p.2
Pedigree Analysis in Genetic Counseling
What is the first step in establishing the pattern of transmission for single-gene disorders?
The first step is to obtain information about the family history and construct a pedigree.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the most common mating that leads to homozygous offspring affected with an autosomal recessive disease?
Mating between two unaffected heterozygotes (carriers).
p.1
Genotype vs. Phenotype
What does it mean to be homozygous?
Having a pair of identical alleles at a locus encoded in nuclear DNA.
p.9
Dominant vs. Recessive Traits
What happens to homozygous individuals with achondroplasia?
They have a disorder far more severe than heterozygotes, often resulting in death soon after birth.
p.2
Single-Gene Disorders Overview
What is the significance of Mendelian disorders in adult medicine?
Mendelian disorders are important in adult medicine because they can include common adult illnesses such as heart disease, stroke, cancer, and diabetes, and have implications for the health of other family members.
p.2
Pleiotropy and Variable Expressivity
How can the same disease-causing genotype affect individuals differently?
Individuals with the same disease-causing genotype may develop the disease at very different ages and show different signs and symptoms.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
How can heterozygotes prevent the occurrence of an autosomal recessive disease?
The remaining normal gene copy in a heterozygote can compensate for the mutant allele.
p.10
Pedigree Analysis in Genetic Counseling
What is the significance of the pedigree in Figure 7-10?
It demonstrates failure of penetrance in the mother of the proband and his sister, highlighting the importance of considering reduced penetrance in genetic counseling.
p.10
Penetrance in Genetic Disorders
What can cause exceptions to the rule that the phenotype appears in every generation in autosomal dominant inheritance?
Exceptions can be caused by fresh mutations in a gamete of a phenotypically normal parent or by nonpenetrance or subtle expression of the disorder.
p.8
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the expected distribution of offspring in a D/d by D/d mating?
Three fourths affected to some extent and one fourth unaffected.
p.8
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the inheritance pattern of achondroplasia?
Incompletely dominant (or semidominant).
p.4
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
How are mutant alleles on an X chromosome distributed to offspring?
Males pass their Y chromosome to their sons and their X to their daughters; they cannot pass an allele on the X chromosome to their sons and always pass the allele to their daughters.
p.11
Pleiotropy and Variable Expressivity
What is an example of a disorder with variable expressivity?
Neurofibromatosis 1 (NF1) is an example of a disorder with variable expressivity, where symptoms can range from mild skin lesions to severe tumors and intellectual disability.
p.2
Penetrance in Genetic Disorders
What does it mean when a disorder shows reduced or incomplete penetrance?
It means that some individuals with the relevant genotype completely fail to express the phenotype.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
Do autosomal recessive disorders show the same frequency and severity in males and females?
Yes, because males and females both have the same complement of autosomes.
p.3
Pedigree Analysis in Genetic Counseling
What is the difference between a proband and a consultand?
A proband is the affected individual through whom a genetic disorder is first brought to attention, while a consultand is the person who consults a geneticist.
p.6
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
How can mutant alleles be handed down for numerous generations without causing overt disease?
They remain hidden in carriers and only cause disease if both parents pass on the mutant allele to their child.
p.6
Single-Gene Disorders Overview
Why might the estimate of deleterious alleles in our genomes be imprecise?
It may not include mutant alleles with non-obvious deleterious effects or may include mutations in genes not known to cause disease.
p.7
Impact of Consanguinity on Genetic Disorders
Why is consanguinity more frequently found in the background of patients with very rare conditions?
Because it is less likely that two individuals mating at random will both be carriers of a very rare disorder by chance alone.
p.10
Pleiotropy and Variable Expressivity
What is split-hand/foot malformation?
A type of ectrodactyly that originates in the sixth or seventh week of development, affecting the hands and feet.
p.5
Genotype vs. Phenotype
What is the reciprocal relationship in the ABO blood group system?
The relationship between the antigens present on the red blood cells and the antibodies in the serum.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the difference between X-linked recessive and X-linked dominant disorders?
X-linked recessive disorders are expressed only in hemizygotes, while X-linked dominant disorders are expressed in both heterozygotes and hemizygotes.
p.8
Dominant vs. Recessive Traits
How does Huntington disease differ in heterozygotes and homozygotes?
