Updated: 1/4/2021

Modes of Inheritance

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Pedigree Nomenclature

 pedigree

Autosomal Dominant (AD) 
  • Genders affected
    • male and female at equal frequency
  • Generations affected
    • does not skip generations
      • if two parents without the AD disease have child with an AD disease
        • possibility is reduced penetrance
          • have mutant gene but phenotypically normal
        • de novo germline mutation
    • an affected child must receive disease from an affected parent
      • a homozygote dominant parent has a 100% of having an affected child
      • two heterotyzgote parents with the AD disease condition have a 75% chance of having a child with the disease phenotype 
  • Pathology
    • defects in structural genes
  • Presentation timing
    • usually after puberty
  • Other notes
    • often pleiotropic
      • several organ systems affected by single genetic defect
    • only one copy of the defective gene is required to express the disease phenotype
  • Examples
    • von Willebrand disease (most common)
    • Huntington's disease
    • osteogenesis imperfecta
    • achondroplasia
    • Marfan syndrome
    • neurofibromatosis type I
    • acute intermittent porphyria
Autosomal Recessive (AR)
  • Genders affected  
    • male and female
  • Generations affected  
    • 1/4 of offspring affected when both parents are carriers 
    • 1/2 of offspring are carriers when both parents are carriers 
      • 2/3 of nonaffected children are carriers
    • usually 1 generation
  • Pathology
    • defects in enzymes
  • Presentation timing
    • infancy to childhood
  • Other notes
    • most often more severe than AD
    • must have 2 defective copies of the gene
    • chances greatly increased with consanguinity
  • Examples
    • cystic fibrosis - deficiency in the chloride channel CFTR
    • inborn errors of metabolism 
      • PKU, von Gierke's, Pompe's, glycogen storage diseases, sphingolipidoses (except Fabry's), and mucopolysaccharidoses (except Hunter's)
    • sickle cell anemia
    • thalassemias
    • albinism
    • ARPKD
    • hemochromatosis
 
X-linked Recessive (XR)
  • Genders affected
    • males must receive defective gene from carrier mother
      • carrier mother's sons have 50% of having disease 
    • affected males give copy to all of their daughters
  • Generations affected
    • skips generations
      • male-to-male transmission not allowed
      • diseases passes through carrier daughters
  • Pathology
    • defects in enzymatic genes
      • similar to AR diseases
  • Presentation timing
    • usually after puberty
  • Other notes
    • only one defective copy necessary for disease in males
      • because males are hemizygous for X chromosome
    • two defective copies necessary for disease in females
      • can be affected with just one defective copy if normal X chromosome is inactivated to Barr body
        • called manifesting heterozygotes
          • phenotype usually milder than affected males
  • Examples
    • hemophilia A and B 
    • Menke's disease 
    • Duchenne muscular dystrophy 
    • Lesch-Nyhan syndrome
    • Ornithine transcarbamoylase deficiency
    • red-green color blindness
X-linked Dominant (XD)
  • Genders affected
    • male and female at equal frequency
  • Generations affected
    • does not skip generations
      • only possibility is reduced penetrance
    • females of affected fathers are always affected 
      • male-to-male transmission not seen
    • male or females of affected mothers can be affected
  • Pathology
    • defects in structural genes
  • Presentation timing
    • usually after puberty
  • Examples
    • hypophosphatemic rickets
    • Fragile X syndrome
    • Alport syndrome
Mitochondrial Inheritance 
  • Genders affected
    • male and females at equal frequency
  • Generations affected
    • does not skip generations
    • only transmitted from affected female 
      • gives to all offspring
      • due to the fact that the sperm do not contribute mitochondria to the zygote
  • Pathology
    • defects in electron transport/oxidative phosphorylation process
      • presents as neuropathies/myopathies 
        • neurons and muscle cells require high amounts of energy and depend on mitochondria
  • Presentation timing
    • usually after puberty
  • Other notes
    • variable expression due to heteroplasmy
      • a small percentage of mitochondria within a cell are affected leading to variable severity
  • Examples
    • myoclonic epilepsy with ragged red muscle fibers  
    • Leber hereditary optic neuropathy 
    • MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) 
Inheritance Algorithm
  • Does offspring with disease have a parent with disease? (Y/N)
    • if YES
      • dominant (does not skip generations)
        • is there male-to-male transmission of disease? (Y/N)
          • if YES
            • autosomal dominant
          • if NO
            • do daughters of affected male have disease? (Y/N)
              • if YES
                • X-linked dominant
              • if NO
                • mitochondrial
    • if NO
      • recessive (can skip generations)
        • predominantly males with disease? (Y/N)
          • if YES
            • X-linked recessive
          • if NO
            • autosomal recessive

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Questions (23)
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(M1.BC.17.4708) An 11-year-old male is brought to his pediatrician for continuing management of a chronic lung infection. He has had many lung infections throughout childhood, and current sputum samples show oxidase positive, non-lactose fermenting gram-negative rods that produce a blue-green pigment. Physical exam shows nasal polyps and nail clubbing. He has also recently been experiencing floating foul smelling diarrhea, so he is prescribed enzymes and vitamin supplementation tablets. Which of the following chromosomes most likely contains the gene mutation responsible for this patient's symptoms?

