mendelian inheritance by duggybrown

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									            MEDICAL GENETICS


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• About 1% of the live births in the United Kingdom
  will have a single gene disorder that will be serious
  enough to require special medical treatment or
  hospital care.
• Each of these single gene disorders, often called
  Mendelian traits or diseases, is relatively
• The frequency often varies with ethnic background,
  with each ethnic group having one or more
  Mendelian traits in high frequency when compared
  to the other ethnic groups.

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               Ethnic group differences
• Cystic fibrosis has a frequency of about 1/2000 births in
  western European Caucasians but is much rarer in those of
  western African descent.
• Sickle cell anaemia has a frequency of about 1/600 births in
  people of western African descent but is much rarer in
• Greeks and Italians of Mediterranean descent have a high
  frequency of thalassaemia.
• Eastern European Jews have a high frequency of Tay-Sachs
• It has been estimated that each of us, each "normal"
  member of the human race is carrying between 1 and 8
  mutations which, if found in the homozygous state would
  result in the expression of a Mendelian disease.

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           Mendelian Inheritance
• Since we each have between 25,000 and
  35000 genes (loci) it is unlikely that any two
  unrelated individuals would be carrying the
  same mutations, even if they are from the
  same ethnic background, thus most of our
  offspring are not suffering from a genetic
• Most Mendelian diseases are rare, affecting
  about 1/10,000 to 1/100,000 live births.

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 Mendelian modes of inheritance.
• Shortly after the re-discovery of Mendel's work, Sir
  Archibald Garrod published an article in the
  ‘Lancet’ 13th December 1902, showing evidence of
  recessive Mendelian inheritance of the human
  disease Alkaptonuria (black urine), and suggesting
  that Cystinuria may follow the same pattern.
• In 1905, Farabee reported the first human
  autosomal dominant trait, Brachydactily, (shortened
  fingers and toes).
• The facts about the inheritance of Haemophilia and
  red-green colour blindness were interpreted as
  following a sex-limited Mendelian inheritance by W.
  Bateson (1909).
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       Mendelian Inheritance I
• Mendelian traits, or single gene
  disorders, fall into 5 categories or
  modes of inheritance based on
  where the gene for the trait is
  located and how many copies of the
  mutant allele are required to
  express the phenotype:

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              Mendelian Inheritance II
• Autosomal dominant inheritance: the locus is on an
  autosomal chromosome and only one mutant allele is
  required for expression of the phenotype.
• Autosomal recessive inheritance: the locus is on an
  autosomal chromosome and both alleles must be
  mutant alleles to express the phenotype.
• X-linked recessive inheritance: the locus is on the X
  chromosome and both alleles must be mutant alleles
  to express the phenotype in females.
• X-linked dominant inheritance: the locus is on the X
  chromosome and only one mutant allele is required
  for expression of the phenotype in females.
• Y-linked inheritance.
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           Mendelian principles

1. Segregation. In diploids, alleles occur in
   pairs. They are organized so only one factor
   can be present in a single gamete (n).
2. Independent assortment. Characteristics
   are inherited independently. Any one of a
   pair of characteristics may combine with
   either of another pair.

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                 Mendel’s Laws
• Mendel based his laws on mathematical probabilities
  that allowed predictions of resulting phenotypes when
  certain crosses were made in the garden pea.
• When he published in 1866, the discovery of the
  chromosomal basis of inheritance (meiosis and
  gametogenesis) was still a generation away.
  Therefore, there was no physical basis for explaining
  the Mendelian segregation ratios.
• The discoveries of Sutton, Boveri, and others allowed
  a re-examination of Mendel's apparently forgotten
• In 1900, Correns, DeVries, and Tschermak, all
  independently "rediscovered" Mendel's laws of
    3/4/2010                                       9
           Support of Mendel’s laws

• By 1902 the first human Mendelian "inborn
  error of metabolism", alkaptonuria, was found
  by Sir Archibald Garrod.
• Mendel's laws are grounded in the
  chromosomal      movements       in  meiosis,
  gametogenesis, and fertilization.
• Understanding the fundamental processes of
  cell division is the key to understanding
  Mendelian genetics.
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               Pedigree Construction
• The study of inherited Mendelian traits in humans
  must rely on observations made while working with
  individual families.
• Classical cross fertilization breeding experiments as
  performed by Mendel are not allowed in humans!
• Human geneticists are not allowed to selectively
  breed for the traits they wish to study.
• One of most powerful tools in human genetic studies
  is pedigree analysis.
• When human geneticists first began to publish family
  studies, they used a variety of symbols and
  conventions. Now there are agreed upon standards
  for the construction of pedigrees.
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           Pedigree Symbols

