Topics 1 and 2 Patterns of inheritance; mutations; genetic testing procedures Flashcards
1
Q
Autosomal dominant
A
- When a single gene trait has the controlling alleles located on an autosomal chromosome, and the trait is expressed regardless of whether the person is homozygous or heterozygous for the dominant allele.
- Found in approximate equal distribution between male and female family members.
- Has no carrier status - the person with even one dominant allele expresses the trait; the trait appears in every generation with clear transmission from parent to child.
- Unaffected people do not have the allele and have essentially zero risk for transmitting the trait to their children.
2
Q
Autosomal recessive
A
- When a single gene trait has the controlling alleles located on an autosomal chromosome, and the trait is expressed only when both alleles are present (homozygous for the recessive allele).
- Found in approximate equal distribution between male and female family members.
- Carrier status - the trait often appears first in siblings rather than in the parents of affected children; may not appear in all generations of any one branch of a family.
- Unaffected carriers can transmit the trait to their children if their partner is either a carrier or is affected.
3
Q
X-linked dominant - rare
A
- Females do express the disorder in the heterozygous state and have a 50% chance of transmitting the trait with each pregnancy to children of either gender.
- An affected father transmits the disorder to all of his daughters (who then express the disorder) and to none of his sons.
4
Q
X-linked recessive
A
- The incidence of the trait is much higher among males in a family than among females.
- The trait cannot be transmitted from father to son; transmission occurs from an affected father to all daughters (who will be obligate carriers) and from a carrier mother to both sons and daughters.
- If no sons are born to carrier mothers, the trait may not be expressed overtly for many generations.
- If no daughters are born to affected fathers who have children with noncarrier mothers, the trait is not transmitted further.
5
Q
Monogenic trait (single gene trait)
A
A trait whose expression is determined by the input of the two alleles of a single gene.
6
Q
Penetrance
A
- How often, within a population, a gene is expressed when it is present. Higher penetrance = nearly 100% of people who have one allele will express the disorder.
- Calculated by examining a population of people known to have the gene mutation and assessing the percentage of people in that population who actually express the condition coded by the gene.
7
Q
Expressivity
A
- The degree of trait expression a person has when a dominant gene is present.
- The gene is always expressed, but some people have more severe problems than do other people. Example: Neurofibromatosis - a few café au lait spots in the mild form, hundreds of protruding tumors in the severe form.
8
Q
Why are X-linked recessive disorders expressed at a higher rate in males than in females?
A
Because X gene alleles have no corresponding allele on the Y chromosome, any X-linked allele in a male is expressed as if it were a dominant allele, a condition known as hemizygosity. Males do not have a second X chromosome to balance the presence of a recessive gene allele on the first X chromosome.
9
Q
Polygenic trait
A
A trait or structure that involves the input of more than one gene.
10
Q
Allele
A
An alternative or variable form of a gene at a specific chromosome location.
11
Q
Codominant expression
A
A single gene trait in which two different dominant gene alleles are both expressed equally.
12
Q
Expression of any monogenic trait depends on _
A
Inheritance of dominant or recessive alleles and on whether the gene is located on an autosome or on a sex chromosome.
13
Q
Autosomes
A
The 22 pairs of human chromosomes that do not code for the sexual differentiation of the individual.
14
Q
Transmission
A
The term used to describe how a trait is inherited (passed) from one human generation to the next.
15
Q
Kindred
A
Extended family relationships over several generations.
16
Q
To draw supportable conclusions about trait transmission, at least _ family generations must be explored.
A
Three.
17
Q
The risk for an affected person who is heterozygous for the dominant allele to pass the trait to his or her child is _ with each pregnancy.
A
50%.
18
Q
The risk for an affected person who is homozygous for the dominant allele to pass the trait to his or her child is _ with each pregnancy.
A
100%.
19
Q
Examples of autosomal dominant traits
A
Blood type A; blood type B; achondroplastic dwarfism; type 2 diabetes; familial hypercholesterolemia; familial hyperlipidemia; Huntington disease; malignant hyperthermia; Marfan syndrome; polycystic kidney disease; polydactyly; von Willebrand disease.
20
Q
Examples of autosomal recessive traits
A
Blood type O; albinism; beta thalassemia; cystic fibrosis; phenylketonuria; sickle cell disease; Tay-Sachs disease.