QID: 108475
1

7

60%

(78/129)

2

11

16%

(21/129)

3

17

8%

(10/129)

4

22

5%

(6/129)

5

X

7%

(9/129)

M 2 C

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(M1.BC.15.73) A pregnant woman presents to your office with concerns regarding the risk that her fetus will suffer from an inherited disease. She reports a family history of hemophilia A in several of her relatives. Figure A shows a pedigree created after a thorough review of her family history (the pregnant woman in this scenario is represented by the arrow). This is her first child, and the father does not report any family history of blood disorders or other diseases. Which of the following is the probability that this woman's male offspring will have hemophilia A?

QID: 106552
FIGURES:
1

0%

15%

(3/20)

2

25%

40%

(8/20)

3

50%

35%

(7/20)

4

67%

5%

(1/20)

5

75%

5%

(1/20)

M 1 B

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(M1.BC.15.73) A 1-year-old boy with blonde hair, blue eyes, and fair skin is found to have mental retardation, eczema, and vomiting. A mousy body odor is apparent. Which of the following pedigrees best resembles the inheritance pattern of this disease?

QID: 106554
FIGURES:
1

Figure A

22%

(57/255)

2

Figure B

52%

(132/255)

3

Figure C

10%

(26/255)

4

Figure D

9%

(22/255)

5

Figure E

4%

(10/255)

M 1 D

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(M1.BC.15.1) A 19-year-old male presents to the university health clinic after a year of daily jerking in his limbs and experiencing a tonic clonic seizure witnessed by his roommate earlier today. He had been too embarrassed to come discuss his myoclonus, but he noticed that it had been increasing in frequency over the past few months. He noted that he tires very quickly when exercising, has poor vision and hearing, and was told that his mother, who passed away at his birth, also had similar symptoms. The physician sends for a muscle biopsy, which shows the following Gömöri trichrome stain (Figure A). What is the mode of inheritance of this disorder?

QID: 106971
FIGURES:
1

Autosomal recessive

8%

(8/97)

2

Autosomal dominant

1%

(1/97)

3

X-linked dominant

9%

(9/97)

4

X-linked recessive

14%

(14/97)

5

Mitochondrial inheritance

66%

(64/97)

M 1 D

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(M1.BC.15.0) A 5-year-old boy with a history of seizures presents to the pediatrician for several seizures occurring over the past month. The mother states that her son typically avoids recess, as he exhausts quite easily with any physical activity. He has also had headaches and vomits after he eats. A family history reveals that a maternal uncle and grandmother both had similar symptoms and both lost their vision and hearing by the age of 40. The mother explains that she also tires easily. With consent of the mother, a muscle biopsy was taken and a Gömöri trichrome stain was performed (Figure A). A blood analysis also revealed significantly elevated lactate levels. Which of the following statement best describes the mode of inheritance of the boy's disease?

QID: 107004
FIGURES:
1

Females of affected fathers are always affected

0%

(0/40)

2

3/4 of the offspring are affected when both parents are affected and heterozygous for the diseased allele

18%

(7/40)

3

1/4 of the offspring are affected when both the parents are carriers

8%

(3/40)

4

Males are affected more often than females

10%

(4/40)

5

Transmission only occurs from females and may have variable expression

60%

(24/40)

M 1 D

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(M1.BC.14.44) A 34-year-old male suffers from inherited hemophilia A. He and his wife have three unaffected daughters. What is the probability that the second daughter is a carrier of the disease?

QID: 103407
1

0%

6%

(3/48)

2

25%

6%

(3/48)

3

50%

42%

(20/48)

4

75%

2%

(1/48)

5

100%

42%

(20/48)

M 1 B

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(M1.BC.14.27) The incidence of red-green color blindness in males in a certain population is 1/100. Which of the following is closest to the probability of a female and a male with normal vision having a daughter with red-green color blindness?

QID: 107025
FIGURES:
1

1/100

15%

(4/27)

2

99/100

4%

(1/27)

3

1/50

11%

(3/27)

4

98/100

4%

(1/27)

5

0

67%

(18/27)

M 1 E

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(M1.BC.14.2) A 27-year-old G1P0 at 12 weeks gestation presents to her obstetrician for her first prenatal visit. She and her husband both have achondroplasia, and she is curious what are the chances that they will have a child of average height. What percent of pregnancies between two individuals with achondroplasia that result in a live birth will be expected to be offspring that are unaffected by this condition?

QID: 102720
1

25%

30%

(90/304)

2

33%

33%

(101/304)

3

50%

14%

(43/304)

4

75%

8%

(24/304)

5

0%

14%

(44/304)

M 1 D

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