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              Pedigree Notation
• Males are always represented by square symbols,
  females with circular symbols.
• A line drawn between a square and a circle
  represents a mating of that male and female.
• Children of a mating are connected to a horizontal
  line, called the sibship line, by short vertical lines.
  The children are always listed in order of birth, the
  oldest being on the left.
• Normal individuals are represented by an open
  square or circle, depending upon the gender, and
  affected individuals by a solid square or circle.

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               Human Pedigrees
• Sometimes to simplify a pedigree only one parent is
  shown, the other is omitted.
• This neither signifies parthenogenic development nor
  does it signify divinely inspired conception, it merely
  means the parent left out is not from the family being
• Each generation is numbered to the left of the
  sibship line with Roman Numerals. Individuals in
  each generation are numbered sequentially,
  beginning on the left, with Arabic Numerals.
• For example the third individual in the second
  generation would be identified as individual II-3.
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   Autosomal Dominant Inheritance
• The pattern of autosomal dominant inheritance
  is perhaps the easiest type of Mendelian
  inheritance to recognize in a pedigree.
• One dose of the mutant gene, one mutant allele,
  is all that is required for the expression of the
• There are three reasons why an individual with
  an autosomal dominant disease should always
  be considered as being a heterozygote until
  proven otherwise:
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                AD Inheritance I
• The disease is usually rare, with only about 1/10,000
  individuals affected.
• To produce a homozygote, two affected
  heterozygotes would have to mate. This probability
  is 1/100,000,000 and then they would have only a
  1/4 chance of having a homozygous affected
• Affected individuals are most likely to come from
  affected by normal matings. The normal parent is
  homozygous recessive, thus assuring that each
  product of the mating has at least one normal gene.

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               AD Inheritance II
• In the extremely rare instances where two affected
  individuals have mated, the homozygous affected
  individuals usually are so severely affected they
  are not compatible with life. The exceptions are the
  autosomal dominant diseases caused by the
  somatic expansion of trinucleotide repeat
  sequences (e.g., Huntington's disease).
• With the understanding that almost all affected
  individuals are heterozygotes, and that in most
  matings involving a person with an autosomal
  dominant trait the other partner will be
  homozygous normal, there are four hallmarks of
  autosomal dominant inheritance.
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    Characteristics of AD Inheritance
• Except for new mutations, (and the complexities of
  incomplete penetrance, to be discussed next week), every
  affected individual has an affected biological parent. There
  is no skipping of generations.
• Males and females have an equally likely chance of
  inheriting the mutant allele and being affected. The
  recurrence risk of each child of an affected parent is 1/2.
• Normal siblings of affected individuals do not transmit the
  trait to their offspring.
• The defective product of the gene is usually a structural
  protein, not an enzyme. Structural proteins are usually
  defective when one of the allelic products is non-functional;
  enzymes usually require both allelic products to be non-
  functional to produce a mutant phenotype.

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             The Punnet Square
• In 1910, Punnett developed a simple method of
  depicting the possible genotypes one could get
  from various matings.
• We call it the Punnett Square.
• Suppose a father is heterozygous for an
  autosomal dominant gene, with allele D, the
  mutant dominant allele, and allele d, the
  recessive normal allele.
• He can produce two types of gametes, D and d.
• Suppose also his wife is homozygous normal,
  having both d alleles.
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The Punnett Square is constructed as

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           Sample Pedigree

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       Pedigree of family with hyper-
    Each of the four hallmarks of autosomal dominant
    inheritance are fulfilled.
•   Each affected individual has an affected parent; there is no
    skipping of generations.
•   Males and females are equally likely to be affected.
•   About 1/2 of the offspring of an affected individual are
    affected (the recurrence risk is 1/2). Normal siblings (II-3) of
    affected individuals have all normal offspring.
•   Low density lipoprotein receptors are structural proteins or
    polypeptides, not enzymes. If III-1, an affected female, were
    to produce a child that child would have a 1/2 chance of
    being normal and a 1/2 chance of being affected. If her
    normal brother, III-2, were to produce a child that child
    would have a nearly 0 chance of being affected.
    3/4/2010                                                  22
            True Dominance
• With      true     dominance,       individuals
  homozygous for the mutant allele are no
  more severely affected than heterozygotes
  (e.g. Huntington's disease).
• In other cases, such as achrondroplasia,
  homozygotes are more severely affected than
  heterozygotes and homozygosity may be
  incompatible with life (see later).

