Updated: 7/10/2018

Genetic Principles

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Principles
  • Codominance
    • both allelic copies are expressed
      • e.g.) blood groups (A, B, AB)
  • Variable expression
    • nature and degree of phenotype vary from 1 individual to another with the same mutation
      • e.g.) 2 patients with neurofibromatosis may have varying disease severity
  • Incomplete penetrance
    • not all individuals with a mutant genotype have diseased phenotype
      • explanation for a dominant disease "skipping" a generation
    • penetrance can be calculated by ( # with symptoms) / (# with disease genotype)
      • must be figured into recurrance calculations
        • if parents have a 50% chance of giving defective gene but the penetrance is 50%
          • 0.5 x 0.5 x100 = 25% of recurrence
    • observed in recessive and dominant diseases
  • Pleiotropy
    • single mutation has diverse effects upon several organ systems
      • e.g.) PKU
  • Anticipation 
    • changes in disease presentation in succeeding generations
      • ↑ severity
      • earlier onset 
    • caused by trinucleotide expansion
      • region of repeating triplets expands in each generation
      • e.g.) Huntington's disease, fragile X, myotonic dystrophy, Friedreich ataxia
  • Loss of heterozygosity
    • "two-hit model"
    • individual inherits or develops a mutation in one copy of gene
      • disease occurs when the complementary allele is lost
    • e.g. tumor suppressor diseases (Li-Fraumeni, retinoblastoma)
  • Dominant negative mutation
    • mutant gene product antagonizes wild-type gene product
      • exerts a dominant effect
      • e.g.) common in multimeric proteins where one mutant subunit can change function of entire enzyme
  • De novo mutation
    • genetic disease in an individual with no familial history
    • recurrence risk for offspring of same parents is low
  • Locus heterogeneity 
    • different mutations can produce the same phenotype
      • e.g., marfanoid habitus caused by
        • Marfan's syndrome, MEN 2B, homocystinuria
  • Heteroplasmy
    • presence of both normal and mutated mitochondrial (mt)DNA in the same cell
      • results in variable expression in mitochondrial inherited disease   
  • Uniparental disomy 
    • offspring receives both copies of a chromosome from 1 parent
      • no copies from the other parent
      • causes disease if the chromosome is usually imprinted
        • see Epigenetics topic
  • Polygenic inheritance 
    • multiple genes are responsible for inheritance of a disease
    • e.g.) androgenic alopecia
  • Heritability
    • can measure the relative effect of genetic vs. environmental factors on a phenotype
      • calculated by phenotypic relationship between dizygotic (DZ) and monozygotic (MZ) twins
      • heritability = (CMZ-CDZ) / (1-CDZ)
        • where C = concordance
          • prevalence of disease in both twins
          • entirely environmental disease should have CMZ = CDZ
          • entirely genetic disease should have CMZ=1.0 and CDZ=0.5
            • siblings share 50% of their genes
 

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Questions (10)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.BC.72) A 3-year-old is brought to the pediatrician by his mother because she is concerned about recent changes to his behavior. She states that he has seemed to regress in his motor development and has been having occasional brief episodes of uncontrollable shaking. During the subsequent work up, a muscle biopsy is obtained which demonstrates red ragged fibers and a presumptive diagnosis of a genetic disease made. The mother asks if her other son will be affected. What should be the physician's response? Review Topic

QID: 106531
1

There is a 100% he will be affected, but the severity may be different

59%

(64/108)

2

There is a 25% chance he will be affected

8%

(9/108)

3

He will be unaffected

5%

(5/108)

4

There is a 100% he will be affected, and the severity will be the same

15%

(16/108)

5

There is a 50% chance he will be affected

11%

(12/108)

M1

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PREFERRED RESPONSE 1
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(M1.BC.72) A 35-year-old male is brought to the physician by his wife who is concerned because he has begun to demonstrate odd behavior which has worsened over the past several months. She states that he has become very aggressive and at times will have sudden, jerky movements which he is unable to control. The patient states that his father had the same problem which he died of at age 69. The patient had a recent, "cold," with fevers, chills and, "throat pain," which resolved on its own, "some time ago." Which of the following is true of this disease? Review Topic

QID: 106511
1

A mutation in ATP7B on chromosome 13 is responsible

7%

(1/14)

2

Erythema marginatum is a complication associated with this disease

0%

(0/14)

3

Overactivity of dopamine in the mesolimbic pathway is the underlying pathology

0%

(0/14)

4

Underactivity of dopamine in the nigrostriatal cortex is the underlying pathology

14%

(2/14)

5

It demonstrates anticipation

71%

(10/14)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(M1.BC.73) A mother brings her 3-year-old daughter to the pediatrician because she is concerned about her development. She states that her daughter seemed to regress in her motor development. Furthermore, she states she has been having brief episodes of uncontrollable shaking, which has been very distressing to the family. During the subsequent work-up, a muscle biopsy is obtained which demonstrates red ragged fibers and a presumptive diagnosis of a genetic disease is made. The mother states that she has another 6-year-old son who does not seem to be affected or have any similar symptoms. What genetic term explains this phenomenon? Review Topic

QID: 106546
1

Allelic heterogeneity

21%

(6/29)

2

Phenotypic heterogeneity

17%

(5/29)

3

Genetic heterogeneity

17%

(5/29)

4

Heteroplasmy

34%

(10/29)

5

Locus heterogeneity

7%

(2/29)

M1

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PREFERRED RESPONSE 4

(M1.BC.1) A mother from rural Louisiana brings her 4-year-old son to a pediatrician. Her son is intellectually disabled, and she hopes that genetic testing will help determine the cause of her son's condition. She had previously been opposed to allowing physicians to treat her son, but his impulsive behavior and learning disabilities are making it difficult to manage his care on her own. On exam, the child has a long, thin face with a large jaw, protruding ears, and macroorchidism. The physician also hears a high-pitched holosystolic murmur at the apex of the heart that radiates to the axilla. Which of the following trinucleotide repeats is most likely affected in this individual? Review Topic

QID: 106988
1

CTG on chromosome 19

22%

(4/18)

2

CAG on chromosome 4

6%

(1/18)

3

GAA on chromomsome 9

0%

(0/18)

4

CGG on the sex chromosome X

72%

(13/18)

5

CTG on chromosome 8

0%

(0/18)

M1

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PREFERRED RESPONSE 4

(M1.BC.27) An 8-year-old male child presents to the pediatrician for slight exercise intolerance, headaches, and difficulty with hearing. The patient's father explains that the patient's mother had similar symptoms, however hers were much more severe and also included vision loss and seizures; the mother passed away two years ago as she developed significant dementia and profound weakness. The child was given an exercise test, and after 5 minutes of walking his blood lactate levels were 6 mmol/L (nl < 2 mmol/L). A muscle biopsy was performed and a Gömöri trichrome stain was done on the sample (Figure A). What genetic principle best explains the difference in symptoms seen between the mother and the child? Review Topic

QID: 107022
FIGURES:
1

Codominance

6%

(1/18)

2

Incomplete penetrance

39%

(7/18)

3

Pleiotropy

6%

(1/18)

4

Anticipation

6%

(1/18)

5

Heteroplasmy

44%

(8/18)

M1

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PREFERRED RESPONSE 5
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