Genetics

Question 1

Codominance

Answer 1

Both alleles contribute to the phenotype of the heterozygote

Ex: blood groups A,B,AB

Question 2

Variable expressivity

Answer 2

Phenotype varies among individuals with same genotype

Ex: 2 pts with neurofibromatosis type 1 may have varying disease severity

Question 3

Incomplete penetrance

Answer 3

Not all individuals with a mutant genotype show the mutant phenotype

Ex: BRCA1 gene meutations do not always result in breast or ovarian cancer

Question 4

Pleiotropy

Answer 4

One gene contributes to multiple phenotypically effects

Ex: PKU manifests with light skin, intellectual disability, and musty body odor

Question 5

Anticipation

Answer 5

Increased severity or earlier onset of disease in succeeding generations

Ex: trinucleotide repeats in Huntington

Question 6

Loss of heterozygosity

Answer 6

The complementary allele of a mutated tumor suppression gene becomes mutated or deleted resulting in cancer

Ex: retinoblastoma

Question 7

Dominant negative mutation

Answer 7

Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning

Ex: mutation of transcription factor in its allosteric site leading to blocking of functioning wild type transcription factor from binding

Question 8

Linkage disequilibrium

Answer 8

Tendency for certain alleles at 2 linked loci to occur together more often expected by chance

Question 9

Mosaicism

Answer 9

Presence of genetically distinct cell lines in the same individual. Arises from mitotic errors (chromosomal nondisjunction)

Ex: McCune-Albright syndrome: endocrine excess, polyostotic fibrous dysplasia, unilateral cafe au lait spots

Question 10

Locus heterogeneity

Answer 10

Mutations at different loci can produce a similar phenotype

Ex: albinism

Question 11

Allelic heterogeneity

Answer 11

Different mutations in the same locus produce the same phenotype

Ex: beta-thalassemia

Question 12

Heteroplasmy

Answer 12

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondiral inherited disease

Question 13

Uniparental disomy

Answer 13

Offspring receives 2 copies of a chromosome from 1 parent an no copies from the other parent

Question 14

Hardy weinberg population genetics

Answer 14

p^2 + 2pq + q^2 =1
p+q =1
p^2 = allele frequency for p
q^2 = allele frequency for q
2pg = allele frequency for heterozygosity

Assumes:
No mutations occuring at locus
Natural selection is not occuring
Complete random mating
No net migration

Question 15

Imprinting

Answer 15

At some loci, only one allele is active, the other is inactive

With one allele inactivated, deletion/mutation of active allele leads to disease

Question 16

Prader-Willi syndrome

Answer 16

Maternal imprinting: gene from mom is normally silent and Paternal gene is mutated or deleted

Resulting in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia

25% due to uniparental disomy

Question 17

AngelMan Syndrome

Answer 17

Paternal imprinting: gene from dad is normally silent and Maternal gene is mutated or deleted

Resulting in inappropriate laughter (happy puppet),
seizures, ataxia, and severe intellectual disability

5% due to uniparental disomy

Question 18

Autosomal dominant

Answer 18

Often due to defect in structural genes

Many generations affected, both male and female

Often pleiotropic, family hx very important

Question 19

Autosomal recessive

Answer 19

25% of offspring from 2 carrier parents are affected

Often due to enzyme deficiencies

Usually only seen only in 1 generation

Commonly more severe than dominant disorders and patients often present in childhood

Question 20

X-linked disease

Answer 20

Located on X chromosome

Sons of heterozygous mothers have 50% chance of being affected. No male-to-male transmission

Commonly more severe in males, females usually must be homozygous to be affected

Question 21

X-linked dominant

Answer 21

Transmitted through both parents, mothers transmit to 50% of sons and daughters, fathers transmit to all daughters by no sons

Question 22

Hypophosphatemic rickets

Answer 22

X-linked dominant disorder

Vitamin D resistant rickets, increased phosphate wasting at proximal tubule resulting in ricket like presentation

Question 23

Mitochondrial inheritance

Answer 23

Transmitted through the mother. All offspring of affected females may show signs of disease

Question 24

Mitochondrial myopathies

Answer 24

Mitochondrial inherited disease

Often present w/ myopathy, lactic acidosis, and CNS disease

Secondary to failure in oxidative phosphorylation

Muscle biopsy often shows “ragged fibers”

Question 25

Autosomal dominant polycystic kidney disease

Answer 25

Autosomal dominant disorder

Always bilateral, massive enlargement of kidneys due to multiple large cysts

85% cases due to mutation in PKD1 (chromosome 16, 16 letters in polycystic kidney)

Remainder due to mutation in PKD2 (chromosome 4)

Question 26

Familial adenomatous polyposis

Answer 26

Autosomal dominant

Colon becomes covered in polyps after puberty, progress to colon cancer unless colon is resected

Mutation of APC gene on chromosome 5 (5 letters in polyp)

