Genetics Flashcards
Codominance
Both alleles contribute to the phenotype of the heterozygote
Ex: blood groups A,B,AB
Variable expressivity
Phenotype varies among individuals with same genotype
Ex: 2 pts with neurofibromatosis type 1 may have varying disease severity
Incomplete penetrance
Not all individuals with a mutant genotype show the mutant phenotype
Ex: BRCA1 gene meutations do not always result in breast or ovarian cancer
Pleiotropy
One gene contributes to multiple phenotypically effects
Ex: PKU manifests with light skin, intellectual disability, and musty body odor
Anticipation
Increased severity or earlier onset of disease in succeeding generations
Ex: trinucleotide repeats in Huntington
Loss of heterozygosity
The complementary allele of a mutated tumor suppression gene becomes mutated or deleted resulting in cancer
Ex: retinoblastoma
Dominant negative mutation
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
Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more often expected by chance
Mosaicism
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
Locus heterogeneity
Mutations at different loci can produce a similar phenotype
Ex: albinism
Allelic heterogeneity
Different mutations in the same locus produce the same phenotype
Ex: beta-thalassemia
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondiral inherited disease
Uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent an no copies from the other parent
Hardy weinberg population genetics
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
Imprinting
At some loci, only one allele is active, the other is inactive
With one allele inactivated, deletion/mutation of active allele leads to disease
Prader-Willi syndrome
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
AngelMan Syndrome
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
Autosomal dominant
Often due to defect in structural genes
Many generations affected, both male and female
Often pleiotropic, family hx very important
Autosomal recessive
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
X-linked disease
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
X-linked dominant
Transmitted through both parents, mothers transmit to 50% of sons and daughters, fathers transmit to all daughters by no sons
Hypophosphatemic rickets
X-linked dominant disorder
Vitamin D resistant rickets, increased phosphate wasting at proximal tubule resulting in ricket like presentation
Mitochondrial inheritance
Transmitted through the mother. All offspring of affected females may show signs of disease
Mitochondrial myopathies
Mitochondrial inherited disease
Often present w/ myopathy, lactic acidosis, and CNS disease
Secondary to failure in oxidative phosphorylation
Muscle biopsy often shows “ragged fibers”
Autosomal dominant polycystic kidney disease
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)
Familial adenomatous polyposis
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)
Familial hypercholesterolemia
Autosomal dominant
Elevated LDL due to defective or absent LDL receptor
Leads to severe atherosclerotic disease early in life and tendon xanthomas
Hereditary hemorrhagic telangiectasia
Autosomal dominant
Inherited disorder of blood vessels
Commonly present w/ telangiectasia, recurrent epitaxis, AVMs, GI bleeding
Hereditary spherocytosis
Autosomal dominant
Spheroid erythrocytes due to spectrin or ankyrin defect, leading to hemolytic anemia
Treatment: splenectomy
Hungtinton disease
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
Marfan syndrome
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
Multiple endocrine neoplasias (MEN)
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
Neurofibromatosis type 1 (von Recklinghausen)
Automsomal dominant
Neurocutaneous disorder characterized by cafe-au-lait spots and cutaneous neurofibromas
Caused by mutations in the NF1 gene on chromosome 17
Neurofibromatosis type 2
Autosomal dominant
bilateral acoustic schwannomas, juvenile cataracts, menigiomas
Caused by mutations in the NF2 gene on chromosome 22
Tuberous sclerosis
Autosomal dominant
Neurocutaneous disorder with mutli-organ system involvement characterized by benign hamartomas
Von Hippel-Lindau
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
Cystic fibrosis
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)
Duchenne muscle dystrophy
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
Becker muscle dystrohpy
X-linked recessive
Point mutation in dystrophin gene, less severe than Duchenne
Myotonic type 1 muscle dystrophy
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
Fragile X syndrome
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
Down syndrome
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
Edward syndrome
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
Patau syndrome
Trisomy 13 (puberty)
Findings: severe intellectual disability, rocker-bottom feet, microphthalamic, microcephaly, cleft lip/palate, holoprosencephaly, congenital heart disease
Inc nuchal transparency
Cri du chat syndome
Deletion of short arm of chromosome 5
Findings: microcephaly, high pitched crying, congenital heart disease (VSD)
Williams syndrome
Deletion of long arm of chromosome 7
Findings: elfin facies, hypercalcemia, extreme friendliness w/ strangers
DiGeorge syndrome
CATCH 22
Cleft palate, abnormal facies, thymic dysplasia, cardiac defects, hypocalcemia 2ndary to parathyroid aplasia, microdeletion at chromosome 22q11
