Genetics Flashcards
Variable expressivity
Phenotype varies among individuals with same genotype
Ex: 2 pts with neurofibromatosis type I (NF1) may have varying disease severity
Incomplete penetrance
Not all individuals with a mutant genotype show the mutant phenotype
Ex: BRCA1 gene mutations do not always result in breast or ovarian cancer
Pleiotropy
One gene contributes to multiple phenotypic effect Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor
Anticipation
Increased severity or earlier onset of disease in succeeding generations
Trinucleotide repeat disease (e.g. Huntington disease)
Loss of heterozygosity
If a pt inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenesis
Retinoblastoma and the “two-hit hypothesis”, Lynch syndrome (HNPCC), Li-Fraumeni syndrome
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 a transcription factor in its allosteric site. Nonfunctioning mutation can still bind DNA, preventing wild-type TF from binding
Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more or les often than expected by chance. Measures in a population, not a family, and often varies in different populations
Mosaicism
Presence of genetically distinct cell lines in the same individual
Somatic mosaicism
Mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs
Gonadal mosaicism
Mutation only in egg or sperm cells
McCume-Albright syndrome
Due to mutation affecting G-protein signaling.
Presents with cafe-au-lait spots, polyostoic fibrous dysplasia, precocious puberty, multiple endocrine abnormalities
Lethal if mutation occurs before fertilization (affecting all cells) but survivable in pts with mosaicism
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
Beta-thalassemia
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondria lily inherited disease
Uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other.
Uniparental is eUploid (correct number of chromosome), not aneuploid. Most occurrences of UPD - normal phenotype
Consider UPD in an individual manifesting a recessive disorder when one parent is a carrier
Heterodisomy
Heterozygous
Indicates a meiosis I error
Isodisomy
Homozygous
Indicates a meiosis II error or post zygotes chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair
Codominance
Both alleles contribute to the phenotype of the heterozygote
Ex: blood groups A, B, AB; alpha-1 antitrypsin deficiency
Hardy-Weinberg population genetics
If population is in equilibrium and if p and q are the frequencies of separate alleles, then:
p2+2pq+q2=1 and p+q=1 which implies that
p2=frequency of homozygousity for allele p
q2=frequency of homozygousity for allele q
2pq=frequency of heterozygosity (carrier frequency if AR disease)
Frequency of an X-linked disease
X-linked recessive
Males=q
Females=q2
Hardy-Weinberg law assumptions
No mutation occurring at the locus
Natural selection is not occurring
Completely random mating
No net migration
Imprinting
At some loci, only one allele is active while the other inactive
Inactivated by methylation
With one allele inactivated, deletion of the active allele = disease
E.g. Prader-Willi and Angelman syndromes are due to mutation or deletion of genes on chromosome 15
Prader-Willi syndrome
Maternal imprinting:
Gene from mom is normally silent and Paternal gene is deleted/mutated
Results in hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
25% cases due to maternal uniparental disomy (two maternally imprinted genes are received and no parental gene)
AngelMan syndrome
Parental imprinting:
Gene from dad is normally silent and Maternal gene is deleted/mutated
Results in inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual ability
5% cases due to paternal uniparental disomy (two paternally imprinted genes are received and no maternal genes)
Modes of Inheritance: Autosomal Dominant
Often due to defects in structural genes
Many generations, both male and female affected
Often pleiotropic (multiple apparently unrelated effects) and variably expressive (different between individuals). Family history is crucial to diagnosis.
With one affected (heterozygous) parent, on average 1/2 of children will be affected
Modes of Inheritance: Autosomal recessive
Often due to enzyme deficiencies. Usually only seen in one generation
Commonly more severe than dominant disorders; pts often present in childhood
Increased risk in consanguineous families
With two carrier (heterozygous) parents on average 1/4 of children will be affected (homozygous) and 1/2 will be carriers and 1/4 will not be affected
Modes of Inheritance: X-linked recessive
Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transmission. Skips generations
Commonly more severe in males
Females usually must be homozygous to be affected
Modes of Inheritance: X-linked dominant
Transmitted through both parents. Mothers transmit to 50% of their daughters and sons. Fathers transmit to all daughters but no sons.
