11.1 Genetic disorders and inherited diseases

Genetic disorders and inherited diseases are crucial topics in molecular biology, linking DNA mutations to health outcomes. These conditions arise from alterations in genes, affecting protein function and cellular processes. Understanding their mechanisms is key to diagnosing and treating genetic illnesses.

This section explores how genetic changes lead to diseases, inheritance patterns, and testing methods. It covers various mutation types, inheritance modes, and ethical considerations in genetic testing. These concepts are fundamental to grasping the molecular basis of diseases.

Molecular Mechanisms of Monogenic Disorders

Gene Mutations and Protein Dysfunction

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• Monogenic disorders stem from mutations in a single gene categorized as dominant, recessive, or X-linked
• Point mutations alter protein-coding sequences resulting in dysfunctional or non-functional proteins
  • Missense mutations change a single amino acid in the protein sequence
  • Nonsense mutations create premature stop codons, truncating the protein
  • Frameshift mutations shift the reading frame, altering the entire downstream sequence
• Insertions and deletions of genetic material cause frameshift mutations or disrupt gene expression
  • Small indels can add or remove one or more nucleotides
  • Large deletions or duplications can affect entire exons or genes
• Trinucleotide repeat expansions disrupt gene function leading to progressive disorders (Huntington's disease)
  • CAG repeat expansion in the huntingtin gene causes Huntington's disease
  • CGG repeat expansion in the FMR1 gene results in Fragile X syndrome

Gene Expression and Regulation Alterations

• Splice site mutations affect mRNA processing producing abnormal proteins or reduced protein levels
  • Mutations in splice donor or acceptor sites can lead to exon skipping or intron retention
  • Creation of new splice sites can result in inclusion of intronic sequences or partial exon deletion
• Epigenetic modifications influence gene expression contributing to monogenic disorders
  • DNA methylation can silence gene expression (Prader-Willi syndrome)
  • Histone modifications alter chromatin structure affecting gene accessibility
• Gene dosage effects lead to genetic disorders due to altered levels of gene products
  • Haploinsufficiency occurs when one functional copy of a gene is not enough (BRCA1 in breast cancer)
  • Triplosensitivity results from an extra copy of a gene causing overexpression (Down syndrome)

Patterns of Inheritance for Genetic Disorders

Autosomal Inheritance Patterns

• Autosomal dominant disorders manifest with only one copy of the mutated gene
  • Huntington's disease affects individuals with a single mutated copy of the huntingtin gene
  • Marfan syndrome results from mutations in the fibrillin-1 gene
• Autosomal recessive disorders require two copies of the mutated gene for expression
  • Cystic fibrosis occurs when both copies of the CFTR gene are mutated
  • Sickle cell anemia results from mutations in both copies of the HBB gene
• Multifactorial inheritance involves multiple genes and environmental factors
  • Complex disorders like diabetes and heart disease have genetic and lifestyle components
  • Autism spectrum disorders involve multiple genes and environmental influences

Sex-Linked and Non-Nuclear Inheritance

• X-linked recessive disorders primarily affect males and pass through carrier females
  • Hemophilia A results from mutations in the factor VIII gene on the X chromosome
  • Duchenne muscular dystrophy affects males due to mutations in the dystrophin gene
• X-linked dominant disorders affect both males and females but are often more severe in males
  • Rett syndrome primarily affects females due to mutations in the MECP2 gene
  • Incontinentia pigmenti affects skin pigmentation and is lethal in most males
• Mitochondrial inheritance follows a maternal pattern
  • Leber hereditary optic neuropathy (LHON) results from mutations in mitochondrial DNA
  • Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome

Unique Inheritance Mechanisms

• Genomic imprinting leads to parent-of-origin effects in genetic disorders
  • Prader-Willi syndrome occurs when paternal genes on chromosome 15 are silenced
  • Angelman syndrome results from loss of maternal genes on chromosome 15
• Uniparental disomy can cause genetic disorders due to inheritance of both copies of a chromosome from one parent
  • Prader-Willi syndrome can also result from maternal uniparental disomy of chromosome 15
  • Paternal uniparental disomy of chromosome 11 causes Beckwith-Wiedemann syndrome

Genetic Testing for Inherited Diseases

Types of Genetic Tests

• Karyotyping analyzes chromosomal structure and number
  • Detects large chromosomal abnormalities (Down syndrome, Turner syndrome)
  • Identifies translocations and other structural rearrangements
• Fluorescence In Situ Hybridization (FISH) detects specific DNA sequences
  • Useful for identifying microdeletions and microduplications
  • Detects chromosomal translocations in cancer cells
• DNA sequencing identifies specific genetic mutations
  • Sanger sequencing for targeted gene analysis
  • Next-generation sequencing for comprehensive genetic analysis
• Prenatal genetic testing detects genetic disorders in developing fetuses
  • Amniocentesis samples amniotic fluid for fetal cell analysis
  • Chorionic villus sampling obtains placental tissue for genetic testing
• Newborn screening programs identify inherited metabolic disorders early in life
  • Phenylketonuria (PKU) screening prevents intellectual disability through early intervention
  • Congenital hypothyroidism detection allows for timely hormone replacement therapy

Advanced Genetic Testing Approaches

• Carrier testing identifies individuals with recessive disease-causing mutations
  • Cystic fibrosis carrier screening in couples planning pregnancy
  • Tay-Sachs disease screening in populations with higher carrier frequency
• Predictive genetic testing assesses risk for late-onset genetic disorders
  • BRCA1/2 testing for hereditary breast and ovarian cancer risk
  • Huntington's disease testing for at-risk individuals
• Pharmacogenetic testing evaluates genetic variations influencing drug metabolism and efficacy
  • CYP2C19 testing for clopidogrel response in cardiovascular patients
  • TPMT testing for thiopurine drug dosing in leukemia treatment
• Next-generation sequencing technologies enable comprehensive genetic analysis
  • Whole-genome sequencing analyzes the entire genomic sequence
  • Whole-exome sequencing focuses on protein-coding regions of the genome

Ethical and Social Implications of Genetic Testing

Privacy and Discrimination Concerns

• Genetic information privacy protection prevents misuse by employers or insurers
  • Genetic Information Nondiscrimination Act (GINA) in the United States
  • European General Data Protection Regulation (GDPR) for genetic data
• Psychological impact of genetic test results affects individuals and families
  • Anxiety and depression following positive results for late-onset disorders
  • Survivor guilt in unaffected family members of those with genetic conditions
• Genetic counseling helps individuals understand implications of genetic test results
  • Provides support for decision-making regarding family planning
  • Offers resources for coping with genetic disorder diagnoses

Ethical Dilemmas in Genetic Testing

• Genetic determinism impacts personal autonomy and societal perceptions
  • Overemphasis on genetic factors may neglect environmental influences
  • Potential for fatalistic attitudes towards genetic predispositions
• Prenatal genetic testing raises ethical concerns about pregnancy termination
  • Debate over selective abortion based on genetic test results
  • Concerns about eugenics and societal attitudes towards disability
• Direct-to-consumer genetic testing presents challenges in result interpretation
  • Lack of medical guidance may lead to misunderstanding of health risks
  • Potential for anxiety or false reassurance based on incomplete information
• Genetic testing in minors raises issues of autonomy and future privacy
  • Debate over testing for adult-onset conditions in children
  • Concerns about the right to an open future and informed consent