Single Gene Disorders Mendelian Inheritance

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Single Gene DisordersMendelian Inheritance

• History
• Gregor Mendel (1822-1884) studied traits of
  garden pea plants
• All of the published information indicated that
  each trait that Mendel studied was determined by
  a single factor
• The concepts of DNA, genes and chromosomes as we
  currently understand them were not known.

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Alleles

• alternative variants of genetic information (at a
  given locus)(of a gene)
• locus a physical position on a chromosome
• gene a sequence of nucleotides which, when
  transcribed produce a biologically active nucleic
  acid (almost always single stranded RNA)
• The prevailing version of an allele is the
  wild-type (normal) allele

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Alleles 2

• Mutation may be used to describe a new genetic
  change or may be used to indicate a
  disease-causing allele
• Once a wild-type allele is defined, all other
  alleles are mutant
• exception polymorphic alleles
• Polymorphism many forms
• Arbitrarily defined if there is an alternative
  allele of a frequency greater than 0.02
• More precisely defined under terms of genetic
  selection in a later lecture.

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More Definitions

• Genotype the set of alleles which make up an
  individuals genetic constitution. May be used to
  describe the sum of all alleles (all genes) or be
  used to describe the set of alleles for a given
  gene or locus
• Phenotype the observable expression of a
  genotype
• may be a biochemical, morphological,
  physiological, clinical or molecular trait

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Single Gene Disorder

• A phenotype produced by alleles of a single locus
  which is abnormal.
• A phenotype may be the result of one or two
  mutant alleles
• If the two alleles at a locus are identical to
  each other, the individual is homozygous.
• This term applies regardless of the alleles being
  normal, mutant or polymorphic forms.
• If the two alleles are different, the individual
  is heterozygous.
• If one of the two alleles in a heterozygote is
  the wild-type allele, the term carrier can be
  used.

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• If the two alleles are both mutant, but different
  from each other, the individual is said to be a
  compound heterozygote.
• If there is no second allele at a locus in a
  normal individual, that person is hemizygous
• The obvious situations are the human X and Y
  chromosomes in a chromosomally normal male. The
  DNA sequences are represented by one copy.

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Dominant and Recessive

• Defined at the level of the phenotype
• Classically, any phenotype expressed in both the
  homozygote and heterozygote states was said to be
  dominant.
• A phenotype only expressed in a homozygote state
  is recessive
• Practically, any phenotype expressed in
  heterozygotes is dominant
• even if heterozygotic and homozygotic individuals
  do not have the same phenotype

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• When the phenotype of the heterozygote is
  intermediate between the phenotypes of the two
  homozygotic genotypes, the disorder is considered
  to demonstrate incomplete dominance
• If the expression of both alleles can be detected
  in the presence of each other, the alleles are
  co-dominant.

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Example

• An child with a coding sequence change of L444P
  in the both copies of the galactocerebrosidase
  gene has severe Gaucher disease.
• One parent of that child has one copy of the
  L444P change. This individual has no disease
  manifestations on the basis of physical, mental
  or radiographic examination
• Therefore the normal phenotype is dominant to the
  disease phenotype
• We often say that the normal allele is dominant

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Dominant and Recessive

• The distinction is not absolute
• based on clinical phenotypes
• therefore, it is arbitrary
• not of significance at the level of gene action
• many recessive traits have manifestations at the
  cellular, biochemical or molecular levels
• sickle cell disease
• mutation in the b-globin gene so that glutamic
  acid is changed to valine at amino acid 6
• heterozygotes have a mild anemia and both
  products are found by electrophoresis.
• under appropriate conditions sickling can occur
  in the RBCs of heterozygotes
• Therefore at the level of protein codominance, at
  the level of physiologic function, incomplete
  dominance and clinically recessive

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Dominant or Recessive

• Many recessive disorders are enzyme defects
• enough activity exists in heterozygotes to allow
  normal cellular/organ function
• In dominant disorders, disease occurs despite the
  presence of the normal allele
• When one copy of a gene is not enough to prevent
  disease, it is a condition of haploinsufficiency.
• If the abnormal product interferes with the
  normal product. a dominant negative effect
  exists.
• example osteogenesis imperfecta

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Other situations where one copy is not enough

• haploinsufficiency
• dominant negative mutation
• The mutant gene product may be enhanced in one or
  more of its normal properties
• achondroplasia
• Loss of a single copy is the first event in a
  several step cascade
• predisposition to cancers
• second mutation occurs at a somatic cellular level

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Achondroplasia
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Mimics of single gene disorder genetics