E.g. Hypophosphatemic Rickets: VitaminD resistant rickets, inherited disorder resulting in phosphate wasting at PCT. Results in rickets-like presentation
Other examples: Rett syndrome, fragile X syndrome, Alport syndrome
Modes of Inheritance: Mitochondrial inheritance
Transmitted only through the mother. All offspring of affected females may show signs of disease
Variable expression in a population or even within a family due to heteroplasmy
E.g. Mitochondrial myopathies - rare disorders; often present with myopathy, lactic acidosis, and CNS disease (MELAS syndrome)
Secondary to failure in oxidative phosphorylation. Muscle biopsy often shows “ragged red fibers_
Achondroplasia
AD
Mutation of FGFR3 inhibits chondrocyte proliferation. Most common cause of dwarfism; limb length affected more than head or torso size.
Full penetrance
Autosomal Dominant Polycystic Kidney disease
AD
Bilateral massive enlargement of kidneys due to multiple large cysts, 85% of cases are due to mutation in PKD1 (chromosome 16 - 16, letters in polycystic kidney), remainder due to mutation in PKD2 (chromosome 4)
Familial adenomatous polypsis
Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless colon is resected. Mutations on chromosome 5q (APC gene)
(5 letters in polyp)
Familial hypercholesterolemia
AD
Elevated LDL due to defective or absent LDL receptor. Leads to severe atherosclerotic disease early in life, corneal arcus, tendon xanthomas (classically Achilles)
Hereditary hemorrhagic telangiectasia
AD
Inherited disorder of blood vessels. Findings: branching skin lesions (telangiectasia), recurrent epistaxis, skin discoloration, arteriovenous malformations (AVMs), GI bleeding, hematuria
AKA: Osler-Weber-Rendu syndrome
Hereditary spherocytosis
AD
Spheroid erythrocytes due to spectrum or ankyrin defect. Hemolytic anemia
Increased MCHC, increased RDW
Tx: splenectomy
Huntington Disease
AD
Findings: depression, progressive dementia, choreiform movements, caudate atrophy
Increased DA, decreased GABA & ACh in brain
Gene on chromosome 4: trinucleotide repeat disorder (CAG)
Demonstrates anticipation: increased number of repeats = younger age of onset
Li-Fraumeni syndrome
AD
Abnormalities in TP53 - multiple malignancies at an early age. AKA SLBA cancer syndrome
(Sarcoma, breast, leukemia, adrenal gland)
Marfan syndrome
AD
FBN1 gene mutation on chromosome 15 - defective fribrillin (scaffold for elastin), CT disorder affecting skeleton, heart and eyes
Findings: tall with long extremities, pectins excavatum, hypermobile joints, long tapering fingers and toes (arachnodactyly), cystic medial necrosis of the aorta - aortic incompetence and dissecting aortic aneurysms; floppy mitral valve, subluxation of lenses, typically upward and temporary
Multiple endocrine neoplasias (MEN)
Several distinct syndromes (1,2A,2B) characterized by familial tumors of endocrine glands including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla
MEN1: associated with MEN1 gene (3Ps)
MEN2A&B: are associated with RET gene (medullary thyroiditis)
Neurofibromatosis type 1 (vonRecklinghausen disease)
AD
Neurocutaneous disorder characterized by cafe-at-lait spots, cutaneous neurofibromas, optic gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas)
100% penetrance, variable expression.
