Patterns of Inheritance

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Patterns of Inheritance

• Segregation of a trait (disorder) within a family

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Modes of Inheritance

• Mendelian Inheritance
• - autosomal recessive
• - autosomal dominant
• - X-linked recessive
• - X-linked dominant
• Non-Mendelian inheritance
• - mitochondrial inheritance
• - imprinting
• - uniparental disomy
• - triplet repeat expansion/
  anticipation
• - digenic inheritance

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Modes of Inheritance (cont.)

• Chromosomal disorders
• - caused by alterations in number, or
  structure of chromosomes
• Multifactorial disorders
• - determined by one or more genes, as well
  as environmental factors

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Definitions

• Genetic locus specific position of each gene on
  the chromosomes
• allele(s) alternate forms of genes
• i) may be variations of
  normal
• e.g., blood group alleles
• ii) may result in a medical
  disorder
• e.g., cystic fibrosis,
  hemophilia, Marfan disease

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Definitions (cont.)

• homozygous both alleles the same dd, DD
• heterozygous alleles are different Dd
• hemizygous only one copy (genes on the X
  chromosome in males)
• trait observed expression of
  the gene

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Definitions (cont.)

• Genotype genetic constitution (at one or all
  loci)
• Phenotype observed expression of a genotype
• (depends on how you define the trait -- at
  the morphological, cellular, or biochemical
  level)

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HETEROGENEITY

• Genetic heterogeneity (locus heterogeneity)
• - mutations of different genes causing the same
  disease
• Clinical heterogeneity (allelic heterogeneity)
• - mutations of the same gene causing different
  diseases

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MENDELIAN INHERITANCE

• Single gene disorders (Mendelian disorders) are
  due to mutations in one or both members of a pair
  of autosomal genes, or to mutations on the X or Y
  chromosomes

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Mendelian Inheritance

• Dominant inheritance
• - When the trait (disorder) is expressed in the
  heterozygote (Dd)
• Recessive inheritance
• - When the trait is only expressed in the
  homozygote (dd)
• autosomal inheritance
• - Genes on chromosomes 1-22
• X-linked (sex-linked) inheritance
• - Genes on the X (or Y) chromosomes

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• You determine the inheritance pattern by
  observing the segregation of the trait within
  families
• -- must obtain a family history
• (usually diagrammed in a pedigree)

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Autosomal dominant inheritance

• - both males and females affected
• - persons affected in each generation
  (vertical inheritance pattern)
• - every affected person has an affected parent
• - offspring of an affected person have a 50
  risk of being affected
• - unaffected persons do not transmit the
  condition
• - males can transmit the condition to males and
  females (and vice versa)

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Exceptions

• Variable expression
• Reduced penetrance / non-penetrance
• New mutations

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HNPCC (hereditary non-polyposis colon cancer)

• 5-10 of all colorectal cancer
• predisposition to colon and extra-colonic cancers
  (e.g. endometrial, ovarian, stomach, urogenital
  ca)
• variable age at onset (20s 70s)
• due to mutations in mismatch repair genes (MSH2,
  MLH1, MSH6 etc)

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HNPCC screening protocol

• colonoscopy every 1-2 yrs from mid-twenties
• annual pelvic exam, endometrial biopsy,
  transvaginal US, CA125 testing
• upper GI endoscopy every 3 yrs
• (subtotal colectomy rather than partial
  colectomy if surgery required)

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• RULES -- Every affected person has an
  affected parent
• -- Unaffected persons do not transmit
  the condition
• EXCEPTION Affected person with normal parent
• Possible explanations
• Parents died young/never examined
• No medical information available
• Variable expressivity (different expression that
  is not
• recognized)
• Variable age at onset
• Non-penetrance ( penetrance
  expressing trait
• 
  with mutation )
• New mutation

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Hereditary Breast Cancer

• 5-10 of all breast cancer
• variable expressivity
• -predisposition to breast /or ovarian ca
  (/- male breast ca, prostate, colon,
  pancreatic ca, etc)
• variable age at onset
• two genes known
• -BRCA1 chr17
• -BRCA2 chr13

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Screening Protocol

• self-breast examination
• clinical breast exam (every 6-12 mos)
• annual mammograms from age 25-30
• pelvic exam, transvaginal US
• CA125 testing

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Types of dominant mutations

• reduced gene function (haplo-insufficiency)
• increased or constitutive gene function
• (e.g. in regulatory genes)
• dominant negative gene product that interferes
  with the normal allele
• altered structural protein (e.g. collagen /
  fibrillin)
• Recessive mutations - often defective enzymes

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