• Pedigree pattern simulates a single gene disorder
• teratogenic effects
• inherited chromosomal disorders
• balanced translocations
• contiguous gene syndromes
• microdeletion disorders
• common environmental exposures

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Factors affecting a pedigree pattern

• Age of onset
• not all genetic disorders are congenital in their
  expression
• prenatal
• Thanatophoric dwarfism
• congenital
• inborn errors of metabolism
• later in life
• Huntington chorea
• Size of families
• in small families the information to determine
  inheritance pattern may not be present

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Genetic Heterogeneity

• A number of similar or identical phenotypes are
  caused by different genotypes
• albinism
• mutations at different loci
• locus heterogeneity
• Text example Retinitis pigmentosa
• look for different patterns of inheritance in
  different families
• may be the result of different mutations at the
  same locus
• allelic heterogeneity
• some cases of allelic heterogeneity cause
  different phenotypes
• RET Dominant Hirschprung Dx, MEN types Iia or
  IIb

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Autosomal Recessive Inheritance

• Disease occurs in individuals with two mutant
  alleles (either the same mutation of different
  ones)
• In general an individual inheritance a mutant
  allele from each parent
• new mutations are generally rare
• Since each parent has two alleles
• the chance of inheriting a mutant allele from one
  parent is ½ and for the other parent is also ½
• the net chance of inheritance two mutant alleles
  is ½ X ½ or 1/4

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Punnett Square
Way to illustrate various crosses in a simple
diagram
Female
t
T
Male
Tt heterozygote carrier
TT homozygote (wild type)
T
tt homozygote mutant
Tt heterozygote carrier
t
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Punnett Squares 2
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Autosomal Recessive Inheritance

• Consanguinity
• Parents have a common ancestor
• The chances of inheriting an allele identical by
  descent from both parents increases the chance of
  inheriting a recessive disorder
• Consanguinity is not the most common cause of
  individuals having autosomal recessive traits
• Genetic Isolation
• Small populations of individuals with a common
  genetic background may have increased risk of
  recessive disease
• Ashkenazi Tay-Sachs, Gaucher Disease
• Finnish Congenital Chloride-Losing Diarrhea

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Characteristics of AR Inheritance

• Phenotype more likely in siblings of proband than
  in other relatives
• Males and females are equally affected
• Parents of an affected individuals are
  asymptomatic
• Recurrence risk for each sib is ¼
• Potential for consanguinity

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Autosomal Dominant Inheritance

• Over half of the known Mendelian phenotypes are
  AD traits
• Incidence of some is very high
• 1/500 Familial hypercholesterolemia
• 1/2500-1/3000 Neurofibromatosis
• 1/2500-1/3000 AD polycystic kidney disease
• New mutations are common
• In a dominant lethal (pre-reproductive) disorder
  all cases are due to new mutations

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Autosomal Dominant Inheritance

• In a typical pedigree, every affected person has
  one affected parent
• Male to male transmission is possible
• Equal numbers of affected females and males are
  expected
• One-half of the children of an affected
  individual are expected to have inherited the
  dominant allele
• Not all will express the mutant phenotype
• Phenotypically normal individuals generally do
  not transmit the mutant phenotype

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Variation in the Phenotype

• Penetrance
• the probability that a gene will have ANY
  phenotypic expression
• it is an all or none concept
• if some people with an appropriate genotype fail
  to express the phenotype, there is reduced
  penetrance
• Expressivity
• Severity of the manifestations of the phenotype
• when phenotypic severity varies among those with
  identical genotypes, variable expressivity is
  shown
• Pleiotropy
• Multiple phenotypic effects of a single gene or
  gene pair
• when the effects are not obviously related

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Neurofibromatosis, type 1

• AD, 1/3000, 17q GTPase activating protein/signal
  transduction
• Almost complete penetrance by age 5 years
• Clinical features
• Cafe-au-lait spots 94-100
• Dermal neurofibromata
• Axillary freckling
• Lisch nodules (hamartomas) on iris 90-95
• Macrocephaly 45
• Short Stature 30-35
• Plexiform neurofibroma 30
• Mental retardation 5
• CNS tumors 3-10
• Scoliosis 10

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NF1

• Less than half of infants show any sign of the
  disease
• Lisch nodules develop over time (over 6 months of
  age)
• Cutaneous changes occur over time
• Mutation rate is very high
• estimated to be 1/10,000
• Severity is unpredictable for new mutations or
  for inherited disease

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Homozygotes for AD disorders