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                Non-medical Dominance
• Of course a great number of
  polymophisms exist in the
  human population.
• There are many traits not
  associated with disease that
  are caused by autosomal
  dominant genes.

• E.g. Tongue rolling
• Dominant = roller
• Recessive = non-roller roller

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             More Dominant Traits
• Dominant=
 Free earlobes

• Recessive =
  Attached earlobes

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          Some Pathological Examples
•   Huntington's Disease,
•   FAP (familial adenomatous polyposis),
•   retinoblastoma,
•   retinitis pigmentosa,
•   achondroplasia,
•   myotonic dystrophy,
•   neurofibromatosis,
•   Marfan's syndrome,
•   familial hypercholesterolaemia

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    Examples of Autosomal Dominant
• Achondroplasia is the most common form of disproportionate
  short stature.
• Affected individuals exhibit short stature caused by
  shortening of the limbs, characteristic facies with frontal
  bossing and midface hypoplasia, exaggerated lumbar
  lordosis, limitation of elbow extension, and trident hand.
• Achondroplasia is inherited as an autosomal dominant with
  essentially complete penetrance (see next week).
• About seven-eighths of cases are the result of new mutation,
  there being a considerable reduction of effective
  reproductive fitness.

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• This girl has short limbs relative to
  trunk length. Note also the
  prominent forehead, low nasal root,
  and redundant skin folds in the
  arms and legs.
• Achondroplasia occurs in all races
  and affects 1 in 25,000 to 1 in
  40,000 children.
• Achondroplasia is caused by
  mutation in the fibroblast growth
  factor receptor-3 gene (FGFR3;
  134934), which is located at

     3/4/2010                             28
               Huntington's disease I
• Huntington's disease is caused by a faulty gene on
  chromosome 4 (increase in size of CAG
  trinucleotide repeat at 5’ end of the gene).
• The gene, which produces a protein called
  huntingtin, was discovered in 1993.
• The faulty gene leads to damage of the nerve cells
  in areas of the brain, including the basal ganglia and
  cerebral cortex, leading to gradual physical, mental
  and emotional changes.
• Each person whose parent has Huntington's disease
  is born with a 50% chance of inheriting the
  symptoms of the disease.
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             Huntington's disease II
• The symptoms of Huntington's disease usually
  develop when people are between 30-50 years
  old, although they can start much earlier.
• Slight, uncontrollable muscular movements
• Stumbling and clumsiness
• Lack of concentration
• Short-term memory lapses
• Changes of mood, sometimes including
  aggressive or antisocial behaviour.

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           Huntington's disease III

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  Autosomal Recessive Inheritance
• The first, and most important, thing to remember about
  autosomal recessive inheritance is that most, if not all,
  affected individuals have parents with normal phenotypes.
• Why? Suppose the disease affects one in ten thousand
  live births (good estimate for most autosomal recessive
• Heterozygote frequency in the population is one in fifty. The
  likelihood of two affected persons mating would be
  1/10,000 x 1/10,000 or 1/100,000,000. The likelihood of an
  affected and a heterozygote mating would be 1/10,000 x
  1/50 x 2 (since either parent could be the affected) or
• The likelihood of two heterozygotes (heterozygotes are
  usually called "carriers") mating is 1/50 x 1/50 or 1/2500,
  more than 99% of all possible matings.
  3/4/2010                                                32
     The Punnett Square for autosomal
 recessive diseases with an affected child
 in the family almost always looks like the