Question 27

Familial hypercholesterolemia

Answer 27

Autosomal dominant

Elevated LDL due to defective or absent LDL receptor

Leads to severe atherosclerotic disease early in life and tendon xanthomas

Question 28

Hereditary hemorrhagic telangiectasia

Answer 28

Autosomal dominant

Inherited disorder of blood vessels

Commonly present w/ telangiectasia, recurrent epitaxis, AVMs, GI bleeding

Question 29

Hereditary spherocytosis

Answer 29

Autosomal dominant

Spheroid erythrocytes due to spectrin or ankyrin defect, leading to hemolytic anemia

Treatment: splenectomy

Question 30

Hungtinton disease

Answer 30

Autosomal dominant

Gene on chromosome 4 with trinucleotide CAG repeat mutation, increased # of repeats lead to decreased age of onset

Usually present w/ depression, progress dementia, and choreiform movements accompanied by decreased lvl of GABA and ACh

Question 31

Marfan syndrome

Answer 31

Autosomal dominant

Fibrillin-1 gene mutation leading to connective tissue disorder

Usually presents with long extremities, hypermobile joints, aortic incompetence and dissecting aorta, subluxation of the lenses

Question 32

Multiple endocrine neoplasias (MEN)

Answer 32

Autosomal dominant

MEN1: pituitary, parathyroid, pancrease
MEN2a: pheochromocytoma, medullary thyroid, parathyroid
MEN2b: pehochromocytoma, medullary thryoid, marfanoid, mucosal and digestive neurofibromatosis

MEN2a MEN2b associated w/ ret gene

Question 33

Neurofibromatosis type 1 (von Recklinghausen)

Answer 33

Automsomal dominant

Neurocutaneous disorder characterized by cafe-au-lait spots and cutaneous neurofibromas

Caused by mutations in the NF1 gene on chromosome 17

Question 34

Neurofibromatosis type 2

Answer 34

Autosomal dominant

bilateral acoustic schwannomas, juvenile cataracts, menigiomas

Caused by mutations in the NF2 gene on chromosome 22

Question 35

Tuberous sclerosis

Answer 35

Autosomal dominant

Neurocutaneous disorder with mutli-organ system involvement characterized by benign hamartomas

Question 36

Von Hippel-Lindau

Answer 36

Autosomal dominant

Disorder characterized by development of numerous tumors, both benign and malignant (pheo, pancreatic cyst, renal carcinoma)

Associated w/ deletion of VHL gene (tumor suppressor) on chromosome 3

Question 37

Cystic fibrosis

Answer 37

Autosomal recessive

Defect in CFTR gene on chromosome 7, commonly a deletion of Phe508

CFTR mutation (misfolded proteins) leads to decreased lung and GI secretion of Cl and decreased resorption of Cl in sweat glands leading to abnormally thick mucus secreted into lungs and GI tract

Diagnosed with increased Cl concentration (> 60 mEq) in sweat

Complications include recurrent pulmonary infections, bronchiectasis, pancreatic insufficiency, malabsorption, nasal polyps, meconium ileus in newborns, and infertility in males (absence of vas deferens or sperms)

Question 38

Duchenne muscle dystrophy

Answer 38

X-linked recessive

Frameshift mutation leading to truncated dystrophin protein and accelerated muscle breakdown

Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscles

Gower sign: pts use upper extremity to help themselves stand up

Question 39

Becker muscle dystrohpy

Answer 39

X-linked recessive

Point mutation in dystrophin gene, less severe than Duchenne

Question 40

Myotonic type 1 muscle dystrophy

Answer 40

X-linked recessive

CTG trinucleotide repeat expansion in the DMPK gene leading to abnormal expression of mytonin protein kinase

Presents w/ myotonia, muscle wasting, cataracts, and arrythmia

Question 41

Fragile X syndrome

Answer 41

X-linked recessive

Defect affecting the methylation and expression of the FMR1 gene, trinucleotide repeat CGG

2nd most common cause of intellectual disability

Findings: post pubertal macroorhidism, long face w/ large jaw, autism, mitral valve prolapse

Question 42

Down syndrome

Answer 42

Trisomy 21 (drinking)

Findings: intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, duodenal atresia, Hirsprung disease, congenital heart disease (ASD)

Inc nuchal transparency
Quad screen: dec AFP, inc bHCG, dec estriol, inc inhibin A

Question 43

Edward syndrome

Answer 43

Trisomy 18 (election)

Findings: severe intellectual disability, rocker bottom feet, micrognathia, low set ears, clenched hands, congenital heart disease

Quad screen: dec AFP, dec bHCG, dec estriol, dec inhibin A

Question 44

Patau syndrome

Answer 44

Trisomy 13 (puberty)

Findings: severe intellectual disability, rocker-bottom feet, microphthalamic, microcephaly, cleft lip/palate, holoprosencephaly, congenital heart disease

Inc nuchal transparency

Question 45

Cri du chat syndome

Answer 45

Deletion of short arm of chromosome 5

Findings: microcephaly, high pitched crying, congenital heart disease (VSD)

Question 46

Williams syndrome

Answer 46

Deletion of long arm of chromosome 7

Findings: elfin facies, hypercalcemia, extreme friendliness w/ strangers

Question 47

DiGeorge syndrome

Answer 47

CATCH 22
Cleft palate, abnormal facies, thymic dysplasia, cardiac defects, hypocalcemia 2ndary to parathyroid aplasia, microdeletion at chromosome 22q11