1-25 Genetics (general)

Question 1

Populations at increased risk for some genetic diseases

Answer 1

AA: SCD
Ashkenazi Jews: Tay Sachs, Gaucher, Canavan
Mediterraneas: B-thalassemia (decreased hemoglobin produciton)
Southeast Asians, Chinese: a-thalassemia, hemoglobin E

Question 2

Heterozygote advantage

Answer 2

reason for higher SCD in african folk

carriers are less likely to die of malaria in childhood thus making them more fit

Question 3

founder effect

Answer 3

few individuals migrate and found a new isolated population, and now any mutant allele is higher represented in this population

ashkenazi jews

Question 4

genetic drift

Answer 4

change in freq in gene resulting from its transmission (by chance) at higher or lower freq than predicted

this has greatest impact in small populations

Question 5

Ashkenazi Jewish Prenatal Panel

Answer 5

screening for a panel of common disorders, couples are screened prenatally ususally blood test or cheek swab

sample tested for abnormalities

if both parents heterozygote, can have prenatal diagnosis by amniocentesis, preimplantation genetic diagnosis, sperm/egg donor, adoption, accept risk

has significantly reduced incidence of tay sachs in US, amniocentesis and termination of effected pregnancies

Question 6

Bacterial Inhibition Assay

Answer 6

urine samples of individuals used to ID those who were outputting higher rates of phenylalanine

Question 7

Principles of newborn screening

Answer 7

1. there should be a recognizable latent or early symptomatic state
2. natural history of condition including development from latent to declared disease should be adequately understood
3. There should be an agreed policy on whom to treat as patients

should be important health problem, accepted treatment, facilities and treatement are available, suitable test or exam, test/exam should be acceptable to population, cost should be economically balanced, case fidning is continous proccess

Question 8

Disorders included in newborn screenings

Answer 8

PKU, phyothyroidism, Galactosemia, Congential adrenal hyperplasia, biotinidase deficiency, SCD, CF

4 million births per year one of these, dictated by state laws

Question 9

New born screening in practice

Answer 9

governed by state laws

physician of record at birth in charge of conducting

sample should be collected after 24 hours of age but prior to discharge
blood collected from heel stick and placed on filter paper to dry

Question 10

Neurofibromatosis-1 diagnostic criteria

Answer 10

1:3500 autosomal dominant
50% of cases are from new gene mutations

1. 6+ cafe au lait spots: collections of heailyt pigmented melanocytes, occur in normal people, often present at birth and incrase in number during 2-3 years of life, benign
2. axillary or inguinal freckling: unusual sites for normal freckling
3. 2+ neurofibromas OR 1+ Plexiform NF: benign tumors made of schwann cells nerve fibrs fibroblasts, cutaneous NFs are fleshy soft, deeper ones are harder, since they arise from the nerve cells they can be throughout the body; Intraspinal Neurofibroma: grow out of vertebral column and press against spinal cord and vertebrae
4. optic pathway tumors: glioma, benign tumors but problematic because of location
5. 2+ iris lisch nodules: raised, clinically unimportant but useful diagnostic sign, 98% present in adults with NF1
6. Bone dysplasia: Tibial pseudarthrosis: thinning and bowing of tibia from tibial dysplasia from abnormal formation of bones, prone to fracturing; Sphenoid dysplasia: eyeball socket is fibrous not bony; Limb hypertrophy: impossible to treat with current therapy :(
7. first degree relative with NF-1

Cognitive function: mean IQ is 10% lower than mean, children are clumsy, learning disabilities are common 40%, no specific cognitive phenotype

Question 11

Plexiform neurofibromas

Answer 11

usually present at birth, histologically similars to NFs, overlying hyperpigmentation is common, “wormy” tumors with indistinct margins, grow along nerves and extend into contingous tissues and wrap around deep structures, may get very large, complete excision is usually impossible

have potential for malignant generation, malignancy is particularly resistant to treatments

Question 12

NF-1 gene

Answer 12

large, 350 kb, high mutation rate, more than 100 known mutations in NF1, no “common” mutation, no clear genotype-phenotype correlation, most mutations lead to decreased levels of gene product (haploinsufficiency)

Product: Neurofibromin: expressed in all tissues, especialy high in neurons, oligodendrocytes, schwann cells, acts as tumor suprpressor, downregulates Ras oncogene and may therby modulate cell growth and prolif

The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body.