It appears to have a somewhat accelerated time course in homozygotes.
p.8
Pedigree Analysis in Genetic Counseling
What does the pedigree of a sporadic case of thanatophoric dwarfism show?
A genetic lethal in the proband.
p.2
Penetrance in Genetic Disorders
What is penetrance in genetic disorders?
Penetrance is the probability that a mutant allele or alleles will have any phenotypic expression at all.
p.9
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What evidence shows that a disorder is autosomal and not X-linked?
The disorder can be transmitted directly from father to son.
p.9
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
How can male-limited precocious puberty be transmitted?
It can be transmitted by affected males or by unaffected carrier females.
p.1
Genotype vs. Phenotype
What is the difference between genotype and haplotype?
Genotype refers to both alleles at a locus on homologous chromosomes, while haplotype refers to the set of alleles at two or more neighboring loci on one of the homologous chromosomes.
p.6
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What determines the risk that a carrier of an autosomal recessive disorder will have an affected child?
The chance that his or her mate is also a carrier of a mutant allele for the condition.
p.1
Pleiotropy and Variable Expressivity
What is an example of a pleiotropic disorder?
A mutation in the VHL gene causing hemangioblastomas, renal cysts, pancreatic cysts, renal cell carcinoma, pheochromocytoma, and other tumors.
p.6
Pleiotropy and Variable Expressivity
What is an example of an autosomal recessive disease with a sex-influenced phenotype?
Hereditary hemochromatosis.
p.4
Single-Gene Disorders Overview
What are the factors that determine the patterns of inheritance shown by single-gene disorders in families?
Whether the chromosomal location of the gene locus is on an autosome, a sex chromosome, or in the mitochondrial genome, and whether the phenotype is dominant or recessive.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What is the term 'fitness' used to measure in the context of autosomal dominant disorders?
Fitness is a measure of the impact of a condition on reproduction, defined as the ratio of the number of offspring of affected individuals who survive to reproductive age compared to those who do not carry the mutant allele.
p.1
Single-Gene Disorders Overview
What are the three main categories of genetic disorders?
Single-gene, chromosomal, and complex.
p.8
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the probability of offspring being affected in a D/d by d/d mating?
50% chance of being D/d and 50% chance of being d/d.
p.8
Dominant vs. Recessive Traits
Why are homozygotes for dominant phenotypes rarely seen in medical practice?
Because matings that could produce homozygous offspring are rare.
p.1
Single-Gene Disorders Overview
What is a single-gene disorder?
A disorder determined primarily by the alleles at a single locus.
p.6
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
Why are people with rare autosomal recessive disorders typically compound heterozygotes?
Because most mutant alleles are uncommon in the population.
p.4
Pedigree Analysis in Genetic Counseling
What is the significance of examining a pedigree in genetic counseling?
Examining a pedigree is an essential first step in determining the inheritance pattern of a genetic disorder in a family.
p.2
Pleiotropy and Variable Expressivity
What is expressivity in genetic disorders?
Expressivity refers to the severity of expression of a phenotype among individuals with the same disease-causing genotype.
p.3
Pedigree Analysis in Genetic Counseling
What is a pedigree in genetic counseling?
A graphical representation of the family tree using standard symbols.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is required for an individual to have an autosomal recessive disease?
Two mutant alleles and no wild-type allele.
p.3
Pedigree Analysis in Genetic Counseling
What does an arrow pointing to an individual in a pedigree chart signify?
The consultand seeking counseling.
p.6
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the carrier frequency of cystic fibrosis among white populations?
Approximately 1 in 23 individuals is a silent carrier.
p.7
Impact of Consanguinity on Genetic Disorders
In which regions is first-cousin marriage relatively common?
Rural areas of the Indian subcontinent, other parts of Asia, and the Middle East.
p.4
Dominant vs. Recessive Traits
What is an example of a trait that demonstrates codominant expression?
The ABO blood group system.
p.4
Mitochondrial Inheritance
How are mitochondria inherited?
Mitochondria are inherited from the mother only, regardless of the sex of the offspring.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What is the significance of new mutations in autosomal dominant disorders?
