Podcast
Questions and Answers
Which type of mutation results in a gene product with a completely absent or severely reduced normal function?
Which type of mutation results in a gene product with a completely absent or severely reduced normal function?
A patient presents with progressive muscle weakness and a family history of similar symptoms, what type of mutation is most likely responsible?
A patient presents with progressive muscle weakness and a family history of similar symptoms, what type of mutation is most likely responsible?
A mutation in which the gene product acquires a new and abnormal function is best described as a:
A mutation in which the gene product acquires a new and abnormal function is best described as a:
In Huntington's disease, the expansion of a CAG repeat leads to:
In Huntington's disease, the expansion of a CAG repeat leads to:
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A key characteristic of a loss of function mutation is that:
A key characteristic of a loss of function mutation is that:
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What is the clinical outcome of a gain of function mutation?
What is the clinical outcome of a gain of function mutation?
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Why might different mutations in the dystrophin gene all lead to Duchenne Muscular Dystrophy?
Why might different mutations in the dystrophin gene all lead to Duchenne Muscular Dystrophy?
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What is the primary molecular consequence of an expanded CAG repeat in the HTT gene associated with Huntington's disease?
What is the primary molecular consequence of an expanded CAG repeat in the HTT gene associated with Huntington's disease?
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In the context of Huntington's disease, how does the number of CAG repeats impact the phenotype?
In the context of Huntington's disease, how does the number of CAG repeats impact the phenotype?
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What is the defining characteristic of a dominant-negative mutation?
What is the defining characteristic of a dominant-negative mutation?
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What is the structural configuration of Type I collagen?
What is the structural configuration of Type I collagen?
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Why do mutations in either COL1A1 or COL1A2 genes result in osteogenesis imperfecta (OI)?
Why do mutations in either COL1A1 or COL1A2 genes result in osteogenesis imperfecta (OI)?
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In the context of osteogenesis imperfecta (OI), what is the determining factor between a mild and lethal phenotype?
In the context of osteogenesis imperfecta (OI), what is the determining factor between a mild and lethal phenotype?
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How does an extra copy of chromosome 21 in Down Syndrome lead to the observed phenotype?
How does an extra copy of chromosome 21 in Down Syndrome lead to the observed phenotype?
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What is the primary effect of some mutations on the level of gene product, as discussed in the context of gene dosage effects?
What is the primary effect of some mutations on the level of gene product, as discussed in the context of gene dosage effects?
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What is the common thread among the pathology of CAG repeat diseases, Alzheimer disease, Parkinson disease, and prion diseases?
What is the common thread among the pathology of CAG repeat diseases, Alzheimer disease, Parkinson disease, and prion diseases?
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If a female offspring inherits a mutant allele from her father in an X-linked inheritance pattern, what is the risk of her being affected?
If a female offspring inherits a mutant allele from her father in an X-linked inheritance pattern, what is the risk of her being affected?
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A male offspring inherits a mutant allele from his mother in an X-linked inheritance pattern. What is the risk of him being affected?
A male offspring inherits a mutant allele from his mother in an X-linked inheritance pattern. What is the risk of him being affected?
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In cases of locus heterogeneity, how might parents who both carry a recessive disorder not have affected children?
In cases of locus heterogeneity, how might parents who both carry a recessive disorder not have affected children?
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Which of the following is the MOST accurate description of locus heterogeneity?
Which of the following is the MOST accurate description of locus heterogeneity?
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What common feature is shared by the multiple genes involved in Bardet-Biedl syndrome?
What common feature is shared by the multiple genes involved in Bardet-Biedl syndrome?
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What is a key distinction between a phenotype and a trait?
What is a key distinction between a phenotype and a trait?
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Which resource provides the most comprehensive information on human Mendelian phenotypes and their underlying genes, including historical context?
Which resource provides the most comprehensive information on human Mendelian phenotypes and their underlying genes, including historical context?
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In the context of genetic terminology, what does 'locus' refer to?
In the context of genetic terminology, what does 'locus' refer to?
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What is a major limitation of information found in Genecards?
What is a major limitation of information found in Genecards?
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When discussing the cause of Down syndrome, which of the following is NOT explicitly identified as a common major congenital malformation?
When discussing the cause of Down syndrome, which of the following is NOT explicitly identified as a common major congenital malformation?
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Why is the study of single-gene disorders important despite them being rare?
