Phenotypes

    Cards (32)

    • Linkage analysis

      Why do we want to know which of the informative meiosis in a pedigree is recombinant or non-recombinant?
    • Recombination rate
      • Markers
      • The "disease gene" must be around here
    • Linkage analysis: Logarithm of Odds
      i.e., Genetic distance between the marker and the disease gene
    • Two-point linkage analysis

      • Linkage analysis
      • LOD scores plotted against recombination fraction
    • Z ≥ 3 is significant for linkage. Z < −2 is significant against linkage.
    • Finding disease genes using genetic linkage and high-throughput sequencing

      1. Collect multi-case, multi-generation family/families
      2. Linkage analysis
      3. Local gene list, prioritisation
      4. Candidate gene sequencing, segregation analysis
    • Finding disease genes by exome/genome sequencing
      1. Collect multi-case and/or several core families
      2. Long list of variants in different locations
      3. Shortlist of candidate variants
      4. High-throughput sequencing
      5. Gene list, filtering, prioritisation
      6. Segregation analysis, independent cases
    • Exome sequencing can be used to find disease genes for facial abnormalities, missing fingers/toes, frequent mosaicism, extremely rare disease (approximately 1 case per 1 million newborns)
    • Mode of inheritance?
      Miller syndrome
    • Exome sequencing: Filter
      1. 2 affected sibs
      2. Genetic model (dominant, recessive)
      3. Mutation type
      4. Databases
      5. Prediction
    • DHODH (dihydroorotate dehydrogenase) is the gene found to cause Miller syndrome
    • Mutation types
      • Missense
      • Insertion & deletion
      • Silent
      • Splice site
      • Nonsense
      • Dynamic
    • Dynamic mutations
      Can occur by extension of short 'tandem' repeats. Above a certain size, these sequences become unstable. Dynamic mutations in UTR or coding sequences can be associated with disease.
    • Examples of diseases caused by dynamic mutations
      • Fragile X syndrome (FMR1)
      • Myotonic dystrophy (DMPK)
      • Huntington disease (HTT)
      • Spinocerebellar ataxia 1 (ATXN1)
      • Synpolydactyly 1 (HOXD13)
    • Huntington disease is caused by CAG repeat expansion in the gene HTT, which codes for huntingtin. The mutant huntingtin has an expanded poly-glutamine tract and forms protein aggregates, which do not promote secretion of neurotransmitters and lead to apoptosis.
    • Propensity for somatic expansion of CAG repeats increases over the course of life in Huntington disease
    • Anticipation
      Occurs when a disease manifests earlier and/or increases severity with successive generations. Anticipation is suspected when a mild disorder is observed in a parent/relative after diagnosis in the child/index patient.
    • Fragile X syndrome is an important example for diseases that show anticipation.
    • Loss of function
      Mutations are mainly recessive. For some genes, product amounts from one copy instead of two are not sufficient, leading to haploinsufficiency. Mutations causing haploinsufficiency are usually dominant.
    • Gain of function
      Can be associated with gross overexpression of certain genes, acquisition of a novel function and production of chimeric genes, modification of cellular signalling responses.
    • Diseases caused by gain of function mutations

      • Charcot-Marie-Tooth disease 1A (PMP22)
      • Albright syndrome (GNAS)
      • AML (GSTP1)
      • Hypokalemic periodic paralysis (SCN4A)
      • Osteogenesis imperfecta (COL1A1/A2)
      • Chronic myeloid leukemia (BCR-ABL)
    • Chronic myeloid leukemia is caused by a translocation between chromosomes 9 and 22 resulting in a fusion gene BCR-ABL1, which encodes a constitutively active tyrosine kinase.
    • Protein aggregation
      Changes in the physical surface properties can result in protein aggregation, as seen in sickle cell anemia.
    • Protein misfolding
      Mutations in genes for connective tissue proteins such as collagens can explain normal protein assembly and disease mechanisms caused by protein misfolding.
    • Type I collagen biosynthesis
      Collagen type I consists of two α1-chains and one α2-chain. These chains have to align in order to start the folding process of procollagen type I into a triple helix. After this folding process, post-translational modifications and collagen trimming by specific proteins have to take place.
    • Protein dimers
      Mutations can lead to mild disease by loss of interaction or severe disease by dominant negative activity.
    • Osteogenesis imperfecta (OI) can be caused by mutations in COL1A1 and COL1A2 (and several other genes). The severity of the disease depends on the type and position of the mutation.
    • Genotype/phenotype correlation in Osteogenesis imperfecta
      Dominant negative mutations that impair the coordinated assembly of collagen fibers explain the strong genotype/phenotype correlation. Mutations in N-terminal domains lead to milder diseases than mutations in C-terminal domains.
    • Types of genetic diseases
      • Monogenic (Mendelian)
      • Polygenic
      • Multifactorial
    • Polygenic inheritance
      Variants contributing to the disease, threshold for being clinically affected
    • Multifactorial diseases
      Combinations of genetic and environmental factors
    • Most diseases are caused by the combined effects of multiple genes and environmental factors
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