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                    AR Inheritance
• Where the father and mother are both Dd (dd is the
  recessive affected individual, Dd the heterozygous carrier
  individual, and DD the homozygous normal individual), the
  Punnet Square shows the origin of the famous Mendelian
  ration of 3/4 normal to 1/4 affected.
• For most autosomal recessive diseases, but not all, the
  heterozygote cannot be distinguished from the normal
• In the normal phenotype categories of offspring in the above
  Punnett Square (Dd and DD produce the same normal
  phenotype), please note that two of the three are
  heterozygotes (carriers); one of the three is homozygous
• Within the normal siblings of an affected individual the
  probability of being a carrier is 2/3.
    3/4/2010                                             34
  There are five hallmarks of autosomal
         recessive inheritance:
• Males and females are equally likely to be affected.
• On average, the recurrence risk to the unborn sibling of an
  affected individual is 1/4.
• The trait is characteristically found in siblings, not parents
  of affected or the offspring of affected.
• Parents of affected children may be related. The rarer the
  trait in the general population, the more likely a
  consanguineous mating is involved.
• The trait may appear as an isolated (sporadic) event in
  small sibships.

     3/4/2010                                                 35
Typical Autosomal recessive pedigree

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                Typical AR pedigree
• The previous pedigree illustrates four of the five hallmarks of
  autosomal recessive inheritance.
• I-1 and I-2 are unrelated, yet they produced an affected
  offspring (affected offspring have normal parents). By
  chance, they both must have been carriers.
• Even though II-2 is affected, she produced no affected
  offspring (trait appears in siblings, not parents or
  offspring). By far the most probable genotype for an
  individual from outside the family (II-1) is homozygous normal.
  III-1, III-2 and III-3 are all obligate carriers (heterozygotes),
  since they are not affected but could only have inherited the
  recessive gene from II-2.
• II-3, II-5, and II-6 each have a 2/3 chance of being a carrier
  and a 1/3 chance of being homozygous normal. They are not
  affected, but they come from a carrier x carrier mating. II-4
  and II-7 have a high probability of being homozygous normal
  since they are from outside the family.
      3/4/2010                                                37
                   Consanguinity I
• When consanguinity is involved, i.e., matings between
  related individuals, in the production of an affected child the
  assignment of probabilities changes, especially in the rarer
  autosomal recessive diseases.
• Consanguinity introduces the possibility of one founding
  parent being a carrier, with the recessive allele being passed
  through carrier offspring and meeting itself to produce an
  affected homozygous offspring some generations later.
• When an affected child is produced as the result of a
  consanguineous mating, those individuals in the direct line of
  descent are most probably carriers and those from outside
  the family are most probably normal homozygotes.
• In the following pedigree, V-1 is affected with an autosomal
  recessive disease. Her parents are second cousins.

     3/4/2010                                                38
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                 Consanguinity II
• Before he had any children, II-5 had a 2/3 chance of being
  a carrier and a 1/3 chance of being homozygous normal.
• But III-5 had to get her recessive allele from someone, and
  her other parent, II-6 had at most a 1/50 chance before her
  children were born. One can compare the two probabilities
  and for practical purposes one can say he is the carrier.
• In rare autosomal recessive diseases, when consanguinity
  is involved, those individuals in the direct line of descent
  within the family are considered to be carriers and those
  individuals from outside the family are considered
  homozygous normal unless there is evidence to the

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      Common autosomal recessive
Disease                   Incidence / 1000
Cystic fibrosis           0.5
Rec. mental retardation   0.5
Congenital deafness       0.2
Phenylketonuria           0.1
Spinal muscular atrophy   0.1
Recessive blindness       0.1
Adrenogenital syndrome    0.1
Mucopolysaccharidoses     0.1
 3/4/2010                 0.3                41
      Autosomal recessive diseases
• OMIM (11th edition, c1999) features a total of
  approximately 1,800 different autosomal recessive
• In the 'general population', most autosomal recessives
  show frequencies <<0.1 per thousand live births.
• Autosomal recessives tend to show already at birth, and
  they often involve enzymes in metabolic pathways (inborn
  errors of metabolism, see later lecture).
• In most cases, heterozygous individuals do not show any
  clinical sign, but they may show 50% of the normal
  enzyme levels (for instance, hexosaminidase A in Tay-
  Sachs disease).
  3/4/2010                                            42
            Cystic Fibrosis I
• Cystic fibrosis (CF) is a genetic disease
  affecting approximately 7,000 children and
  adults in the United Kingdom.
• A defective gene (CFTR) causes the body to
  produce an abnormally thick, sticky mucus
  that clogs the lungs and leads to life-
  threatening lung infections.
• These thick secretions also obstruct the
  pancreas, preventing digestive enzymes from
  reaching the intestines to help break down
  and absorb food.