Why is the study of single-gene disorders important despite them being rare?
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Which of the following best describes the role of PubMed identifiers (PMIDs) in the context of GeneReviews?
Which of the following best describes the role of PubMed identifiers (PMIDs) in the context of GeneReviews?
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What is the relationship between a phenotype and genetic variation, according to the text?
What is the relationship between a phenotype and genetic variation, according to the text?
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GeneReviews are described as 'clinically and genetically oriented'. What does this imply?
GeneReviews are described as 'clinically and genetically oriented'. What does this imply?
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Based on the resources provided, what would be the best resource to understand the underlying cause of Huntington's Disease?
Based on the resources provided, what would be the best resource to understand the underlying cause of Huntington's Disease?
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In autosomal dominant inheritance, what is the probability that an affected individual will have an affected offspring?
In autosomal dominant inheritance, what is the probability that an affected individual will have an affected offspring?
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In autosomal recessive inheritance, what is the typical genotype of affected individuals?
In autosomal recessive inheritance, what is the typical genotype of affected individuals?
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What is the term for individuals who have two different mutant alleles at the same locus for an autosomal recessive condition?
What is the term for individuals who have two different mutant alleles at the same locus for an autosomal recessive condition?
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In autosomal recessive disorders, the parents of an affected individual are typically:
In autosomal recessive disorders, the parents of an affected individual are typically:
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What distinguishes autosomal dominant inheritance from autosomal recessive inheritance regarding who manifests the phenotype:
What distinguishes autosomal dominant inheritance from autosomal recessive inheritance regarding who manifests the phenotype:
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If both parents are carriers of an autosomal recessive disorder, but are not affected themselves, what is the risk that their child will be affected?
If both parents are carriers of an autosomal recessive disorder, but are not affected themselves, what is the risk that their child will be affected?
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What is true about the possibility of inheritance in autosomal dominant and recessive disorders?
What is true about the possibility of inheritance in autosomal dominant and recessive disorders?
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In the context of a pedigree for an autosomal recessive disorder, what information is typically NOT directly revealed?
In the context of a pedigree for an autosomal recessive disorder, what information is typically NOT directly revealed?
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If two unrelated parents are carriers of different recessive mutant alleles for the same gene, what is the likely genotype of their affected offspring?
If two unrelated parents are carriers of different recessive mutant alleles for the same gene, what is the likely genotype of their affected offspring?
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Which statement best describes the nature of autosomal disorders?
Which statement best describes the nature of autosomal disorders?
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Flashcards
Loss of function mutation
Loss of function mutation
A type of mutation where the gene product loses its normal function, resulting in reduced or no activity.
Gain of function mutation
Gain of function mutation
A type of mutation where the gene product gains a new, abnormal function.
Dominant negative mutation
Dominant negative mutation
This mutation occurs when a mutated gene product interferes with the normal function of the wild-type gene product.
Mutations that affect gene dosage
Mutations that affect gene dosage
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Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD)
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Huntington Disease (HD)
Huntington Disease (HD)
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Trinucleotide repeat disease
Trinucleotide repeat disease
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Huntington's Disease
Huntington's Disease
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CAG Repeat
CAG Repeat
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CAG Repeat Number
CAG Repeat Number
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Mutated HTT Allele
Mutated HTT Allele
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Protein Aggregation
Protein Aggregation
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Osteogenesis Imperfecta
Osteogenesis Imperfecta
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Gene Dosage
Gene Dosage
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Gene Dosage Effect
Gene Dosage Effect
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Mutational Heterogeneity
Mutational Heterogeneity
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Locus Heterogeneity
Locus Heterogeneity
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Single gene disorder
Single gene disorder
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Phenotype
Phenotype
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Locus
Locus
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Genetic variation and Phenotype
Genetic variation and Phenotype
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Genecards
Genecards
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GenereviewsTM
GenereviewsTM
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OMIM (Online Mendelian Inheritance in Man)
OMIM (Online Mendelian Inheritance in Man)
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Allelic heterogeneity
Allelic heterogeneity
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Phenotypic heterogeneity
Phenotypic heterogeneity
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What are single gene disorders?
What are single gene disorders?
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Autosomal dominant inheritance
Autosomal dominant inheritance
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Autosomal recessive inheritance
Autosomal recessive inheritance
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Carrier
Carrier
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Compound heterozygote
Compound heterozygote
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Homozygote
Homozygote
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Heterozygote
Heterozygote
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Study Notes
Genetic Diseases: Lectures 1 and 2
- The lectures cover genetic diseases.
