Single Gene Defects

Question 1

What inheritance pattern does this family tree represent?

Answer 1

Autosomal dominant inheritance

Question 2

What inheritance pattern does this family tree represent?

Answer 2

Autosomal recessive inheritance

Question 3

What inheritance pattern does this family tree represent?

Answer 3

Autosomal recessive inheritance with consanguinity

Question 4

What inheritance pattern does this family tree represent?

Answer 4

X-linked recessive inheritance

Question 5

What inheritance pattern does this family tree represent?

Answer 5

Mitochondrial inheritance

Question 6

List 5 characteristics of a pedigree which demonstrates an autosomal dominant inheritance pattern.

Answer 6

Both sexes are equally affected; both sexes transmit to offspring; disease is present in all generations (although an individual may have been undaignosed 2/2 mild phenotype, incomplete penetrance, or age-related penetrance); every affected child has a parent with the disorder; fathers can transmit to sons.

Question 7

Which Mendelian inheritance pattern has a high “spontaneous” mutation rate?

Answer 7

Autosomal dominant disorders have a high spontaneous mutation rate and, therefore, there are more people who present with a disorder and no accompanying family history.

Question 8

What risk factor increases the likelihood of a child having a new/spontaneous autosomal dominant mutation?

Answer 8

Increased paternal age

Question 9

If an unaffected parent has more than one child with a new autosomal dominant condition, what should be suspected of the parent?

Answer 9

That they have germline mosaicism for the AD disorder.

Question 10

What is germline mosaicism?

Answer 10

When a parent carries a gene mutation in gonadal tissue and germline cells but not somatic cells. The parent would not have signs of disease, but their children are at increased risk of inheriting the condition.

Question 11

List 5 characteristics of a pedigree which demonstrates an autosomal recessive inheritance pattern.

Answer 11

No history of disease in prior generations; males and females are equally affected; males and females can each transmit the altered allele; the risk for two heterozygotes to have an affected offspring is 1/4 (however, two heterozygotes can also have offspring who are all affected or all unaffected); consanguinity increases the risk of having offspring with an AR disorder.

Question 12

What is dosage compensation?

Answer 12

This is the inactivation of one of the two X chromosomes in each cell early in female embryonic life, which means that despite the extra X chromosome in females, they have the same amount of X-linked gene products as males.

Question 13

Which form of classic Mendelian inheritance does not have Male-to-Male transmission?

Answer 13

X-linked disorders

Question 14

Which form of classic Mendelian inheritance has a father passing the disease allele to all of his daughters and none of his sons?

Answer 14

X-linked disorders

Question 15

What is somatic mosaicism?

Answer 15

This is the result of the random inactivation of the second X chromosome in each cell in females. If the two X chromosomes produce different phenotypes, the mosaicism may be visible in the patient.

Question 16

What is hemizygosity?

Answer 16

This refers to males; since they only have one X chromosome, they are considered to be hemizygous for every allele at each locus on the X-chromosome. This means that if a male inherits an X-linked allele for a disease, he will be affected.

Question 17

List 4 characteristics of a pedigree which demonstrates an X-linked recessive inheritance pattern.

Answer 17

There is never male-to-male transmission; if a generation has only females, the disease will appear to have skipped that generation; an affected father transmits the disease allele to all his daughters but none of his sons; carrier females have a 50% chance of transmitting the disease to each son.

Question 18

What is genomic imprinting? Describe an example.

Answer 18

Genomic imprinting refers to differences in gene expression that depend on whether the disease allele is inherited from the mother or the father. The classic example is Prader Willi (microdeletion inherited from father) vs Angelman (same microdeletion, but from mother).

Question 19

What is uniparental disomy?

Answer 19

Uniparental disomy occurs if both copies of a chromosome - or a piece of a chromosome - are inherited from only one parent.

Question 20

How might uniparental disomy result in a child developing Prader Willi or Angelman syndrome?

Answer 20

If the child inherits both copies of chromosome 15 from either the mother or the father, it’s functionally the same as if they inherited a deletion from the parent whose chromosomal material is missing. The result is Prader Willi/Angelman.