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           Cystic Fibrosis II
• People with CF have a variety of
  symptoms including: very salty-tasting
  skin; persistent coughing, at times with
  phlegm; wheezing or shortness of
  breath; an excessive appetite but poor
  weight gain; and greasy, bulky stools.
• Symptoms vary from person to person
  due, in part, to the more than 1,000
  mutations of the CF gene.

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           Normal & CF lung

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• The word "albinism" refers to a group of inherited
• People with albinism have little or no pigment in
  their eyes, skin, or hair. They have inherited genes
  that do not make the usual amounts of the pigment
• 1 person in 17,000 in the U.K. has some type of
  albinism: it affects all races.
• Both parents must carry an albinism gene to have a
  child with albinism. As the body has two sets of
  genes, a person may have normal pigmentation but
  carry the albinism gene.
   3/4/2010                                      46
                         Albinism II
• High-fashion photographer
  Rick                 Guidotti's
  groundbreaking photo essay,
  "Redefining           Beauty,"
  published in the June 1998
  issue of Life Magazine, is
  a tribute to the uniqueness of
  people with albinism and a
  welcome contrast to the
  degrading images of the
  condition        so      often
  perpetrated by other media

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              AR Heterozygotes
• Very often in autosomal recessive disease both
  parents have different mutations on the same
  gene, and their affected child is a compound
• The converse situation also occurs; clinically
  similar individuals may have genetic causes for
  their condition, but have mutant alleles at different
  genes (genetic heterogeneity).
• For instance, two deaf parents may have a
  normal-hearing child if both parents have
  deafness-causing mutations on different genes.
  The child is a double heterozygote.
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             X-Linked Inheritance
• When the locus for a gene for a particular trait or disease
  lies on the X chromosome, the disease is said to be X-
• The inheritance pattern for X-linked inheritance differs
  from autosomal inheritance only because the X
  chromosome has no homologous chromosome in the
  male, the male has an X and a Y chromosome.
• Very few genes have been discovered on the Y
• The inheritance pattern follows the pattern of segregation
  of the X and Y chromosomes in meiosis and fertilization. A
  male child always gets his X from one of his mother's two
  X's and his Y chromosome from his father.
  3/4/2010                                              49
                X-Linked Genes
• X-linked genes are never passed from father to son.
• A female child always gets the father's X chromosome and
  one of the two X's of the mother.
• An affected female must have an affected father.
• Males are always hemizygous for X linked traits, that is,
  they can never be heterozygotes or homozygotes. They are
  never carriers.
• A single dose of a mutant allele will produce a mutant
  phenotype in the male, whether the mutation is dominant or
• On the other hand, females must be either homozygous for
  the normal allele, heterozygous, or homozygous for the
  mutant allele, just as they are for autosomal loci.

   3/4/2010                                             50
   X-Linked Dominant Inheritance
• When an X-linked gene is said to express
  dominant inheritance, it means that a single
  dose of the mutant allele will affect the
  phenotype of the female.
• A recessive X-linked gene requires two doses
  of the mutant allele to affect the female
• The following are the hallmarks of X-linked
  dominant inheritance:

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               X-Linked Dominance
• The trait is never passed from father to son.
• All daughters of an affected male and a normal
  female are affected. All sons of an affected male
  and a normal female are normal.
• Matings of affected females and normal males
  produce 1/2 the sons affected and 1/2 the daughters
• Males are usually more severely affected than
  females. The trait may be lethal in males.
• In the general population, females are more likely to
  be affected than males, even if the disease is not
  lethal in males.
    3/4/2010                                       52
X-linked dominant inheritance has
   a unique heritability pattern.

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     X-linked dominant inheritance

• The key for determining if a dominant trait is
  X-linked or autosomal is to look at the
  offspring of the mating of an affected male
  and a normal female.
• If the affected male has an affected son, then
  the disease is not X-linked.
• All of his daughters must also be affected if
  the disease is X-linked. In the previous
  pedigree, both of these conditions are met.
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  Lack of males in some X-linked
       dominant pedigrees
• What happens when males are so severely
  affected that they can't reproduce?
• Suppose they are so severely affected they never
  survive to term, then what happens?
• This is not uncommon in X-linked dominant
• There are no affected males to test for X-linked
  dominant inheritance to see if they produce all
  affected daughters and no affected sons.