- Learning outcomes include understanding how mutations cause pathology, describing different types of mutations, understanding genetic pedigree analysis, recognizing Mendelian inheritance patterns, inheriting autosomal dominant and recessive alleles, and the influence of locus, allele, and phenotype heterogeneity on single-gene disorders.
- Mutations can cause pathology by altering gene function.
- Types of mutations include Deletions (1bp-Mbp's), Insertions (1bp-Mbp's, including gene duplications), single base substitutions (missense, nonsense, and splice shifts).
- Missense is when one amino acid is replaced by a different amino acid.
- Nonsense is when an amino acid codon is replaced by a stop codon.
- Splice shifts occur when intron/exon splice sites are lost or created and can affect the protein reading frame.
Molecular Pathology
- Molecular pathology explains how genetic changes result in clinical phenotypes.
- Types of mutations include deletions (ranging from 1 base pair to megabases), insertions (ranging from 1 base pair to megabases, including gene duplications), and single-base substitutions.
- Single-base substitutions can lead to missense (different amino acid), nonsense (stop codon), and splice shifts (altered reading frame or frameshift mutations)
Effects of Mutations in Humans
- Mutations can affect the process of protein synthesis, leading to differences in protein structure and function.
- Mutations can occur in the promoter regions of genes, affecting transcription initiation or within the coding regions of genes, changing the amino acid sequence of the protein product.
- Mutational heterogeneity refers to the various types of mutations that can cause similar phenotypic effects.
Loss of Function Mutations
- Loss-of-function mutations result in reduced or absent gene product function.
- Any mutation inactivating the gene product leads to the same clinical phenotype.
- An example is Duchenne Muscular Dystrophy (DMD), a severe muscular disorder.
- Clinical characteristics include progressive muscular weakness, death in the third decade, primarily affects males (1 in 3500 births).
- Treatment for DMD is currently unavailable.
- Inheritance of DMD is X-linked recessive.
Gain of Function Mutations
- Gain-of-function mutations result in abnormal gene product function, giving the product a new function.
- The specific mutation causing the new function leads to the clinical phenotype.
- An example is Huntington Disease (HD).
- Clinical characteristics include late onset (30-50 years), neurodegenerative disease, dominant inheritance, death within 15-20 years.
- HD arises from an unstable CAG repeat expansion in the huntingtin gene, disrupting protein function and leading to aggregation and neuronal death.
HD - Trinucleotide Repeat Disease
- Huntington Disease involves an expanded, unstable CAG repeat in exon 1 of the huntingtin gene.
- Normal alleles have 9-35 repeats, while affected alleles have 36-100 repeats.
- More repeats lead to earlier disease onset and more severe symptoms.
Dominant Negative Mutations
- Mutant gene products impede the function of other multimeric protein components.
- An example is Osteogenesis Imperfecta (OI).
- OI arises from mutations in Type I collagen genes, causing brittle bones with varying degrees of severity.
Osteogenesis Imperfecta (OI)
- Type I collagen, critical to bone structure, consists of a triple helix of protein chains.
- OI results from mutations affecting either COL1A1 or COL1A2 genes, leading to brittle bones.
- Phenotypes range from mild to lethal.
- Mild phenotypes involve exclusion of the mutated alpha chain.
- Lethal phenotypes involve incorporation of the mutated alpha chain into collagen, disrupting normal alpha chain function.
Gene Dosage Effects
- Gene dosage refers to the level of gene product resulting from variations in gene number.
- Down Syndrome (OMIM) is a characteristic chromosomal abnormality caused by trisomy of chromosome 21.
- Individuals with Down Syndrome exhibit a particular phenotypic combination including mental retardation and facial characteristics.
- Congenital malformations in the heart (30–40% of individuals) and gastrointestinal tract are common.
Genetic Pedigree Analysis and Terminology
- Pedigree analysis uses symbols to depict family relationships (e.g., male, female, unaffected, affected, carrier) and shows the inheritance of a trait or condition through generations.
- The proband is the first family member who brings the disorder to the attention of clinicians.
- Consanguinity refers to marriage between close relatives.
Single Gene Disorders
- Single gene disorders are rare genetic conditions caused by mutations in a single gene.
- They often follow defined inheritance patterns.
