high levels of phenylalanine; however, block inhibition by thienylalanine. B. subtilis growth suggests PKU but does not specify the cause; i.e., the problem could be in the PAH cofactor tetrahydrobiopterin (BH4).

Answer 264

expanded CTG repeats at the 3' UTR The novel function of DM1 is due to expanded CTG repeats at the 3'UTR. The disease is inherited in an autosomal dominant. DM1 has two variants: congenital, which is more severe, and mild. The congenital form demonstrates maternal anticipation (associated with increased maternal age); can be lethal and results in severe intellectual disability. Females can pass on thousands of repeats, dads can only pass on about 1,000.

Answer 265

Friedreich's Ataxia Friedreich's Ataxia is caused by a loss-of-function mutation. Fragile X/FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome) are X-linked. Huntington is autosomal dominant. Myotonic dystrophy is autosomal dominant.

Answer 266

multiplex families (families with multiple cases of a disease) share genome segments that are disproportionately co-inherited Affected relatives share disease susceptibility genes (not phenocopies) Genetic linkage studies are best for Mendelian traits (rare alleles with strong effects); less powerful for complex traits.

Answer 267

microsatellites Microsatelites are a common way to track haplotypes and do genetic linkage analysis. Recombination blocks are used for genetic association studies. SNPs are commonly used for Genome-Wide Association Studies (GWAS). CNVs are less useful for genetic studies

Answer 268

association suggests linkage disequilibrium with a causal mutation Real association doesn't imply causation but you can identify linkage disequilibrium that is linked to causal mutation. Simple studies with simple stats (chi square, Fisher) and small sample size (100s) must apply multiple test correction if testing multiple variants. Must match cases and controls ethnically.

Answer 269

ethnic categories are often the product of two more ancient populations so controls may have 2 different allele frequencies but are counted as genetically similar 2 populations may have mixed so 2 separate allele patterns are considered one ethnic category example would be if ‘African American’ were an ethnicity. If African American = African + European + Spanish + Italian + Native American then a single ethnic group will have a lot of variation.

Answer 270

high, because penetrance is 100% The Population Attributable Risk (PAR) is high for diseases that are 100% penetrant even if the odds ratio is low because the odds ratio only calculates the risk of having/not having the variant, not the chance of disease if you have it.

Answer 271

two alphas, two deltas There are two forms of adult hemoglobin. The major form (97%) is HbA and is comprised of two alphas and two betas, the minor form is HbA2 and is comprised of two alphas and two deltas.

Answer 272

alpha, beta, gamma, and delta alpha and gamma are turned on in early embryogenesis 1. Zeta and Epsilon turned off, alpha and gamma turned on early in embryogenesis 2. Gamma turned off eventually, beta and delta turned on at birth. The switch from gamma to beta is gradual, taking ~120 days. At birth there is still gamma.

Answer 273

Sickle Cell Anemia The diagnostic test for sickle cell anemia is a restriction digest test. A restriction site is deleted in SSA, so that the fragment is actually longer. Longer fragments do not move as far in a gel electrophoresis. Hemoglobin C disease is not distinguishable from sickle cell anemia based on this test. This would not be an appropriate test to diagnose HPFH or Alpha thalassemia.

Answer 274

Loss of function Osteogenesis imperfecta type 1 is the diagnosis. The mechanism is loss of function of the COL1A1 protein. The inheritance pattern is autosomal dominant.

Answer 275

HbA Cooley's anemia = no good copies of the beta-globin gene. Patients cannot make HbA and are severely anemic, have low MCV (small RBCs) and will be transfusion dependent. Physical findings of Cooley's: Osteopenia Dense skull, marrow expansion Iron overload and endocrine failure Enlarged spleen Treatment: Vitamin C, RBC infusions, iron chelation, splenectomy, bone marrow transplant.

Answer 276

HbA2 production HbA2 would not make much of a difference because they produce normal amount (it's made from alpha and delta) Osteopenia, splenomegaly, iron overload Treat with: blood transfusion, iron chelation therapy, bone marrow transplant, vitamin C You will not know a child has beta-thalassemia major until after birth

Answer 277

anti-malarial drugs G6PD is a metabolic disease, treatment = avoid anti-malarial drugs because you can't break them down

Answer 278

during adolescence As girls affected with Turner's syndrome progress through adolescence, the process of transitioning to adult PCP's and specialists becomes paramount.

Unit 2 Flashcards

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