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Lecture 61-62: Human Genetics II, III- Autosomal & Sex-Linked…

- - - - Fewer & less prevalent
      - Ex:
        -Hypophosphatemic rickets
        -Incontinentia pigmenti Type I
        -Rett syndrome
        -Fragile X Syndrome
        
        Fragile X Syndrome :checkered_flag:
        
        50-60% reduced penetrance (females)
        
        1: 30K-40K male births
        
        MOST common form of inherited moderate intellectual disability! :!!:
        
        CGG Expansion
        
        normal up to 55 repeats
        
        56-200 premutation intermediate
        
        200 (up to sev thousand) get disease
        
        leads to excessive methylation CH3 of FMR1 promoter :!:
        
        Physical Traits
        
        long face w/long palpebral fissures + broad philtrum
        
        prominent forehead + protruding ears + soft cartilage
        
        High-arched palate & dental crowding
        
        Hyperextensible finger joints & thumbs
        
        Post-pubertal macroorchidism
        
        Hypotonia
        
        Biting, hand flapping, poor eye contact, language disorders
        
        Mild -> profound IQ disability
        
        Autism
      - Caused by mutations by genes on X chrom.
      - Females (XX)
        mutation in 1 copy sufficient
      - Males (XY)
        mutation ONLY copy, causes disease
        -more severe; LETHAL in males!
    - - Hemophilia A :black_flag:
        
        Deficiency in Factor VIII of Clotting cascade
        
        Nonsense/frameshift mutations: severe!
        
        Missense mutations: mild --> moderate
        
        Main Clinical: Easy Bruising!
        
        Mainly in MALES, some females
      - Color Blindness
      - Duchenne & Becker Muscular Dystrophy
      - Glucose-6-D.H. Deficiency
      - Hypohidrotic Ecodermal Dysplasia :black_flag:
        
        Cause: Mutations in EDA gene
        
        Deficiency impairs development of:
        -hair
        -sweat glands
        -teeth
        
        Females: shows as Mosaicism
        
        Why?
        X-chrom. inactivation
        Ex: Calico cat
        
        Somatic mutation event occurs and ALL daughter cells contain mutation
        
        Leads to patches of cells w/mutations surrounded by normal genome cells
      - Males (XY):
        1 altered gene copy sufficient to cause
        
        Females (XX):
        mutation has to occur in BOTH copies b/c unlikely F will have 1 altered copy
    - - ~800 Genes
        300 Non-coding RNAs
        300 genes known assoc. w/disease
      - Y Chromosome
        -carries FEW genes assoc. w/sex determination
      - X Chrom. has Dominant & Recessive traits!
        
        Female Carrier
        
        HAS Phenotype= dominant
        NO phenotype= recessive
        
        Male (XY) Carrier
        
        If X-linked, males get disease! :fire: :explode:
  - - - 1 Mutant copy causes disease
        
        M/F equally affected
        Equally transmitted M/F
        
        NO generation skipping!
        
        Marfan Syndrome :fire:
        
        1: 5K (world-wide)
        
        Fibrillin-1 (FBN1): 25% novel mutations
        
        Defective Connective tissue!
        
        Skeletal, ocular, cardiac systems
        
        30-40% die from Aortic dissection
        
        Complete penetrance
        
        Variable expressivity
        
        Achondroplasia :fire:
        
        1: 15K-40K newborns
        
        FGFR3
        (80% novel mutations)
        
        Defect in cartilage growth
        
        Homozygous letal condition
        
        100% penetrant
        
        Avg. size trunk w/short arms/legs
        
        Apnea, bowed legs, kyphosis, spinal stenosis
      - can also be
    - - 2 mutant copies cause disease
        
        M/F equally affected
        
        Proband parents, offspring, other relative asymptomatic
        (Parents each carry 1 copy of mutation gene, but often do NOT show signs/symptoms)
        
        Cystic Fibrosis :star:
        
        CFTR: cystic fibrosis transmembrane conductance regulator
        
        European-descent: 1: 2,500
        
        African-American: 1: 17K
        
        Asian-American: 1: 30K
        
        ~2,000 mutant variants
        
        Sickle Cell Anemia :star:
        
        African-Americans: 1:500
        Hispanic-Americans: 1:1K-1400
        
        Common in malaria-endemic regions
        
        HSB gene
        
        Single mutant alleles PROTECTIVE against Malaria!
        
        -Anemia
        -repeated infections
        -acute vaso-occlusive pain
        -functional hyposplenism
  - - - Maternal Inheritance!
    - - Mito DNA RANDOMLY distirbuted!
      - Homoplasmy
        (every mito has identical genomes)
      - Heteroplasmy
        (no longer homogenous population)
  - - - mutation of Y chromosome & that male carrier passes to male offspring
        -disrupts Mendelian patterns of inheritance!
  - - - M allele= normal
        S allele= low amount
        Z allele= almost nothing (bad)
        
        MZ or MS= higher risk!
        
        ZZ= always gets disease!