- Phenotypes describe observable characteristics associated with single gene disorders.
- Genetic variation is the primary determinant of phenotypes, influenced by environmental factors.
- Electronic sources providing information on single gene disorders include Genecards, Genereviews, and OMIM.
Genetic Terminology
- Locus refers to the specific chromosomal location of a gene.
- Allele refers to a variant form of a gene.
- Genotype refers to the combined set of alleles at a locus.
- Homozygotes have two identical alleles at a given locus, and heterozygotes have different alleles.
- Hemizygous individuals have only one allele at a locus, like sex chromosomes (X and Y) in males.
Mendelian Inheritance in Humans
- Mendelian characters are determined by chromosomal loci (autosomes or sex chromosomes).
- Females have 23 pairs of homologous chromosomes, while males have one X and one Y chromosome.
- Autosomal Dominant, Autosomal Recessive, X-linked Dominant, and X-linked Recessive are forms of Mendelian inheritance.
Autosomal Dominant Inheritance
- Affected individuals are almost always heterozygous.
- Homozygotes for a dominant allele may have a more severe phenotype and an earlier onset of the disorder than heterozygotes.
- For example, Achondroplasia.
- Characteristics include short limbs and disproportionately large heads.
- Another example is Familial Hypercholesterolemia (FH).
- FH results in elevated serum cholesterol, leading to atherosclerotic plaque formation.
Achondroplasia
- A genetic disorder leading to disproportionate short stature.
- Characteristics include short limbs, large head, and characteristic facial features.
- Caused by mutations in the FGFR3 gene.
- Diagnosed with clinical and radiographic findings, and confirmed with molecular genetic testing.
- Inheritance of achondroplasia follows an autosomal dominant pattern.
Familial Hypercholesterolemia (FH)
- Characterized by elevated LDL cholesterol.
- Genetic predisposition for accelerated atherosclerosis.
- Diagnostic ranges of serum cholesterol are variable based on the form of FH.
- Severity varies, leading to a range of possible clinical features and effects on organs..
X-Linked Recessive Inheritance
- Affected individuals are usually male and inherit the mutation from their mothers.
- Males cannot pass the mutated allele to their sons.
- An example is Duchenne Muscular Dystrophy.
X-Linked Dominant Inheritance
- Affected individuals may be either male or female, but more often females are affected.
- Inheritance is directly through the mother.
- The risk of inheriting and being affected differs between males and females.
Autosomal Recessive Inheritance
- Two copies of a mutated allele are necessary for the disorder to be expressed.
- Affected individuals often inherit the disorder through consanguineous parents.
- Examples include Cystic Fibrosis (CFTR gene) and Sickle Cell disease.
Cystic Fibrosis
- Inherited disease causing thick mucus buildup, primarily affecting lungs.
- Causes impaired salt and water transport in cells, leading to thick, viscous mucus.
- Affected tissues and organs include lungs, pancreas, and digestive tract.
- Characterized by chronic lung infections, difficulty breathing, poor nutrient absorption, and pancreatic damage.
Heterogeneity and Variable Expression
- There are variations in single-gene disorders' inheritance modes, including mitochondrial and Y-linked inheritance.
- Locus heterogeneity refers to different genes at different loci causing the same phenotype.
- Examples include Usher syndrome (hearing loss and vision impairment) and Bardet-Biedl syndrome (multiple organ system abnormalities).
- Mutational heterogeneity refers to mutations within the same gene but at different locations.
- Variable expressivity accounts for differences in phenotype severity in individuals with mutations in the same gene.
Penetrance
- Penetrance refers to the probability that a person with a particular genotype will express the associated phenotype.
- Full penetrance means all individuals with the genotype display the phenotype.
- Incomplete penetrance signifies that some individuals with the genotype do not show the phenotype
Variable Expressivity
- Variable expressivity describes the different severities or degrees of a phenotype that can be observed in individuals with the same genotype.
- It arises from the influence of other genes, epigenetic regulatory processes, and environmental factors which can modify the expressivity of the condition.
- Example includes Tuberous Sclerosis Complex (TSC), a genetic disorder producing benign tumors in multiple organs.
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Description
Test your knowledge on different types of genetic mutations, their effects on gene products, and their clinical implications. This quiz covers loss of function, gain of function mutations, and specific conditions like Huntington's disease and Duchenne Muscular Dystrophy.
