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GENETIC 🧠 :man-woman-girl-boy:, GENOMIC MUTATION THROUGHOUT TIME, HARDY…

- - - - late onset repeat expansion disease
      - appeared already in a family
      - increase repeat # repeats across generation
      - increase phenotype severity
    - - 5'UTR
      - ORF = open reading frame
      - 3' UTR
    - - disrupt gene function
      - affected phenotype
  - - - neurological disorder
      - expanded microsatellite
      - affect cellular process
      - cause disease
      - depending on location
    - - loss of function disorder FMR1 :red_cross:
        
        CGG location: 5'UTR
        
        FRAXA = fragile X syndrome
        
        FMR-1 gene
        
        CGG expansion
        
        level of mutation
        
        full range >200
        
        2 more items...
        
        normal : 6-50
        
        premutation: 55-200
        
        3 more items...
        
        site of methylation
        
        attract DNA methylase
        
        hypermethylate microsatellite CpGs
        
        spread 5'UTR + promoter
        
        silence FMR1 gene
        
        makes FMRP protein for mRNA transport out of nucleus in CNS
        
        deletion of FMR1 gene
        
        similar phenotype as FRAXA
        
        pattern: x-linked dominant
        
        female 50% penetrant
        
        Male 100% penetrant
        
        X sperm with full mutation has premutation in FMR1
        
        microsatellite shortened
        
        phenotype presentation
        
        severe intellectual disability
        
        infancy
        
        little/ no FMR1 protein
      - CAG/polyglutamine repeat disorder :books:
        
        diseases
        
        huntington disease
        
        appear 30s-40s
        
        hirschsprung disease
        
        huntintin gene mutation
        
        prevent protein expression
        
        different phenotype from HD
        
        spinocerebellar ataxias
        
        SCA1
        
        SCA2
        
        SCA6
        
        SCA7
        
        CAG location: ORF
        
        pattern: AD
        
        MOA
        
        CAG expansion
        
        full mutation range
        
        protein misfolding
        
        misfolded protein aggregation
        
        neuronal damage
      - mRNA gain of function disorders :+1:
        
        myotonic dystrophy-1
        
        pattern: AD
        
        MOA
        
        DMPK gene
        
        is kinase involved in cell regulation
        
        muscle
        
        cardiac
        
        CTG expansion into full mutation range
        
        high DMPK mRNA transcribed
        
        2 more items...
        
        DMPK protein level mildly decreased
        
        1 more item...
        
        CTG location: 3'UTR
        
        FXTAS
        
        FMR1
        
        CGG location: 5'UTR
        
        pattern: X-linked
        
        MOA
        
        FMRP mildly reduced
        
        high FMR1 mRNA transcribed
        
        FMR disrupt splicing??
        
        location 5' UTR
        
        phenotype presentation
        
        tremor
        
        ataxia
        
        cognitive decline
        
        older males with premutation
- - - - MOA
        
        GOF in NLRP3
        
        activate cryopyrin
        (usually inactive)
        
        activate IL-1B secretion
        (proinflammatory mediator)
        
        activate IL-2 receptor
        
        inflammation = rash, fever :face_with_thermometer:
      - drug target
        
        rilonacept # fusion protein to
        
        canakinumab # monoclonal antibodies
        
        anakinra # antagonist / block
    - - neonatal onset multisystem inflammatory disease
  - - - triploidy
        
        47 XXY
        
        tall male
        
        reduced verbal IQ
        
        no major disorder; poor social adjustment
        
        hypogonadism, infertility
        
        47 XYY
        
        tall male
        
        reduced verbal IQ
        
        behavioral problem due to low IQ
        
        normal sex development
        
        trisomy 18 and 13 can be live born but limited survival
        
        47 XXX
        
        female; hyptonia
        
        language delay
        
        normal - low-normal range IQ
        
        no behavioral problem; some anxiety
        
        reduced fertility; premature ovarian failure
        
        Trisomy 21 down syndrome
        
        90% case is nondisjunction
        
        maternal meiosis 1
        
        phenotype
        
        hypotonia
        
        short
        
        loose skin on nape
        
        palmar crease
        
        clinodactyly
        
        increase risk
        
        cognitive heart disease + duodenal atresia
        
        leukemia
        
        premature dementia
      - 45 X
        
        short stature
        
        performance IQ < verbal IQ
        
        impaired social adjustment
        
        gonadal dysgenesis; delayed maturation; infertility
    - - duplication
        
        contiguous gene syndrome
      - deletion
        
        microdeletion syndromes = contiguous gene syndrome
        
        EPCAM/ LYNCH SYNDROME
        
        germline
        
        terminal deletion of EPCAM
        
        delete start of MSH2
        
        phenotype
        
        developmental delay
        
        dysmorphic features
        
        structural abnormablities
        
        birth defect
      - balanced translocation #
        
        BCR-ABL translocation
      - unbalance translocation
        
        balanced translocated chromosome from parents passing onto kids
        
        KIDS HAVE 3 copies of the same gene
      - inversion
        
        pericentric
        
        break point in p arm and q arm
        
        reproductive risk
        
        paracentric
        
        breakpoint in same arm
        
        no sig risk
    - - only one autosomal alleles is expressed
      - depending on which allele is lost
        