21
Q
Examples of sex-linked recessive traits
A
Duchenne muscular dystrophy; fragile X syndrome; G6PD deficiency; hemophilia; red-green color blindness.
22
Q
Living people with disorders such as Huntington disease and achondroplasia are always _
A
Heterozygous for the mutated dominant allele, because the homozygous genotype appears lethal, with loss in utero or within the first 12 months after birth.
23
Q
The risk for children of two parents affected by an autosomal recessive disorder to also be affected is _
A
Close to 100%.
24
Q
About _ of the members of a family with an autosomal recessive trait will express the trait or disorder.
A
25%.
25
Carrier
A person who is heterozygous for an autosomal recessive gene allele and does not fully express the trait or disorder, but can transmit the allele to his or her children.
26
Normal human chromosome count
46 (23 pairs - 22 pairs of autosomes and 1 pair of sex chromosomes).
27
X-linked recessive genes have _
Dominant expression in males and recessive expression in females.
28
Female carriers of an X-linked recessive trait have a _ chance of transmitting the gene to their children with each pregnancy.
50%.
29
X chromosome inactivation
Most of the genes on the X chromosome code for *somatic cell functions*, and females receive one X from each parent. During organ differentiation in the embryonic stage, the genes from one X chromosome are randomly *inactivated*, but some portion of the other parental genes remains in the form of a *Barr body*, and can still affect organ function.
30
Genes
Sequence of nucleotides along the DNA of a chromosome that codes for a functional protein (ATCG).
31
Genetics
Study of individual genes and their impact on relatively rare *single gene disorders*.
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Human genomics
Study of *all* the genes in the human genome together, including their interactions with each other, the environment, and the influence of other psychosocial and cultural factors.
33
Polymorphisms
Small variations (one or two base pairs) of a gene which may not cause a disease by themselves, but may cause a disease in combination with other small variations, *or* in combination with environmental factors (e.g., hypertension).
34
BRCA1 and BRCA2 are examples of _ genes.
Predisposition.
35
4 basic genetic nursing responsibilities
1. Identify patients who will benefit from genetic interventions.
2. Provide genetic-based nursing interventions.
3. Communicate genetic information correctly, or be able to make referrals for patients.
4. Reflect on one's own practice.
36
Cystic fibrosis inheritance is _
Autosomal recessive.
37
Neurofibromatosis inheritance is _
Autosomal dominant.
38
A mutation on the _ gene is associated with the development of juvenile ALS, leading to a potential therapeutic target.
SIGMAR1.
39
The _ gene is the first known gene to be required for sperm production in species ranging from insects to mammals.
BOULE.
40
Gene locus
A specific location on a chromosome; often a specific gene.
41
Phenotype
The observed expression of the genes of an individual (expression can be biochemical, physiological or morphological).
42
Genotype
The genetic constitution of an individual; also, the alleles present at a particular locus.
43
Achondroplasia
1. The most common cause of human dwarfism - *autosomal dominant*.
2. Mutation in the Fibroblast Growth Factor Receptor 3 gene (FGFR3).
3. Normal size trunk with short arms and legs.
4. Recurrence risk is *low* if parent is not affected, but *80%* of people with achondroplasia have average height parents - their dwarfism is the result of a *new* FGFR3 mutation.
5. When 2 affected individuals mate (often dwarves prefer other dwarves): 50% chance of having an affected child; 25% chance of homozygous lethal; 25% chance of child with normal stature.
44
Adult Dominant Polycystic Kidney Disease (ADPKD)
1. *Autosomal dominant.*
2. Adult onset disorder in which cysts form throughout the kidneys; causes progressive renal dysfunction and ultimately renal failure.
3. One of the most common inherited disorders in humans (1:300); accounts for 10% of all dialysis patients.
4. Symptoms: Abdominal pain, hematuria, polyuria, intense pain from kidney stones. Comorbid hypertension occurs in about 50% of cases.
5. Increased risk for subarachnoid hemorrhage, cerebral aneurysm, and stroke.
45
ADPKD shows _ expression because less than 5% of nephrons become cystic.
Focal.
46
Marfan syndrome
1. *Autosomal dominant.*
2. Connective tissue disorder in which a person is typically very tall, with long limbs and long thin fingers (arachnodactyly), and loose, hyperextensible joints.
