Mendelian genetics: overview

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Mendelian genetics overview

• James Garbern MD, PhD
• Neurology and Center for Molecular Medicine and
  Genetics
• 577-2648
• jgarbern_at_med.wayne.edu
• 3206 Elliman Bldg

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Notes and slides are online

• Web address for my lecture notes and slides
• http//cmmg.biosci.wayne.edu/jgarbern/jgarbern-hom
  e.html

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Importance of genetics

• The only way to understand hereditary diseases
• What we are begins with our genetic heritage and
  is modified by our environment and experiences
• Our genetic heritage determines susceptibility to
  multifactorial diseases such as
• Hypertension Diabetes
• Vascular disease Cancer
• Osteoarthritis Autoimmune diseases
• Critical to developing new disease treatments
• Statins tPA EPO

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The scope of genetics

• The human genome has been sequenced!
• Approximately 35,000 genes, most of which encode
  a protein, in a haploid genome of 3 X 109 base
  pairs
• Only about 1.5 of the DNA actually encodes
  functional genes
• All living organisms are remarkably similar at
  the genetic level
• Same genetic code
• About 50 of genes comparable between us and
  plants
• All nucleated somatic cells have a complete set
  of genes
• Only a small fraction of genes are active in a
  single cell
• Enables cloning

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The burden of Mendelian (single gene) disorders

• Although individually rare, genetic diseases
  collectively constitute a major health problem
• About 5 - 8 of admissions to a pediatric
  hospital and about 1 of admissions to an adult
  hospital are for Mendelian disorders
• 9 of pediatric deaths are due to Mendelian
  disorders
• About 1- 2 of the population has a Mendelian
  disorder
• Most Mendelian disorders are apparent by
  childhood
• Life span is reduced in about 60 of these
  disorders
• Each person is estimated to have 1 - 5 lethal
  recessive alleles

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From cellular to molecular biology
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Genetic terminology

• Gene The fundamental unit of heredity. About
  35,000 in the human genome. A typical gene

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3
enhancer
promoter
repressor
intron
exon
5 UTR
3 UTR
mRNA
AAAAAAAAA
coding domain (ORF)
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Exons, introns and alternative splicing

• Most genes have introns
• Alternative splicing is common
• Many alternate proteins can be generated from a
  single gene, each of which can have a unique
  function

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Transcription and translation

• Transcription Generation of an RNA copy of a
  single gene
• Translation Synthesis of a protein using the
  mRNA as a template

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Gene expression Transcription and translation
tRNA
Protein chain
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Gene expression transcription
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Gene expression translation
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Important definitions

• Alleles Alternative forms of a gene that can be
  distinguished by their alternate phenotypic
  effects or by molecular differences a single
  allele for each locus is inherited separately
  from each parent
• Autosome One of chromosomes 1 - 22
• Dominant allele An allele whose phenotype is
  detectable (even if only weakly) in a single dose
  or copy
• Recessive allele An allele whose phenotype is
  apparent only in the homozygous or hemizygous
  state.
• Heterozygous Having a normal allele on one
  chromosome and a mutant allele on the other
• Homozygous Having identical alleles on both
  chromosomes

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More terms to know

• Hemizygous Having half the number of alleles
  (e.g. males are hemizygous for all X chromosome
  genes)
• Expressivity The severity or intensity of the
  phenotype of an allele.
• Penetrance The degree to which a gene expresses
  any observable phenotype
• Locus (pl. loci) The position on a chromosome of
  a gene or other chromosome marker also, the DNA
  at that position.
• Proband The first affected individual who comes
  to clinical genetic evaluation. Indicated by an
  arrow on the pedigree diagram.

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Importance of recognizing Mendelian disorders

• Establishment of definitive diagnosis
• Recognition of other relatives with disease or at
  risk for disease
• More accurate prognosis can be given
• Anticipation/prevention of complications, both
  medical and emotional/psychological
• More informed family planning

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Major mutation types

• Single base substitutions that cause premature
  termination of protein synthesis, change of amino
  acid, suppress termination of protein
  translation, alter level of gene expression, or
  alter patterns of mRNA splicing
• Translocations, that bring disparate genes or
  chromosome segments together
• Deletions of a few nucleotides up to long
  stretches of DNA
• Insertions and duplications of nucleotides up to
  long stretches of DNA
• Many different mutations can occur within a given
  gene, although it appears that genes have
  different degrees of mutability
• Different mutations affecting a gene can result
  in distinct clinical syndromes

