Genetics · MU Sofia

6. Monogenic defects. Mutagenesis. Germline and somatic mutations. Gonadal and somatic mosaicism. Definition and classification of types of mutations in the human genome. Phenotypic expression of mutations.

Covers monogenic diseases and their inheritance patterns, with examples such as Marfan syndrome, cystic fibrosis and Duchenne muscular dystrophy. It then goes through mutagenesis, spontaneous and induced, germline versus somatic mutations, and gonadal and somatic mosaicism. The note also sets out classifications by molecular nature, functional effect and genomic context, and ends with factors shaping phenotypic expression such as penetrance, expressivity, pleiotropy and anticipation.

Inside: 9 sections · 8 labelled pictures · 14 flashcards · 6 min

Topic 6 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 9 sections, about 832 words (6 min of reading), with 14 flashcards.

In this note

  1. Monogenic Defects, Mutagenesis, Mosaicism, Types of Mutations, and Phenotypic Expression
  2. I. Monogenic Defects
  3. II. Mutagenesis
  4. III. Germline vs. Somatic Mutations
  5. IV. Mosaicism
  6. V.
  7. Classification of Mutations in the Human Genome
  8. VI. Phenotypic Expression of Mutations
  9. VII. Clinical Relevance

I. Monogenic Defects

  • Definition: Diseases caused by a mutation in a single gene locus. Despite being caused by only one defective gene, they can have systemic effects.
  • Modes of inheritance:
  • Autosomal dominant (AD): One mutated allele is enough for disease. Often due to gain-of-function or dominant-negative mutations.
  • Example: Marfan syndrome → mutation in FBN1 gene (fibrillin-1). Defective microfibrils lead to weak connective tissue, affecting the aorta, skeleton, and eyes.
  • Example: Huntington disease → CAG repeat expansion in HTT gene → toxic gain-of-function polyglutamine tract.
  • Autosomal recessive (AR): Both alleles must be mutated. Usually loss-of-function of enzymes.
  • Example: Cystic fibrosis → CFTR mutation → defective chloride channel → mucus accumulation.
  • Example: Phenylketonuria (PKU) → PAH mutation → phenylalanine hydroxylase deficiency → toxic accumulation of phenylalanine.
  • X-linked: Mutations on the X chromosome. Males more affected (hemizygous).
  • Example: Duchenne muscular dystrophy → frameshift in DMD gene → absent dystrophin protein.
  • Example: Hemophilia A → F8 mutation → factor VIII deficiency.

Key concept: Even a single-gene defect can disrupt whole biochemical pathways → multisystem disease.

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