Genomics

Question 1

Clinical trial phases

Answer 1

• A phase I trial looks at maximum tolerate dose and side effects.
• A phase II trial looks at efficacy and a
• phase III trial compares the treatment to alternatives.
• Long-term effects are monitored in phase IV.

Question 2

Ivacaftor

Answer 2

targets the mutant protein due to the G551D mutation increasing
Cl- flow through the mutant CFTR.

Question 3

deletions at 15q13.3

Answer 3

Those with deletions at 15q13.3 are at risk for epilepsy, in addition to
autism.

Question 4

MYO7A mutation

Answer 4

• MYO7A mutation can lead to
• AD deafness,
• deafness,
• or Usher syndrome;
• the fact that heterozygous mutation was found here suggests an AD mode of inheritance, and hence deafness.

Question 5

incontinenti pigmenti.

Answer 5

hyperpigmentation. She had had seizures
in the newborn period, which subsequently resolved. She had multiple skin lesions in the early weeks of life that began with vesicular lesions and later evolved

• This is associated with IKBKG mutation, which in 80% of cases is a deletion.

Question 6

Jervell and Lange-Nielsen syndrome

Answer 6

Long QT, deafness,
Explanation: Jervell and Lange-Nielsen syndrome is associated with congenital deafness and long QT interval.

KCNQ1 andKCNE1

Question 7

schwannomatosis

Answer 7

multiple schwannomas plus pain without vestibular tumor is characteristic
of schwannomatosis; mosaicism for NF2 would be a less likely possibility

Question 8

A newborn is having multiple seizures and you learn that there is a family history of the same in multiple relatives on the father’s side.

Answer 8

The history is most compatible with benign neonatal convulsions, which
are associated with mutations in a potassium channel encoding gene.

Question 9

tuberous sclerosis complex

Answer 9

everolimus is FDA approved for treatment of progressive angiomyolipoma
associated with tuberous sclerosis complex

Question 10

myotonic dystrophy

Answer 10

The weakness, preserved reflexes, and occurrence of milder weakness in
the mother are all suggestive of myotonic dystrophy. Charcot-Marie-Tooth would not present at this age and deep tendon reflexes would be absent in spinal muscular atrophy.
Congenital muscular dystrophy would not explain the mother’s weakness.

Question 11

Heritable pulmonary arterial hypertension (PAH)

Answer 11

pulmonary arterial pressure of 33 mmHg and otherwise normal
echocardiogram indicates pulmonary arterial hypertension (PAH).

• Maternal history of right heart failure during pregnancy suggests Heritable PAH.
• Slide 8 states that ~75% of HPAH cases are due to BMPR2 mutations and that ACVRL1, BMPR1B, EAG and SMAD9 are all rare causes of HPAH.

Autosomal Dominant

Question 12

Ivacaftor mechanism

Answer 12

• improves CF symptoms and underlying disease pathology by potentiating the channel open probability (or gating) of CFTR protein in patients with impaired CFTR gating mechanisms.
• The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation.

Question 13

severe combined immunodeficiency (X-SCID)

Answer 13

Key Words: recurring infections, onset 1-3 months, maternal uncle

Explanation: Recurring infections beginning at 1 month, FTT, and maternal uncle who died of recurring infections all suggest XL SCID.

• IL2RG mutations are found in > 99% of males with SCID.
• ADA is AR, FOXP3 causes IPEX syndrome (XL but very different phenotype), STAT3 causes Hyper IgE (AD) and ZAP70 causes AR SCID.