New mutations can cause autosomal dominant disorders in individuals with no family history of the condition, making them appear as isolated cases.
p.2
Pleiotropy and Variable Expressivity
What is variable expressivity?
Variable expressivity occurs when the severity of disease differs in people who have the same genotype.
p.10
Penetrance in Genetic Disorders
How can incomplete penetrance affect the inheritance pattern of split-hand malformation?
It can lead to apparent skipping of generations, complicating genetic counseling as an at-risk person with normal hands may still carry the mutation.
p.8
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
Why might the distribution of affected and unaffected children differ from the theoretical ratio in a family?
Because each pregnancy is an independent event and the sibship might be small.
p.1
Genotype vs. Phenotype
Why are the terms homozygous, heterozygous, and hemizygous not used for mitochondrial loci?
Because mitochondrial DNA molecules are present in tens to thousands of copies per cell.
p.6
Single-Gene Disorders Overview
How many deleterious alleles are estimated to be in each of our genomes?
Estimates range from 50 to 200.
p.6
Pleiotropy and Variable Expressivity
Why is hereditary hemochromatosis more common in males than in females?
Due to lower dietary iron intake, lower alcohol usage, and increased iron loss through menstruation in females.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
How does a late age of onset or mild phenotype affect the fitness of an autosomal dominant disorder?
Disorders with a late age of onset or mild phenotype have virtually normal reproductive fitness, meaning affected individuals can reproduce normally.
p.9
Single-Gene Disorders Overview
What gene mutation is associated with male-limited precocious puberty?
Mutations in the LCGR gene, which encodes the receptor for luteinizing hormone.
p.2
Genotype vs. Phenotype
What is the relationship between genotype and phenotype?
The genotype refers to the information encoded in the genome, while the phenotype is the physical, clinical, cellular, or biochemical manifestation of the genotype.
p.1
Genotype vs. Phenotype
What is phenotype?
Phenotype is the expression of genotype as a morphological, clinical, cellular, or biochemical trait.
p.1
Genotype vs. Phenotype
What is a compound heterozygote?
A genotype in which two different mutant alleles of a gene are present.
p.5
Dominant vs. Recessive Traits
What do the terms 'dominant' and 'recessive' refer to in genetics?
The inheritance pattern of a phenotype rather than the alleles responsible for that phenotype.
p.4
Dominant vs. Recessive Traits
What is the definition of a recessive phenotype?
A phenotype is recessive if it is expressed only in homozygotes, hemizygotes, or compound heterozygotes, all of whom lack a wild-type allele, and never in heterozygotes, who do have a wild-type allele.
p.2
Single-Gene Disorders Overview
What is the difference between genetic and congenital disorders?
A genetic disorder is determined by variation in genes, whereas a congenital disorder is present at birth and may or may not have a genetic basis.
p.3
Pedigree Analysis in Genetic Counseling
What is the role of a consultand in genetic counseling?
The person who brings the family to attention by consulting a geneticist.
p.10
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What are the characteristics of autosomal dominant inheritance?
1. The phenotype usually appears in every generation. 2. Any child of an affected parent has a 50% risk of inheriting the trait. 3. Phenotypically normal family members do not transmit the phenotype. 4. Males and females are equally likely to transmit the phenotype. 5. A significant proportion of isolated cases are due to new mutations.
p.10
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the recurrence risk for a child of an affected parent in autosomal dominant inheritance?
50%, assuming the other parent is phenotypically normal.
p.7
Pedigree Analysis in Genetic Counseling
What is a strong evidence for autosomal recessive inheritance in a genetic disorder?
Finding consanguinity in the parents of a patient with a genetic disorder.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What is an example of a disorder with a fitness of 0?
Thanatophoric dwarfism, a severe short-limb dwarfism syndrome caused by mutations in the FGFR3 gene, is an example of a disorder with a fitness of 0.
p.9
Single-Gene Disorders Overview
What is achondroplasia?
An incompletely dominant skeletal disorder of short-limbed dwarfism and large head caused by mutations in the FGFR3 gene.
p.9
Single-Gene Disorders Overview
What is male-limited precocious puberty?