        15, angelman syndrome
        
        10% UBE3A mutation
        
        15, prader-willi syndrome
        
        rare gene mutation
        
        small deletion within snoRNA gene cluster
      - for imprinted region, need to be imprinted in the right tissue
  - - - GERMLINE :eyes:
        
        new germline
        
        parents: 0% affected
        
        siblings: rare risk
        
        offspring: 50% chance
        
        inherited
        
        parents: > 1 person affected
        
        siblings: 50% affected
        
        offsprings: 50% affected
        
        phenotype presentation
        
        bilateral
        
        multiple tumors
        
        early onset
        
        increase risk for 2nd tumor
      - SPORADIC :EYE:
        
        parents 0%
        
        siblings 0%
        
        offsprings 0%
        
        phenotype presentation
        
        late onset
        
        unilateral
        
        single tumors
        
        no increase risk for 2nd tumor
      - 2 hit hypothesis
    - - GENES INVOLVED
        
        MSH6
        
        PMS2
        
        MLH1
        
        EPCAM
        
        MSH2
      - LYNCH SYNDROME
        
        1 germline mutation
        
        1 somatic mutation
        
        children 50% risk
        
        siblings 50% risk
        
        many MMR mutation
        
        parents: one of them
        
        recessive at cell level/ autosomal dominant pattern
      - CMMRD
        
        2 germline mutation
        
        parents 100%
        
        TMTC MMR mutation
        
        children: recessive inheritance
        
        siblings 100%
    - - LI FRAUMENI could be assoc w/ BRCA
        
        1 germline TP53/ 1LOH
        
        autosomal recessive
        
        childhood cancer
        
        sarcomas
        
        adrenal cortical
        
        early onset
        
        brain
        
        breast
        
        lung
        
        melanoma
      - HEREDITARY
        
        early onset
        
        types
        
        ovarian cancer
        
        bilateral breast cancer
        
        pancreas
        
        male breast cancer
        
        aggressive prostate cancer
      - PARP/platinum-based tx
    - - increased risk
        
        endometrial
        
        thyroid
        
        breast cancer
      - presentation
        
        derm: trichellemomas
        
        GI: hamartomas
        
        macrocephaly
    - - increased risk
        
        GYN
        
        pancreas
        
        breast
        
        colon
      - presentation
        
        lip/oral freckling in childhood
        
        GI intussusception / large polyps
    - - increased risk
        
        gastric cancer
        
        lobular breast cancer
      - recommend gastrectomy
  - - - MELAS
        
        MITOCHONDRIAL ENCEPHALOPATHY #
        
        LACTIC ACIDOSIS #
        
        STROKE-LIKE EPISODES
        
        2 strokes in 2 different parts of brain
        
        mtDNA mutation that encodes tRNA
        
        lack oxidation in brain
      - PHENYLKETOURIA (PKU)
        
        autosomal recessive
        
        microcephaly
        
        seizure
        
        cannot metabolize phenylalanine
      - LEBER HEREDITARY OPTIC NEUROPATHY (LHON)
        
        loss vision during young adult
        
        DNA
        
        mtDNA mutation encoding for complex I
        
        homoplasmic
        
        penetrance
        
        50% male carrier lost vision
        
        10% female lost vision
        
        influenced by
        
        mtDNA haplogroup grouped based on
        
        shared sequence
        
        maternal lineage
        
        environment factors
        
        smoking
        
        alcohol
        
        toxins
      - features
        
        incomplete penetrance # #
        
        variable expressivity
        
        pleiotropy = one gene multiple traits
        
        passing from mom only
    - - brain
      - heart
      - renal
      - skeletal muscle
    - - outermembrane
      - innermembrane
      - matrix
    - - homoplasmy = pure population of 1 WT/mutant
      - heteroplasmy = mixed population of WT and mutant
      - threshold effect = heteroplasmy must reach significant level to produce effect
    - - oocyte
        
        high mitochondria amount
        
        mitochondrial bottle neck during oogenesis #
      - sperm
        
        low mitochondria amount
        
        degraded during fertilization
        
        ubiquitin
        
        proteasome
        
        lysosome-mediated destruction
  - - - developmental disability
        
        delayed speech
        
        delayed motor skills
      - fifth pinky abnormalities
        
        hypoplasia of tips of finger
        
        hypoplasia/absence of nails
      - facial features characteristics
        
        microcephaly
        
        hirsutism
    - - respiratory infection
      - feeding difficulty
      - failure to thrive
    - - WES from parents + child
      - ARID1B deletion = mental retardation
- - - - GENE SEQUENCING
        