  3/4/2010                                     55
• The following pedigree shows the effects of
  such a disease in a family. There are no
  affected males, only affected females, in the
  population. Living females outnumber living
  males two to one when the mother is
  affected. The ratio in the offspring of affected
  females is: 1 affected female: 1 normal
  female: 1 normal male.
• There have also been several spontaneous
  abortions in the offspring of affected females.
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  X-linked dominant pedigree with
         no affected males

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                 Rett Syndrome
• Rett Syndrome (RS) is a
  neurological disorder seen
  almost exclusively in females.
• The prevalence of RS in
  females is approximately one
  in every 10,000-23,000
  individuals and is found in all
  racial and ethnic groups
• It is known that RS can occur
  in males but is extremely rare.
• Recurrence in families is also
  extremely rare. In these
  families males may have a
  very different pattern
  including miscarriage, stillbirth
  or early death due to fatal

   3/4/2010                           58
              Rett Syndrome Gene
• In 1999 a decade-long search for the genetic basis
  for RS succeeded in identifying mutations in the
  MECP2 gene (Xq28) in girls fulfilling the criteria for
  RS. This discovery allows confirmation of clinical
  diagnoses and the development of genotype-
  phenotype correlations.
• At the present time, more than 80% of females
  fulfilling the criteria for RS have mutations in
  MECP2. The remainder either has mutations in as
  yet unexplored regions of MECP2 or is explained by
  alternative genes.
• Predicting the severity of RS for an individual is
  difficult because more than 200 mutations in the
  MECP2 gene have been observed. The range of
  these mutations result in varying degrees of
  neurological and physical complications.
   3/4/2010                                          59
                  Role of MECP2
• The role of MECP2 is to silence certain genes. In RS, the
  MECP2 gene is unable to perform this task, leaving those
  genes over-active.
• The areas of the brain disrupted in RS are the frontal, motor,
  and temporal cortex, brainstem, basal forebrain, basal
  ganglia, which control many basic functions, such as
  movement. They are also critical to the normal development
  of the cortex, or higher brain centre, in late infancy.
• RS, then, ravages centres that control both motion and
• In fact, RS is now known to be one of the leading causes of
  mental retardation in females, occurring with a frequency of
  up to 1 in 10,000 live female births.

   3/4/2010                                                60
           X-Linked Dominant
        Chondrodysplasia Punctata
• Chondrodysplasia Punctata is a hereditary disorder
  that affects infants and young children. It is a
  skeletal abnormality, characterized by punctate
  calcification of the cartilage of the epiphyses, larynx
  and trachea.
• Symptoms include growth retardation, shortening of
  limbs, cataracts, dry and scaly skin (Ichthyosis),
  large skin pores and patches of coarse, dry hair.
• Patients may also become mildly retarded.

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            X-Linked Dominant
        Chondrodysplasia Punctata II
• Different forms of
  Chondrodysplasia Punctata
  exist, the most common of
  which is inherited as an
  autosomal recessive trait.
• The X-linked dominant form,
  also known as Conradi-
  Hunermann Syndrome, is lethal
  to males in early gestation.
• The gene affected is that for
  emopamil-binding protein
  (EBP), located at Xp11-23.

   3/4/2010                            62
    X-Linked Recessive Inheritance
• Everyone has heard of some X-linked recessive
  disease even though they are, in general, rare.
  Haemophilia, Duchenne muscular dystrophy,
  Becker muscular dystrophy, and Lesch-Nyhan
  syndrome are relatively rare in most populations,
  but because of advances in molecular genetics
  they receive attention in the media.
• More common traits, such as glucose-6-phosphate
  dehydrogenase deficiency or colour blindness,
  may occur frequently enough in some populations
  to produce a few affected females. However, their
  effect on individuals is rarely life threatening and
  medical intervention is not needed.
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  X-Linked Recessive Inheritance

