Molecular and Biochemical Genetics
From Iusmgenetics
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====[[Alpha-1-Anti-Trypsin deficiency]]==== | ====[[Alpha-1-Anti-Trypsin deficiency]]==== | ||
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+ | ====[[Phenylketonuria]]==== | ||
====[[Maple Syrup Urine Disease]]==== | ====[[Maple Syrup Urine Disease]]==== | ||
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====[[Inherited Muscular Dystrophies]]==== | ====[[Inherited Muscular Dystrophies]]==== | ||
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+ | ===Newborn Screening=== | ||
+ | *The following criteria for newborn screening assure that our screening has ''analytic validity'', ''clinical validity'', and ''clinical utility'': | ||
+ | **The disorder must be '''well defined'''. | ||
+ | **The disorder must be '''fairly high in population frequency''' (to justify the cost of newborn screening by the cost saved in care for the true-positives). | ||
+ | **The disorder must be '''poorly clinically detected early in life (assymptomatic)''' (otherwise it is more cost effective to let physicians identify the disease at newborn checkups). | ||
+ | **The disorder must be '''significant in morbidity / mortality if left untreated''' (otherwise we might start treating things that have little consequence). | ||
+ | **The disorder must be '''treatable such that there is an improved condition''' (lest we start adding anxiety to insult). | ||
+ | **The test must be '''rapid, inexpensive, specific AND sensitive over an entire population'''. | ||
+ | **The test must be '''acceptable and cost-effective'''. | ||
+ | **The test must be '''appropriately administered'''. |
Revision as of 14:36, 18 October 2011
Contents |
Molecular and Biochemical Genetics
Objectives
- Important terms:
- "Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).
- "Distinct disorder": consistent clinical and radiological findings.
- Important concepts:
- Types of mutations:
- Missense: changed amino acid
- Nonsense: introduced stop codon
- Neutral / silent: no amino acid change
- Polymorphisms are a population term; it means 1% of the pop has it; it does not infer whether it causes disease or not
- RNA splicing: gain or loss of splice site
- Regulation mutation: affects gene regulation
- Indels: gain or loss of one or more bases; leads to frameshift if not a multiple of 3
- Repeat expansion: repeated segment (usually 3 bases) expands as nucleotide copy / repair mechanisms get hung up
- Haploinsufficiency:
- Dominant-negatie effect:
- Types of mutations:
- For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)
Review your fundamentals
Dominant Diseases
- Dominant disease are defined as those manifested when only one allele is mutated.
- Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.
- There are multiple ways we describe a single allele (not both copies) can cause disease:
- Qualitative effects: the protein product gains a function.
- Quantitative effects: the protein product is broken.
- Combination of qualitative and quantitative.
- Others
- It is important to understand the disease pathogenesis in order to think wisely about treatment.
Achondroplasia
Osteogenesis imperfecta
Ehlers Danlos Syndrome
Marfan syndrome
Familial Hypercholesterolemia
Recessive Diseases
- Requires two mutant alleles to show the phenotype or disease state.
- Recall that a proband with a recessive disease usually has parents who are both carriers.
- However, there are exceptions: uniparental disomy, skewed lyonization.
- Recessive disorders usually result from a missing component of a pathway.
- Phenotype usually results from the accumulation of a precursor / metabolite.
Homocysteinuria
Cystic Fibrosis
Hemochromatosis
Alpha-1-Anti-Trypsin deficiency
Phenylketonuria
Maple Syrup Urine Disease
X-linked Diseases
Rett Syndrome
Lesch-Nyhan syndrome
Inherited Muscular Dystrophies
Newborn Screening
- The following criteria for newborn screening assure that our screening has analytic validity, clinical validity, and clinical utility:
- The disorder must be well defined.
- The disorder must be fairly high in population frequency (to justify the cost of newborn screening by the cost saved in care for the true-positives).
- The disorder must be poorly clinically detected early in life (assymptomatic) (otherwise it is more cost effective to let physicians identify the disease at newborn checkups).
- The disorder must be significant in morbidity / mortality if left untreated (otherwise we might start treating things that have little consequence).
- The disorder must be treatable such that there is an improved condition (lest we start adding anxiety to insult).
- The test must be rapid, inexpensive, specific AND sensitive over an entire population.
- The test must be acceptable and cost-effective.
- The test must be appropriately administered.