3. The most serious complication is defects of the heart valves and aorta (aneurysm).
4. More than half of Marfan patients experience dislocation of the lens of the eye.
47
Neurofibromatosis 1
1. *Autosomal dominant.*
2. Results from a mutation in the gene for neurofibromin on chromosome 17; about 50% of cases are due to a new mutation.
3. Neurofibromas, café-au-lait macules - six or more measuring 1.5 cm in their greatest dimension, freckling in the axillary and inguinal areas, sphenoid dysplasia (thinning of the cortex in long bones), Lisch nodules.
48
Osteogenesis imperfecta
1. *Autosomal dominant.*
| 2. "Brittle bone" disease - defect in type I collagen gene.
49
Phenylketonuria (PKU)
1. *Autosomal recessive.*
2. Mutation in phenylalanine hydrogenase (PAH) on chromosome 12 prevents the normal degradation of phenylalanine, which then accumulates in the tissues. Diagnosis is via blood tests in newborns; baby must have had at least 2 feedings.
3. Hyperphenylalaninemia is particularly toxic to the developing nervous system; therefore, untreated PKU can cause *mental retardation*.
4. Management is dietary restriction of phenylalanine intake.
50
Cystic fibrosis
1. *Autosomal recessive.*
2. Usually caused by a deletion mutation on the cystic fibrosis transmembrane regulator (CFTR) gene, which regulates chloride ion channels.
3. Manifestations: Progressive pulmonary disease, elevated sweat chloride, meconium ileus, exocrine pancreatic insufficiency.
51
Tay-Sachs disease
1. *Autosomal recessive.*
2. Lysosomal storage disorder caused by a lack of hexosaminodase A, the enzyme that breaks down fatty wastes.
3. Lack of the enzyme causes waste to accumulate in nerve cells.
4. Child appears normal at birth; deterioration of mental and physical abilities appears about 1 year after birth. The child becomes blind, deaf, and unable to swallow.
5. One in 27 *Louisiana Cajuns are carriers* for the Tay-Sachs gene.
52
Women with PKU should start a restricted diet prior to _
Conception (due to the teratogenic effect of high levels of phenylalanine in maternal serum).
53
Affected grandfather to affected grandson transmission through a carrier female intermediate is a characteristic of _ inheritance.
X-linked recessive.
54
47,XXY
Kleinfelter Syndrome or aneuploidy.
55
Hemophilia
1. *X-linked recessive.*
2. Clotting disorder that causes bleeding into soft tissues; caused by mutations in either factor VIII or factor IX.
3. *Primarily males* affected.
56
Duchenne muscular dystrophy
1. *X-linked recessive.*
2. Mutation in the dystrophin gene; males have a 50% chance of being affected.
3. Manifestations: Fatigue, muscle weakness (begins in the legs and pelvis, but also occurs less severely in the arms, neck, and other areas of the body), progressive difficulty walking.
57
Hypophosphatemic rickets
1. *X-linked dominant.*
2. Genetic defect in the handling of phosphate in the proximal tubules of the kidney.
3. Manifestations: Short stature, leg bowing, tooth anomalies.
58
Rett syndrome
1. *X-linked dominant.*
2. The most severe form of autism that only affects girls.
3. Neurodevelopmental disorder - slowed growth, loss of movement and coordination, severe scoliosis.
59
If a woman has a mitochondrial gene disorder, there is a _ chance that her children will inherit the disorder.
100%.
60
Expert referral for patients with mitochondrial disorders should be made to _
Emory University.
61
Dynamic mutations/trinucleotide expansion disorders
1. Tandem repeats of three base pairs (trinucleotides) that often change size upon transmission to children.
2. Normal people *have the repeat*; longer repeats are abnormal.
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Diseases caused by trinucleotide repeats
1. Fragile X syndrome.
2. Huntington's disease.
3. Friedreich's ataxia.
4. Myotonic dystrophy.
63
Trinucleotide expansion disorders over generations - anticipation
1. Repeat expands with each successive generation.
2. Age of onset becomes younger with each successive generation.
3. Severity of disease increases with each generation.
64
Huntington's disease
1. *Autosomal dominant.*
2. Mutation is a triplet repeat expansion of CAG; causes death of cells in the *caudate nucleus* and an overproduction of the huntingtin protein, whose function is unknown.