Question 21

How is mitochondrial inheritance unique?

Answer 21

Mitochondrial inheritance is unique because the ovum, not the sperm, transmits all the mitochondria to their zygote. Therefore, a mother carrying a mitochondrial DNA mutation passes it on to all her offspring, whereas the father carrying the mutation passes it on to none of his offspring.

Question 22

List 5 disorders which have mitochondrial inheritance.

Answer 22

Myoclonic Epilepsy and Ragged-Red Fibers (MERRF), Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), Leigh syndrome, Kearns-Sayre syndrome, and Pearson syndrome.

Question 23

What is the inheritance pattern and typical clinical picture associated with Myoclinic Epilepsy and Ragged-Red Fibers (MERRF)?

Answer 23

It is a mitochondrial disorder associated with progressive myoclonic epilepsy, myopathy, dementia, and hearing loss.

Question 24

What is the inheritance pattern associated with MELAS, and what are its typical clinical findings?

Answer 24

It is a mitochondrial disorder (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) that presents anytime from toddlerhood to adulthood.

Question 25

What is the inheritance pattern associated with Leigh syndrome and how does it present clinically?

Answer 25

It is a mitochondrial disorder which presents with basal ganglia defects, hypotonia, and optic atrophy in infancy or early childhood.

Question 26

What is the inheritance pattern associated with Duchenne muscular dystrophy and what are some important clinical features of the disease?

Answer 26

It is an X-linked recessive disorder which presents in males with progressive muscle weakness and delayed motor milestones, calf hypertrophy, Gowers sign at ~2 years of age, and wheelchair dependency generally by 12 years of age.

Question 27

What is the inheritance pattern associated with Kearns-Sayre syndrome, and how does it present clinically?

Answer 27

It is a mitochondrial disorder which presents with ophthalmoplegia, retinitis pigmentosa, myopathy, and cardiac conduction defects. It is the diagnosis given to children with Pearson syndrome who survive beyond infancy.

Question 28

What is the inheritance pattern associated with Pearson syndrome, and how does it present clinically?

Answer 28

It is a mitochondrial disorder which presents with anemia, neutropenia, pancreatic dysfunction, and myopathy in infants. Patients who survive beyond infancy (most die in infancy) go on to develop Kearns-Sayre syndrome.

Question 29

List four examples of trinucleotide repeat diseases.

Answer 29

Friedreich ataxia, Huntington disease, Fragile X syndrome, and Myotonic dystrophy.

Question 30

Which 3 DNA bases are repeated pathologically in Fragile X syndrome?

Answer 30

CGG

Question 31

Which 3 DNA bases are repeated pathologically in myotonic dystrophy?

Answer 31

CTG

Question 32

What is the most common inherited intellectual disability syndrome?

Answer 32

Fragile X syndrome

Question 33

Describe anticipation in relation to trinucleotide repeat disorders.

Answer 33

Anticipation refers to the increasing severity of disease with each cycle of genetic transmission due to the expansion of disease-causing trinucleotide repeats.

Question 34

Which gene on which chromosome is affected in Fragile X syndrome?

Answer 34

The FMR1 gene on the X chromosome

Question 35

List 6 classic clinical findings in patients with Fragile X syndrome.

Answer 35

Intellectual disability, large head, long face with large ears, large hands and feet, macroorchidism after puberty, and hyperextensible joints.

Question 36

What is Fragile X-associated tremor/ataxia syndrome (FXTAS)?

Answer 36

It is a neurodegenerative disorder of older adults who are carriers of the fragile X premutation (~50-200 CGG repeats rather than the full disease-causing >200 repeats). Clinical criteria include intention tremor with gait ataxia and parkinsonism.

Question 37

What is the inheritance pattern for myotonic dystrophy?

Answer 37

It is an autosomal dominant trinucleotide repeat disease.

Question 38

What are the typical clinical features of myotonic dystrophy?

Answer 38

Myotonia with progressive weakness and wasting; involvement of facial and jaw muscles (e.g. ptosis, atrophy of sternocleidomastoid muscles); myotonia on grip testing (they grip your hand to shake but then can’t let go because the muscles won’t relax).