        WES/WGS
        
        CON
        
        WES: incomplete genome coverage
        
        WGS: filtering bioinformatics data
        
        labor intensive
        
        lots of filtering needed
        
        incidental finding: what do we do with them?
        
        need extensive consent process
        
        PRO
        
        WGS: detect enhancer, intron, promoter, exon problems
        
        WES: focused on exons
        
        trio testing: parents + child
        
        parents w/ multifactorial problems w/ no diagnosis #
        
        results
        
        primary finding
        
        VUS
        
        related to phenotype
        
        no medical action because unknown pathogenicity
        
        secondary finding
        
        incidental
        
        carrier status
        
        pathogenic/likely pathogenic mutation
        
        associated with actionable intervention (2nd)
        
        unrelated to phenotype (incidental)
        
        ex: Hoffman syndrome
        
        presentation
        
        3 patients w/ facial limb, and urogenital defects
        
        low immunoglobins and absent B cells
        
        WGS
        
        single site/ targeted mutation
        
        Give positive/ negative results for specific mutation
        
        run with positive control sample from relative
        
        when familial mutation already known
        
        single gene/ candidate gene sequencing
        
        confirming diagnosis/ establish diagnosis
        
        suspicion for causative gene must be high
        
        enables accurate genetic testing for family member
        
        ex: acute hemorrhagic leukoencephalitis
        
        presentation: 2 kids w/ acute mental status change
        
        necrotizing vasculitis
        
        hemorrhage
        
        elevated WBCs
        
        workup
        
        abnormal alternate complement levels
        
        low complement factor 1 (CFI) levels
        
        sequencing CFI
        
        found 2 new missense mutation
        
        compound heterozygosity
        
        < 1 gene
        
        indel
        
        dynamic mutation #
        
        SNV
        
        SNPs #
      - STANDARD KARYOTYPING
        
        G banding
        
        gross chromosomal alteration > 5Mb
        
        aneuploidy
        
        trisomy
        
        turner syndrome
        
        large translocation
        
        Philadelphia syndrome aka BCR-ABL
        
        associated with CML
        
        large chromosomal deletion
      - FISH ANALYSIS
        
        gross chromosomal alteration > 5Mb
        
        translocation
        
        amplification
        
        aneuploidy
        
        < 5 Mb, 2 gene microdeletion/ duplication
      - CHROMOSOMAL MICROARRAYS
        
        small chromosomal alteration
        
        copy number variants
        
        contiguous gene syndrome
        
        <5 Mb, 2 gene microdeletion/duplication
        
        measure change in amount
        
        >5 Mb also
      - LINKAGE ANALYSIS #
      - MICROSATELLITE, REPEAT TESTING
        count number of repeats in specific area
        
        dynamic mutation
        
        haplotyping
        
        paternity testing
    - - GWAS
        
        objective:
        
        are there genes involved/ susceptible to multifactorial disease?
        
        Identify region of chromosome that may/may not be susceptible
        
        used for
        
        mendelian disease
        
        linkage analysis
        
        microsattelite loci
        
        many family with same traits
        
        caveats
        
        need complex method to avoid false discovery
        
        need replication studies
        
        population dependent
        
        one SNP doesn't explain much, unless it's known functional SNPs
      - GENE mapping
        
        LINKAGE ANALYSIS
        
        linkage disequilibrium
        
        haploytype block
        
        blocks of identical-base pair variants are frequently inherited as a unit
        
        few - no recombination over generations
        
        alleles at 2 loci are associated with each other #
        
        linkage equilibrium
        
        no association between alleles at 2 different loci
        
        independent recombination
        
        recombination rate
        
        mutation rate
        
        population size
        
        natural selection
        
        measure frequency with 2 genes remain with each other
        
        ex: FCAS
        
        physical mapping
        
        location of genes
        
        exact physical distance between genes
        
        ASSOCIATION OF HAPLOTYPE SHARING
        
        MEASURES frequency differences of alleles between affected/unaffected
        
        ex: congenital tufting enteropathy
        
        2 patients with chronic diarrhea in neonate period
        
        found shared haplotypes in both pt
        
        found same splice site mutation in EpCAM
- - - - blind
      - deaf
      - dwarfism
    - - cultural
      - religion
      - historical
  - - - sickle cell disease
      - non random mating between african american increases the frequency of this allele