An autosomal dominant disorder where affected boys develop secondary sexual characteristics and undergo an adolescent growth spurt at approximately 4 years of age.
p.9
Pleiotropy and Variable Expressivity
Why does male-limited precocious puberty show no effect in heterozygous females?
Because the defect is sex-limited and expressed only in males.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What is the chance of two heterozygotes having a child with an autosomal recessive disorder?
25% (1 in 4) with each pregnancy.
p.8
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What are the possible matings that can produce a D/D homozygote?
D/d by D/d, D/D by D/d, or D/D by D/D.
p.1
Pleiotropy and Variable Expressivity
What is pleiotropy?
When a single abnormal gene or gene pair produces multiple diverse phenotypic effects in multiple organ systems.
p.4
Dominant vs. Recessive Traits
What is the inheritance pattern called when homozygotes or compound heterozygotes for mutant alleles at autosomal loci are more severely affected than heterozygotes?
Incompletely dominant (or semidominant).
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What does a fitness value of 0 indicate in autosomal dominant disorders?
A fitness value of 0 indicates that affected individuals never have children who survive to reproductive age, making the disorder a genetic lethal.
p.3
Pedigree Analysis in Genetic Counseling
Who is the proband in a genetic pedigree?
The affected individual through whom a family with a genetic disorder is first brought to the attention of the geneticist.
p.6
Single-Gene Disorders Overview
Why are mutant alleles responsible for recessive disorders generally rare?
Most people do not have even one copy of the mutant allele.
p.6
Pedigree Analysis in Genetic Counseling
Why is knowledge of the carrier frequency of a disease clinically important?
It helps in genetic counseling to assess the risk of having an affected child.
p.7
Impact of Consanguinity on Genetic Disorders
What is the incidence of first-cousin marriage in many Western societies today?
Approximately 1 to 10 per 1000 marriages.
p.11
Penetrance in Genetic Disorders
What does reduced penetrance mean in the context of genetic disorders?
Reduced penetrance means that not all individuals with a mutation exhibit the clinical symptoms of the disorder.
p.5
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What type of mutation is generally responsible for autosomal recessive diseases?
Loss-of-function mutation.
p.3
Pedigree Analysis in Genetic Counseling
What does a double horizontal line between two individuals in a pedigree chart indicate?
Consanguinity (marriage or union between close relatives).
p.4
Dominant vs. Recessive Traits
What is codominant inheritance?
Codominant inheritance occurs if phenotypic expression of both alleles at a locus occurs in a compound heterozygote.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What is the relationship between fitness and the proportion of inherited versus new mutations in autosomal dominant disorders?
There is an inverse relationship; higher fitness means the disorder is more likely inherited, while lower fitness means it is more likely due to new mutations.
p.10
Fitness and New Mutations in Autosomal Dominant Disorders
How does reduced fitness affect the proportion of new mutation cases in autosomal dominant disorders?
The less the fitness, the greater the proportion of cases due to new mutation.
p.4
Dominant vs. Recessive Traits
What is the definition of a dominant inheritance pattern?
A dominant inheritance pattern occurs when a phenotype is expressed in heterozygotes as well as in homozygotes (or compound heterozygotes).
p.7
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What are the characteristics of autosomal recessive inheritance?
1. Typically seen only in the sibship of the proband. 2. Males and females are equally likely to be affected. 3. Parents of an affected child are asymptomatic carriers. 4. Parents may be consanguineous. 5. Recurrence risk for each sib of the proband is 25%.
p.11
Pleiotropy and Variable Expressivity
Why might heterozygous carriers of NF1 be incorrectly classified as unaffected?
Heterozygous carriers might be incorrectly classified as unaffected due to the mild manifestations of the disease or the age-dependent development of symptoms.
p.4
Inheritance Patterns: Autosomal Recessive, Autosomal Dominant, and X-Linked
What are the three types of inheritance patterns discussed in the text?
Autosomal, X-linked, and mitochondrial inheritance.
p.11
Fitness and New Mutations in Autosomal Dominant Disorders
What is an example of an autosomal dominant disorder with a fitness of approximately 1?
Late-onset progressive hearing loss is an example of an autosomal dominant disorder with a fitness of approximately 1.
