Chapter I: Single Gene Disorders (continued)

Question 1

List some X-linked dominant disorders

Answer 1

• hypophosphatemic rickets
• fragile X syndrome

Question 2

Create a basic decision tree for determining the mode of inheritance in a pedigree.

Answer 2

Create flow tree

Question 3

What are some key strategies to help deduce if a person has a mitochondrially inherited condition? What types of conditions are common when assessing mitochondrially inherited conditions?

Answer 3

• disease are transmitted only from affected females to their offspring
• both males and females are affected
• none of the offspring of the affected male are affected
• disease are typically neuropathies and/or myopathies

Question 4

Heteroplasmy

Answer 4

when a specific mutation occurs in some of the mitochondria, it can be unevenly distributed into daughter cells during cell division

Some cells may inherit more mitochondrial DNA that is normal

Question 5

What is the inheritance pattern shown in this pedigree.

Answer 5

mitochondrial inherited disease

Question 6

List some important mitochondrial diseases.

Answer 6

Leber hereditary optic neuropathy

MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

myoclonic epilepsy with ragged red muscle fibers (MERRF)

Question 7

What does it mean to have variable expression of a gene?

Answer 7

when genes vary in their degree of phenotypic expression

Question 8

What is a modifier loci?

Answer 8

when disease expression is affected by the action of other loci, termed modifier loci

Question 9

What is incomplete penetrance?

Answer 9

disease-causing mutation is said to have incomplete pentrance when some individuals who have the disease genotype (e.g. one copy of the mutation for an AD disease or 2 copies for an AR disease) do not display the disease phenotype

Question 10

What is the inheritance pattern of the pedigree shown?

Answer 10

incomplete penetrance

Question 11

Penetrance must be taken into account when predicting what value?

Answer 11

recurrence risks

Question 12

How is penetrance calculated?

Answer 12

by examining a large number of families and calculating the percentage of individuals who are known to have the disease causing genotype who display the disease phenotype

Question 13

How do you calculate recurrence risk if penetrance is involved?

Answer 13

multiply penetrance with the recurrence risk

Question 14

T/F. Incomplete penetrance can only be seen in dominant disorders?

Answer 14

False.
Can be seen in dominant or recessive disorders

Question 15

What is an example of a condition that can lead to incomplete penetrance?

Answer 15

hereditary hemochromatosis

Question 16

Pleiotropy?

Answer 16

when a single disease causing mutation affects multiple organ systems

Question 17

What is an example of a condition showing pleiotropy?

Answer 17

Marfan syndrome

Question 18

What are some signs/symptoms of Marfan syndrome?

Answer 18

• skeletal abnormalities (thin, elongated limbs; pectus excavatum; pectus carinatum),
• hypermobile joints,
• ocular abnormalities (frequent myopia and detached lens),
• cardiovascular disease (mitral valve prolapse and aortic aneurysm)

Question 19

Where is fibrillin commonly found?

Answer 19

in periosteum and perichondrium, the suspensory ligament of the eye, and the aorta

Question 20

Pathogenetic reason for why Marfan syndrome has its characteristic effects on certain tissue?

Answer 20

because fibrillin causes connective tissue to be ‘stretchy” and leads to all the observed disease features

Question 21

What is locus heterogeneity?

Answer 21

when the same disease phenotype can be caused by mutations in different loci

Question 22

What is an example of a condition that exhibits locus heterogeneity?

Answer 22

OI

Question 23

What type of inheritance pattern is the pedigree showing?

Answer 23

a new mutation

Question 24

What are some diseases that exhibit delayed Age of Onset?

Answer 24

• Acute intermittent porphyria (peri or postpubertal
• Huntington disease
• Hemochromatosis
• Familial breast cancer

Question 25

In this pedigree what does the number on the left and the number in parenthesis mean?

Answer 25

Number on left is age and number on right in parenthesis is the number of repeats.

Question 26

Name 4 symptoms of Huntingons disease.

Answer 26

* movement abnormality * emotional disturbance * cognitive impairment * death 10-15 years after onset

Question 27

Name symptoms of fragile X syndrome?

Answer 27

* intelectual disability * large ears and jaw * post-pubertal macro-orchidism (males) * attention deficit disorder (in females)

Question 28

Name some symptoms of myotonic dystrophy?

Answer 28

* muscle loss * cardiac arrhythmia * testicular atrophy * frontal baldness * cataracts

Question 29

Name some symptoms of Friedreich ataxia?

Answer 29

* early onset progressive gait and limb ataxia * areflexia in all 4 limbs * hypertonic cardiomyopathy * axonal sensory neuropathy * kyphoscoliosis

Question 30

Repeat and location of repeat found in Huntingtons?

Answer 30

CAG 5' coding

Question 31

Repeat and location of repeat found in Fragile X syndrome?

Answer 31

CGG 5' UTR

Question 32

Repeat and location of repeat in Myotonic dystrophy?

Answer 32

CTG 3' UTR

Question 33

Repeat and location of repeat in Freidreich ataxia?

Answer 33

GAA intron 1

Question 34

Which shows AR mode of inheritance? Huntington, Fragile X, Myotonic dystrophy or Freidreichs ataxia

Answer 34

Freidreich ataxia

Question 35

Spinobulbar muscular atrophy repeat?

Answer 35

CAG (polyglutamine disorder) in translating region

Question 36

Symptoms of spinobulbar muscular atrophy.

Answer 36

weakness, atrophy and fasciculations in the limb and bulbar muscles

Question 37

Is imprinting normal?

Answer 37

yes

Question 38

What does imprinting involve?

Answer 38

methylation and possibly other mechanisms to imprint or inactivate the appropriate loci

Question 39

General pathogenesis of both Prader Willi and Angelman Syndrome?

Answer 39

on rare occasion, the transcriptionally active gene may be deleted from the chromosome (perhaps by unequal crossover)

Question 40

Prader willi syndrome is caused by loss from which chromosome? Mother or father?

Answer 40

from father

Question 41

Angelman syndrome occurs because of deletion of father or mother chromsome?

Answer 41

deletion of 15q11-13 from maternal chromsome

Question 42

What is uniparental disomy? Relation of Angelman's and Prader Willi

Answer 42

rare condition in which both copies of a particular chromosome are contributed by one parent. This may cause problems if the chromosome contains an imprinted region or mutation

Question 43

Symptoms of Prader-Willi Syndrome?

Answer 43

* affects males and females * neonatal hypotonia * poor feeding in neonatal period * behavior problems * moderate intellectual disability and developmental retardation * hypogonadism, underdeveloped genitalia * hyperphagia (overeating) and obesity by ages 2-4 years ***** * small hands and feet * deletion from paternal 15q * very low recurrence risk

Question 44

Symptoms of Angelman Syndrome.

Answer 44

* affects males and females * severe intellectual disability * seizures * ataxia * puppet-like posture of limbs * happy disposition ****** * deletion from maternal 15 q * very low recurrence risk