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Types of mutations

• Point mutations Change of the normal base to
  another
• Possible consequences
• Silent mutation No consequence
• Missense mutation changes the codon to one
  encoding a different amino acid
• Nonsense mutation Changes codon from one
  encoding an amino acid to a stop codon
• Splice site alteration can abolish or create a
  splice site
• Regulatory region mutation Can result in net
  increased or decreased gene expression

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Location, location, location
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Small mutations can have subtle or drastic effects
In frame deletion of one codo No frameshift
Deletion of one base Frameshift
Out of frame deletion of three bases Frameshift
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Types of mutations

• Translocations
• Fusion of one chromosomal segment or gene
  fragment with another
• May result in disruption of gene(s)
• May result in a hybrid gene with novel function
  or combination of the functions of both genes

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Most genetic diseases manifest during childhood
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Frequency of Mendelian diseases by organ system
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Distribution of Mendelian disorders

• 68 Autosomal dominant
• 26 Autosomal recessive
• 6 X-linked recessive

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Clues that suggest a Mendelian disease

• Positive family history
• Characteristic syndrome
• Unusual syndrome (e.g. progressive neurologic
  deterioration, multiple organ system
  abnormalities, intermittent neurologic symptoms)
  at any age
• Common syndrome at unusually early age
• Lack of environmental or other primary cause of
  symptoms and signs

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Taking a family history

• Inquire about the health of each family member
  through second degree relatives (grandparents,
  first cousins)
• Pay special attention to any signs or symptoms
  related to your patients condition in relatives
• Inquire about causes of any deaths, including any
  stillbirths or early deaths, institutionalizations
  
• Obtain medical (and death) records of relatives
  as well as of proband
• Inquire about any possible consanguinity
• Recognize that false paternity does occur

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Pedigree symbols
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A famous pedigree
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A nicer pedigree
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A modest pedigree
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A typical X-linked recessive pedigree
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X Linked Recessive Inheritance

• Trait is much more common in males than females
• An affected man passes the gene to all of his
  daughters
• A son of a carrier mother has a 50 chance of
  inheriting the trait
• Male-to-male transmission never occurs
• Carrier females are usually asymptomatic, but
  some may express the condition with variable
  severity because of Lyonization, or
  X-inactivation.

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X linked recessive, normal father, carrier mother
1 carrier daughter 1 normal daughter 1 affected
son 1 normal son
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Clotting cascade
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Hemophilia A

• Clinical syndrome
• Easily prone to hemorrhage from minor trauma
• Hemarthroses common - result in degenerative
  joint disease
• Ecchymoses, but not petechiae
• Laboratory
• Prolonged PTT, normal PT bleeding times
• Normal platelet function
• A treatable genetic disease Plasma (90 of
  those treated with donor blood products developed
  AIDS in the 1980s), recombinant factor 8 (10 -15
  develop antibodies)
• Over 620 different mutations known to affect the
  factor VIII clotting factor gene (allelic
  heterogeneity)
• Gene lies at Xq28

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One common Factor VIII mutation
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Knowing genetic syndromes can help prevent
treatable complications of untreatable diseases
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Locus heterogeneity

• Same or similar syndrome caused by mutations in
  different genes

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Hemophilia B

• AKA Christmas disease (After the name of the
  first family and publication in the Christmas
  issue of the British Medical Journal)
• Similar clinical syndrome as seen in Hemophilia A
• Treatment with plasma or recombinant factor IX
• Antibodies develop in 1 to 3
• Caused by mutations affecting the Factor IX gene
  at Xq27

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Gene therapy pros and cons

• Pros
• No risk of infection from donor blood products
• (Cant rule out infection complications from
  viral vector)
• Potentially life long cure from single treatment
• Cons
• Viral vector may cause disease
• Immunity to viral vector may reduce or prevent
  its taking
• Antibodies may develop to the foreign gene
  product

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Gene therapy using viral vector (AAV)
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Ethnic background and geographic origins are
important risk factors for some genetic conditions
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Glucose-6-phosphate dehydrogenase deficiency

• Common among Africans, Asians and around the
  Mediterranean
• Discovered that about 10 of African American
  servicemen during WWII developed hemolytic anemia
  when given certain drugs, such as sulfonamides,
  antimalarials or when they ate fava beans
• Caused by deficiency of the enzyme, which is
  needed to generate NADPH

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G6PD deficiency

• Affects the G6PD gene at Xq28
• Many mutations and polymorphisms have been
  discovered
• Heterozygosity (technically hemizygosity) in
  women appears to confer resistance to malaria

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Prevalence of G6PD
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Old World Malaria prevalence
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X linked recessive, affected father
2 carrier daughters 2 normal sons Never any
Male-to- Male transmission!