Caused by mutations in the NF1 gene on chromosome 17 (17 letters in vonRecklinghausen)
Neurofibromatosis type 2
AD
Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, ependymomas
NF2 gene on chromosome 22 (type 2=22)
Tuberous sclerosis
AD
Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas
Variable expression
Von Hippel Lindau disease
Disorder characterized by development of numerous tumors, both benign and malignant
Associated with deletion of VHL gene (tumor suppressor) on chromosome 3p
Autosomal Recessive diseases (list)
Albinism, AR polycystic kidney disease, cystic fibrosis, glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except hunter syndrome), phenylkentonuria, sickle cell anemia, sphingolipioses (except Fabry disease), thalassemias, Wilson disease
Cystic Fibrosis: Genetics
AR
Defect in CTFR gene on chromosome 7; Commonly a deletion in Phe508
Most common lethal genetic disease in Caucasian population
Cystic Fibrosis: Pathophysiology
CFTR encodes ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands
Most common mutation - misfolded protein, protein then retained in RER and not transported to the cell membrane, causing a decrease in Cl- (and H20) secretion
Intracellular Cl- results in compensatory increased Na+ reabsorption (more negative trans epithelial potential difference) via epithelial Na+ channels - increased H20 reabsorption - abnormally thick mucus secreted into lungs and GI tract
Cystic Fibrosis: Diagnosis
Increased Cl- concentration (>60mEq/L) in sweat is diagnostic
Can present with contraction alkalosis and hypokalemia (ECF effects analogous to a pt taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting
Increased immunoreactive trypsinogen (newborn screening)
Cystic Fibrosis: Complications
Recurrent pulmonary infections (e.g S. Aureus, P. Aeruginosa), chronic bronchitis and bronchiectasis - reticulonodular pattern on CXR Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies, biliary cirrhosis, liver disease. Meconium ileus in newborns Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus) Nasal polyps (children), clubbing of nails
Cystic Fibrosis: treatment
Multifactorial
Chest physiotherapy, Albuterol, aerosolized dornase Alfa (DNAse) and hypertonic saline to facilitate mucus clearance
Azithromycin used as anti-inflammatory agent
Pancreatic enzymes for insufficiency
X-linked recessive disorders (list)
Female carriers are variably affected depending on the percentage of inactivation of X chromosome carrying the mutant vs. normal gene Obvious Female Will Often Give Her Boys x-Linked Disorders Ornithine transcarbamylase deficiency Fabry disease Wiskott-Aldrich syndrome Ocular albinism G6PD deficiency Hunter syndrome Briton agammaglobulinemia Hemophilia (A&B) Lesch-Nyhan syndrome Duchenne (and Becker) muscular dystrophy
Duchenne MD
X-linked (frameshift or nonsense mutations)
Truncated dystrophin protein - inhibited muscle regeneration
Weakness begins in the pelvic girdle muscles and progresses superiority
Psedohypertrophy of the calf muscles due to fibrofatty replacement of muscle
Onset before age 5 - positive Gower maneuver
Complications: dilated cardiomyopathy (most common cause of death)
Gower Maneuver
Seen in Duchenne MD
Pts use upper extremities to help them stand up
Duchenne MD: genetics
Dystrophin gene (DMD) is the largest protein coding human gene (Increased chance of spontaneous mutation)
Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connects the intracellular cytoskeleton (actin) to the transmembrane proteins alpha and beta dystroglycan, which are connected to the extracellular matrix (ECM)
Loss of dystrophin resulting in myonecrosis
Labs: increased CK and aldolase
Diagnosis: western blot and muscle biopsy
Becker MD
X-linked due to non-frameshift insertions in dystrophin gene (deletion can cause both Duchenne and Becker MD)
Partially functional protein
Less severe than Duchenne
Onset in adolescence or early adulthood
Myotonic Type 1 MD
AD
CTG trinucleotide repeat expansion in the DMPK gene - abnormal expression of myotonic protein kinase
Symptoms: myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
(My Tonia, My Testicles, My Toupee, My Ticker)
Fragile X syndrome
X-linked Dominant inheritance Trinucleotide repeat (CGG) in FMR1 gene - methylation and decreased expression 2nd most common cause of genetic intellectual disability (after Down Syndrome) Findings: post-pubertal macroorchidism (enlarged testes), long face with large jaw, large everted ears, autism, mitral valve prolapse Fragile X = eXtra large testes, jaw ears
