Genetics Flashcards
Both alleles contribute to the phenotype of the heterozygote
Codominance
Patients with the same genotype have varying phenotypes
Variable expressivity
Not all individuals with a mutant genotype show the mutant phenotype
Incomplete penetrance
One gene contributes to multiple phenotypic effects
Pleiotropy
Increased severity or earlier onset of disease in succeeding generations
Anticipation
If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be delete/mutated before cancer develops. This is not true of oncogenes.
Loss of heterozygosity
Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
Dominant negative mutation
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population not in a family, and often varies in different populations
Linkage disequilibrium
Presence of genetically distinct cell links in the same individual
Mosaicism
Mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs. (Subtype of mosaicism)
Somatic mosaicisim
Mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect this (subtype of mosaicism)
Gonadal mosaicism
Mutations at different loci can produce a similar phenotype
Locus heterogeneity
Different mutations in the same locus produce the same phenotype
Allelic heterogeneity
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
Heteroplasmy
Offspring receives 2 copies of a chromosome from one parent and no copies from the other parent. Heterodisomy (heterozygous) indicates a meiosis I error. Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.
Uniparental disomy
Hardy-Weinburg equation
p2 + 2pq + q2 = 1
Hardy-Weinburg Assumptions (4)
1) no mutation occurring at the locus
2) natural selection is not occurring
3) completely random mating
4) no net migration
Maternally derived genes are silenced (imprinted). Disease occurs when the paternal allele is deleted or mutated, although 25% of cases are due to maternal uniparental disomy.
Prader-Willi syndrome
Associated with a mutation or deletion of chromosome 15 of paternal origin. Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia.
Prader-Willi Syndrome
Paternally derived UBE3A gene is silenced (imprinted).
Angelman Syndrome
Disease occurs when the maternal allele is delete or mutated. Results in inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability.
Angelman Syndrome
Inherited disorder resulting in increase phosphate wasting at proximal tubule. Results in rickets-like presentation. X-linked dominant
Hypophosphatemic rickets
Rare disorders, often presenting with myopathy, lactic acidosis, and CNS disease. Secondary failure in oxidative phosphorylation.
Mitochondrial myopathies
Cell death in optic nerve neurons, leads to subacute bilateral vision loss in teens/young adults, 90% males. Usually permanent
Leber hereditary optic neuropathy
Inheritance pattern of cystic fibrosis
Autosomal recessive (defect in CFTR gene on chromosome 7)
X-linked disorder typically due to frameshift deletions or nonsense mutations; truncated or absent dystrophin protein; progressive myofiber damage. Weakness begins in pelvic girdle muscles and progresses superiorly. Psuedohypertrophy of calf muscles due to fibrofatty replacement of muscles.
Duchenne Muscular Dystrophy
deleted dystrophin is the give away
X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional!). Less severe than Duchenne.
Becker Muscular Dystophy
Autosomal dominant. CTG trinucleotide repeat expansion in the DMPK gene -> abnormal expression of myotonin protein kinase -> myotonia (eg difficulty releasing hand from handshake), muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
Myotonic Type 1 Muscular Dystrophy
X-linked dominant inheritance. Trinucleotide repeat in FMR1 gene. Hypermethylation decreases expression. Most common cause of inherited intellectual disability and 2nd most common cause of genetically associated mental deficiency. Findings: enlarged testes, long face with a large jaw, large everted ears, autism, mitral valve prolapse
Fragile X syndrome
Symptoms: intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, incurved 5th finger, gap between 1st 2 toes, duodenal, atresia, Hirschpsrung disease, congeital heart disease, Brushfield spots. Associated with early-onset alzherimer disease
Down Syndrome (Trisomy 21)
5A’s of Down Syndrome
1) Advanced Maternal Age
2) Atresia (duodenal)
3) Atrioventricular septal defect
4) Alzheimer Disease
5) AML/ALL
Findings: Prominent occiput, Rocker-bottom feet, intellectual disability, nondisjunction, clenched fists, low-set ears, micrognathia, congenital heart disease, omphalocele. Death usually by age 1
Edwards Syndrome (Trisomy 18)
Findings: Severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip / palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, polycystic kidney disease, omphalocele. Death usually occurs by age 1.
Patau Syndrome (Trisomy 13)
Occurs when the long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost. Commonly involves pairs 13, 14, 15, 21 and 22
Robertsonian Translocation
Congenital deletion on short arm of chromosome 5 (46, XX or XY, 5p-)
Cri-du-Chat Syndrome
Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying/meowing, epicanthal folds, cardiac abnormalities
Cri-du-Chat Syndrome
Congenital microdeletion of long arm of chromosome 7. Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.
Williams Syndrome