• Generally the result of matings of two
  heterozygous individuals
• Achrondroplasia
• more severe phenotype
• may not survive early infancy
• Familial hypercholesterolemia
• Heterozygotes are 1/500 in population
• Homozygotes 1/ million
• While heterozygotes and homozygotes have elevated
  cholesterol from birth, homozygotes have
  xanthomas early, die from MI by 30,
  hemodynamically like calcified Ao Stenosis

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X-linked Inheritance

• Phenotypes have a sex distribution which is
  characteristic
• Many of the genes have a disease phenotype
• Males are hemizygous
• will express the disease phenotype if one
  mutation is present
• Females may be homozygous ore heterozygous
• Heterozygotes may manifest the disease

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Expression of X-linked Genes 1

• Lyon Hypothesis
• In somatic cells of females only one X chromosome
  is active
• Inactivation occurs in early embryonic life
• Ina any somatic cell either X chromosome may be
  inactivated
• Inactivation is random but permanent for the
  descendent cells
• inactivated X chromosomes can be recognized
  cytologically in interphase cells as Barr bodies

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• An explanation for dosage compensation
• Promoter region of many genes on the inactive X
  are modified by methylation of cytosine in CpG
  dinucleotides altering packing of the chromatin
• Some genes are not inactivated (10-15)
• pseudoautosomal region (very distal short and
  long arms of the X) for which matching sequence
  is present on the Y
• genes for which related sequence is present on
  the Y
• genes which are present only on the X and for
  which expression levels are higher
• steroid sulfatase (X-linked ichthyosis)
• Variable Expression of X-linked genes
• manifesting heterozygotes
• unbalanced inactivation
• mutation on the preferentially inactivated X
• especially structurally abnormal X chromosomes
• Functional mosaicism

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Are there X-linked Dominants?

• Are there X-linked recessives
• expressed in all males but only in homozygous
  females
• Hemophilia A (Factor VIII deficiency)
• X-linked color blindness
• as it is a relatively common disorder homozygotes
  are known
• X-linked Dominants
• Expressed in heterozygotes
• if fully penetrant, all of the daughters and none
  of the sons of an affected male are themselves
  affected
• Vitamin D-resistant rickets
• X-linked lethal in hemizygotes
• Retts syndrome
• Incontientia pigmenti very non-random
  X-inactivation

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Henry
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How Frequent are Genetic Diseases

• Estimated total incidence of genetic diseases
  vary
• AD 3 9.5/1000 (1/200 people) with the most
  common disorders being 1/1-2000
• AR 2-2.5/1000
• X-linked 0.5 2/1000
• Chromosomal disorders 6-9/1000
• Multifactorial disorders 20 50/1000
• Most cancers, diabetes, heart disease, etc.

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Inheritance modified by imprinting

• Prader-Willi and Angelman syndromes
• In PWS about 70 have a cytologic deletion
  15q11-15q13 on the paternally inherited
  chromosome
• In Angelman syndrome, the same cytological
  deletion is found in in 70 of the cases but it
  is always the maternally inherited chromosome
• The other 30 of the cases of PWS have
  uniparental disomy in which there are two copies
  of the maternally derived sequence

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Uniparental Disomy

• Disomic cell line containing two chromosomes (or
  portions of chromosomes) inherited from only one
  parent.
• isodisomy both sequences are identical
• heterodisomy both homologs of a parent are
  present
• Implicated in Beckwith-Wiedermann syndrome
• loss of maternal genes or excess of paternal
  genes on 11p15

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Mosaicism

• The presence of two or more genotypically
  distinct cell lines in an individual
• Somatic
• Special case X-inactivation
• phenotypic mosaic
• Germline
• gives rise to situations where the parent is
  unaffected but the descendents have a mutation
• phenotypic expression in new mutations of AD
• seen in Factor VIII disease, Duchene muscular
  dystrophy

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Germline Mosaicism

• Suspected with the presence of two or more
  affected offspring with AD or X-linked disease in
  the absence of a family history
• Results from a parental clone with a somatic
  mutation in a germline cell/precursor
• Known to occur in some disorders frequently
• Duchenne Muscular Dystrophy 14 - 15
• Hemophilia A 20
• Neurofibromatosis, type 1
• Achondroplasia?
• Osteogenesis imperfecta, type 2 5 - 6

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Maternal Inheritance of mtDNA

• Mitochondrial DNA (mtDNA) is inherited through
  the ovum not the sperm
• Mother could pass it to all children
• Father will pass it to none of this children
• More than one copy of mtDNA are passed
• mutations are common
• more than one type of mtDNA genome is passed
• effects of heteroplasy
• variable expression, pleiotropy, reduced
  penetrance
• functional somatic mosaic

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Loss of mutation
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D-loop
Human Mitochondrial DNA Map
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