3. Manifestations: Dementia, memory loss, chorea (random, jerky, uncontrolled movements).
4. Has a late age of onset (usually in 40s); diagnosis is with PCR.
65
Huntington's disease has _, meaning that every person with the gene will ultimately express the disorder.
100% penetrance.
66
Fragile X syndrome
1. *The most common heritable form of moderate mental retardation.*
2. Trinucleotide repeat on the FMR1 gene.
3. Patients have behavior problems, hyperactivity and autistic features; a long face with a prominent jaw, large ears and macroorchidism. Lifespan is *normal*.
67
Friedreich's ataxia
1. *Autosomal recessive.*
2. Trinucleotide repeat results in loss of sensory ganglion cells, depriving the cerebellar column of the input needed to coordinate movement.
3. Manifestations: Dysarthria (slowness and slurring of speech), ataxia (impaired muscle coordination which starts in the legs and spreads to arms and trunk), heart problems, and muscle weakness/fatigue.
68
Friedreich's ataxia is associated with individuals of _ descent.
Cajun (but they usually have a less severe form with a later onset).
69
Sickle cell anemia
1. *Autosomal recessive.*
2. Most common genetic disease of American Americans (1/700); caused by mutation in hemoglobin B subunit.
3. Not just an oxygen content problem - patients have skeletal problems, infarctions, and repeated infections.
70
The only mutation that is responsible for sickle cell anemia is _
A valine substitution for glutamine on the hemoglobin B subunit.
71
Glucose-6 phosphate dehydrogenase deficiency
1. *X-linked recessive.*
2. Affects about 1 in 10 African American males in the U.S.
3. Patients present with acute hemolytic episode or neonatal jaundice; diagnosed by measuring G6PD activity in red blood cells.
4. Often not seen until an environmental trigger aggravates the disorder - person will have *anemic symptoms*.
5. Triggers: Fava beans and moth balls (naphthalene).
72
Disease phenotype - microcephaly and high pitched cat-like cry
Cri du chat syndrome.
73
Disease phenotype - high mortality due to intracranial aneurysms
Adult dominant polycystic kidney disease.
74
Disease phenotype - pancreatic insufficiency
Cystic fibrosis.
75
Used to diagnose Turner syndrome
Karyotype or FISH.
76
Used to detect carrier status for recessive disorders
Direct gene testing.
77
Sometimes a person might carry a mutation such as BRCA1 but never develop the disease. What is the term for this phenomenon?
Incomplete penetrance.
78
45,XO
Turner syndrome.
79
Heterochromatin
Where the DNA is more condensed, and usually there is not much transcriptional activity. Some heterochromatin will remain condensed throughout the cell cycle.
80
Euchromatin
This is where the "active" genes are - usually this region is much less condensed.
81
46,XY
Normal male karyotype.
82
Cytogenetic analysis can be done on _
Blood, amniotic fluid, chorionic villus samples (CVS), skin fibroblast cultures, bone marrow, or solid tumors.
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Monosomy
Absence of a single chromosome.
84
Trisomy
An extra copy of a single chromosome.
85
Karyotype
A photograph of the chromosomes from one cell.
86
Aneuploidy
Any number of chromosomes that is not diploid; is the result of nondisjunction (failure of chromosome pairs to separate during cell division).
87
Triploidy
3n or 69 chromosomes.
88
Polyploidy
Any multiple of the haploid chromosome number other than the normal diploid number.
89
Solid staining is most useful for _
Counting the number of chromosomes.
90
G-banding is most useful for _
Recognition of banding patterns of each chromosome.
91
Turner syndrome
1. 45,XO - *only affects women*.
2. Short stature; skeletal abnormalities; an early loss of ovarian function (premature ovarian failure) is very common. 30% of Turner patients have a webbed neck and a low hairline at the back of the neck. Hearts defects somewhat common.
3. Most girls and women with Turner syndrome have normal intelligence.
92
Kleinfelter syndrome
1. 47,XXY - *only affects men*.
2. Males with infertility; small penis and testes; enlarged breasts; sparse facial and body hair; tall stature, long limbs; dull mentality and/or behavioral problems are common.
93
5p-
Cri du chat syndrome (deletion of part of the short arm of chromosome 5).
94
9;22 translocation is 100% diagnostic for _
Chronic myelogenous leukemia (CML).
95
FISH is most useful for identifying _
Cytogenetic abnormalities such as trisomy 21 (Down syndrome).
