Topics in genetics

Question 1

What populations are at high risk of which genetic diseases?

Answer 1

• African ancestry => sickle cell
• Ashkenazi Jews => tay-sachs, gaucher, canavan, etc
• Mediterranean => B-thalassemia
• SE Asian and Chinese => a-thalassemia, hemoglobin E

Question 2

Why are certain populations more susceptible to certain genetic diseases?

Answer 2

• Heterozygote advantage
• Founder effect
• Genetic drift
• Inbreeding

Question 3

Heterozygote advantage

Answer 3

• Heterozygotes are genetically more fit even when homozygotes have serious disease
• Sickle cell carriers are less likely to die of malaria during childhood

Question 4

Founder effect

Answer 4

When a small group of individuals migrate and found a new isolated population that is (by chance) genetically different than their original population

Question 5

Genetic drift

Answer 5

Change in frequency of a gene resulting by chance transmission at a higher or lower frequency than predicted

Question 6

What are some key principles of newborn screening?

Answer 6

• there must be a recognizable latent or early phase where intervention is possible before bad health effects begin
• natural history of condition must be understood
• agreed policy on whom to treat as patients

Question 7

How is newborn screening done?

Answer 7

• Physician/midwife must collect blood from heel stick onto filter paper and send to lab
• After 24 hrs of age (after feeding) but before discharge from nursery

Question 8

What kind of disorders are screened for?

Answer 8

• organic acid disorders
• FA ox defects
• AA disoders
• hemaglobinopathies
• CF
• biotinidase deficiency
• galactosemia
• hypothyroidism
• congenital adrenal hyperplasia
• congenital hearing loss
• severe combined immunodeficiency
• cyanotic congenital heart disease

Question 9

What are secondary targets of newborn screening?

Answer 9

Disorders that don’t merit screening for by will be diagnosed based on the testing for other disorders

Question 10

What is the inheritance pattern and cause of neurofibromatosis-1?

Answer 10

• autosomal dominant (haploinsufficiency)

- 50% of cases from new mutations

Question 11

incidence of NF-1

Answer 11

1/3500

Question 12

Diagnostic criteria for NF-1

Answer 12

Need 2+ of:

• 6+ cafe-au-lait spots > 0.5 cm in kids or 1.5 cm in adults
• axillary or inguinal freckling
• 2+ NFs or 1 plexiform NF
• optic pathway tumor
• 2+ iris Lisch nodules
• distinctive osseous lesion
• 1st degree relative with NF-1

Question 13

Neurofibromas

Answer 13

• Benign tumors commonly appearing around puberty
• Schwann cells, nerve fibers, fibroblasts
• cutaneous are soft, subcutaneous are firm
• not likely to become malignant
• dermal, internal, intraspinal (bad b/c of location), optic (bad b/c of location)

Question 14

Plexiform NFs

Answer 14

• present at birth
• “wormy” with indistinct edges, extend deep into tissue => excision difficult
• 10% risk of lifetime malignant transformation

Question 15

Iris Lisch Nodules

Answer 15

• Raised nodules on iris

- Clinically unimportant but useful diagnostic for NF-1

Question 16

Tibial pseudoarthrosis

Answer 16

• Complication of tibial dysplasia in NF-1

- thinning and bowing of tibia => frequent fractures that don’t heal well

Question 17

Sphenoid dysplasia

Answer 17

• posterior wall of orbit is fibrous not bony

- no clinical consequence, but indicative of NF-1

Question 18

Limb hypertrophy

Answer 18

• Not among diagnostic criteria for NF-1, but common

- Overgrowth of limb associated with presence of an NF

Question 19

Cognitive function in NF-1

Answer 19

• mean IQ just below normal and intellectual disability rare
• “clumsy”
• learning disabilities in 40-60%

Question 20

NF-1 gene and associated mutations

Answer 20

• large: > 350 KB
• high mutation rate: 1/10000
• 100+ mutations with none particularly common
• can’t predict phenotype from genotype

Question 21

Neurofibromin

Answer 21

• Expressed in all tissues, especially nerves

- Tumor suppressor than downregulates the Ras oncogene