Trinucleotide repeat expansion diseases (list)
Huntington disease, myotonic dystrophy, Friedreich ataxia, fragile X syndrome (may show genetic anticipation)
FXS: CGG
FA: GAA
HD: CAG
MD: CTG
X-Girlfriend’s First Aid Helped Ace My Test
Down Syndrome (trisomy 21): Findings
Intellectual disabilities (most common cause), flat facies, prominent epicanthal folds, single palmar crease, gap between 1st & 2nd toes, duodenal atresia, Hirschsprung disease, congenital heart disease (ASD), brushfield spots Associated with early ALZ disease (chromosome 21 codes for amyloid precursor protein) and increased risk of ALL (before age 5) and AML (after age 5) Drinking age (21)
Down Syndrome (trisomy 21): Genetics
95% due to meiosis no disjunction
Increased risk with advanced maternal age
4% unbalanced Robertsonian translocation, most typically between chromosomes 14 and 21
1% due to. Mosaicism (no maternal association, post fertilization mitotic error)
Down Syndrome (trisomy 21): Screening
First trimester U/S: increase unchallenged translucency and hypoplastic nasal bone
First trimester blood test: decreased serum PAPP-A, increased free Beta-hCG
Second trimester quad screen: decreased alpha fetoprotein and estriol, increased Beta-hCG and inhibit A
Edwards syndrome (trisomy 18): findings
2nd most common trisomy resulting in live birth
severe intellectual disability, rocker bottom feet, micrognathia (small jaw), low-set Ears, clenched hands with overlapping fingers, prominent occiput
Death usually occurs within 1 year
(Election age = 18)
Edwards syndrome (trisomy 18): Screening
PAPP-A and Free-Beta-hCG are decreased in the first trimester
Quad screen shows decreased alpha-fetoprotein, beta-hCG, estriol, and decreased or normal inhibin A
Patau syndrome (trisomy 13): Findings
Severe intellectual disability, rocker bottom feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, congenital heart disease, cutis aplasia
Death usually occurs within 1 year
(Puberty = 13)
Patau syndrome (trisomy 13): Screening
First trimester pregnancy screen shows decreased free beta-hCG and decreased PAPP-A
Genetic Disorder: Chromosome 3
Von Hippel-Lindau disease
Renal cell carcinoma
Genetic Disorder: Chromosome 4
ADPKD (PKD2), achondroplasia, Huntington disease
Genetic Disorder: Chromosome 5
Cir-du-Chat syndrome, familial adenomatous polyposis
Genetic Disorder: Chromosome 6
Hemochromatosis (HFE)
Genetic Disorder: Chromosome 7
Williams syndrome, cystic fibrosis
Genetic Disorder: Chromosome 9
Friedreich ataxia
Genetic Disorder: Chromosome 11
Wilms tumor, Beta-glob in defects (sickle cell disease, beta-thalassemia)
Genetic Disorder: Chromosome 13
Patau syndrome, Wilson disease, retinoblastoma (RB1), BRCA2
Genetic Disorder: Chromosome 15
Prader-Willi syndrome, Angelman syndrome, Marfan syndrome
Genetic Disorder: Chromosome 16
ADPKD (PKD1), alpha-glob in gene defects (alpha-thalassemia)
Genetic Disorder: Chromosome 17
Neurofibromatosis type 1, BRCA1
Genetic Disorder: Chromosome 18
Edwards syndrome
Genetic Disorder: Chromosome 21
Down syndrome
Genetic Disorder: Chromosome 22
Neurofibromatosis type 2, DiGeorge syndrome (22q11)
Genetic Disorder: Chromosome X
Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)
Robertsonian translocation
Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21 and 22 (one of most common)
Occurs when long ares of 2 Afrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the two short arms are lost
Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (e.g. Down and Patau syndrome)
Cri-du-chat syndrome
Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-)
Findings: microcephaly, moderate to severe intellectual ability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)
Cri-du-chat=cry of the cat
Williams syndrome
Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)
Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia (increased sensitivity to VitD), well developed verbal skills, extreme friendliness with strangers, CV problems
22q11 Deletion syndromes
Aberrant development of 3rd & 4th branchial pouches
Microdeletion at chromosome 22q11 - variable presentations including Cleft palate, Abnormal facies, Thymic aplasia, TC deficiency, Cardiac defects, Hypocalcemia secondary to parathyroid aplasia
DiGeorge Syndrome: Thymic, parathyroid and cardiac defects
Velocardiofacial syndrome: palate, facial and cardiac defects
CATCH-22
