Molecular and Biochemical Genetics

From Iusmgenetics

Contents 1 Molecular and Biochemical Genetics 1.1 Objectives 1.2 Review your fundamentals 1.3 Dominant Diseases 1.3.1 Achondroplasia 1.3.2 Osteogenesis imperfecta 1.3.3 Ehlers Danlos Syndrome 1.3.4 Marfan syndrome 1.3.5 Familial Hypercholesterolemia 1.4 Recessive Diseases 1.4.1 Homocysteinuria 1.4.2 Cystic Fibrosis 1.4.3 Hemochromatosis 1.4.4 Alpha-1-Anti-Trypsin deficiency 1.4.5 Phenylketonuria 1.4.6 Tay-Sachs Disease 1.4.7 Galactosemia 1.4.8 Maple Syrup Urine Disease 1.5 X-linked Diseases 1.5.1 Rett Syndrome 1.5.2 Lesch-Nyhan syndrome 1.5.3 Inherited Muscular Dystrophies 1.6 Newborn Screening 1.6.1 Pitfalls of Screening

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:

• 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

Tay-Sachs Disease

Galactosemia

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.

• In Indiana we screen for:
  • Metabolic disorders:
    • Phenylketonuria
    • Galactosemia
    • Maple Syrup Urine Disease
    • Homocysteinuria
    • Biotinidase Deficiency
  • Endocrine disorders:
    • Hypothyroidism
    • Congenital Adrenal Hyperplasia
  • Hemoglobinopathies:
    • Sickle Cell Disease
  • Cystic fibrosis
• Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem bass spectrometry

Pitfalls of Screening

• False positives cause unecessary stress / anxiety and investigation / treatment.
• False negatives cause false security.
• Recalling the requirement that a screened disease must be "treatable" in some effective way, we see that prolonging the knowledge of a disease may be a form of harm if the disease cannot be treated.
• Procedures prompted by screening can be uncomfortable and unnecessary.