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                X-Linked Recessive Pedigree
• II-2 and II-5 are both carriers,
  their father was affected and
  passed on his only X
  chromosome to his daughters.
• II-3 cannot be a carrier for two
  reasons. First, males are either
  affected or normal, never
  carriers. Second, he didn't
  inherit     his    father's    X
  chromosome. He inherited his
  father's Y chromosome.
• III-3 couldn't have been a
  carrier since neither her father
  nor her mother had the mutant
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 What are the hallmarks of X-linked
      recessive inheritance?
• As with any X-linked trait, the disease is never
  passed from father to son.
• Males are much more likely to be affected than
  females. If affected males cannot reproduce, only
  males will be affected.
• All affected males in a family are related through
  their mothers.
• The trait or disease is typically passed from an
  affected grandfather, through his carrier daughters,
  to half of his grandsons.

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    Some X-linked recessive diseases
• Examples:
• Colour Blindness 60% green / 40% red.
• Haemophilia A (factor VIII deficiency).
• Haemophilia B (factor IX deficiency).
• Glucose-6-phosphate dehydrogenase deficiency.
• Duchenne Muscular dystrophy.
• Fragile X Syndrome.
•  Spinal and bulbar muscular atrophy (Kennedy's
• Retinitis pigmentosa.

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           X-linked colour blindness
• Protanopia (red-catching cones do not work)
  - see blends of blue and green
• Deuteranopia (green-catching cones do not
  work) - hard to distinguish between greens
  and combinations of red and blue. It’s the
  most common type.
• Many mild colour perception anomalies
• 8% of men, 0.05% of women have some form
  of colour blindness.

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How an image would look for 3 of the
   more common types of colour

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           Test yourself

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  Duchenne Muscular Dystrophy I
• DMD is one of a group of inherited diseases
  marked by progressive weakness &
  degeneration of skeletal muscles.
• Most common (1/3500 boys are infected) &
  most severe
• Outward symptoms by 4-6 yrs; death usually
  by 20’s - 30’s
• X-linked recessive disease

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 Duchenne Muscular Dystrophy II
• Protein coded for by DMD gene: large muscle
  protein called dystrophin.
• Role: Maintain structure; it is believed to carry
  signals between outside and inside of muscle
• 3685 amino acids
• 427 kD molecular weight
• Dystrophin gene is the largest found, being
  over 2 million bases long!

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 Duchenne Muscular Dystrophy III
Normal dystrophin staining
around the rim of muscle fibre

                                             Absent dystrophin:
                                 Duchenne muscular dystrophy
                     No staining around the rim of muscle fibres
   3/4/2010                                              73
Female Expression of X-Linked Traits
• At the cellular level, female carriers are in fact mosaics as a
  result of X-inactivation. Some cells will be expressing the
  wild-type allele and others the mutant.
• In some conditions, there may be subtle phenotypic
  evidence of this. For instance, carriers of Duchenne
  muscular dystrophy mutations may have elevated Creatine
  Kinase levels and carriers of X-linked retinitis pigmentosa
  mutations may show evidence of small patches of
  pigmentation in the retina.
• If X-inactivation is non-random and the mutation is
  expressed in significantly more than 50% of cells, the
  female may be moderately or (rarely) severely affected.

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• Y-linked traits would be passed only from
  father to son, but there are no Y-linked
  genetic diseases.

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• Genes can no longer be categorized as dominant or
  recessive since mutations in the same gene (even the
  same mutation) can result in either phenotypic expression.
  The traditional idea of Mendelian inheritance is no longer
  absolute with many diseases "breaking the rules."
• Phenotypic variation poses significant problems with
  respect to diagnosis and counselling of patients since even
  identification of the pathogenic mutation may not be
  sufficient to predict the likely symptoms and vice versa (the
  clinical picture may give no indication as to the underlying
• Only further research into the mechanisms underlying
  phenotypic variation such as modifying factors will help us
  understand and predict the phenotypic outcome of
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             Autosomal Autosomal      X-linked          X-linked
             dominant recessive       dominant          recessive
Pedigree Vertical        Horizontal
Affects      Both        Both sexes   Either sex but    Mainly males
             sexes                    more females
                                      than males
Parents      Usually 1   Both         Child of an       Both usually
             affected    usually      affected female   unaffected,
                         unaffected   has 50%           mother
                                      chance of         asymptomati
                                      being affected    c carrier
Risk for     50%         Small        For an affected   No male to
children                              male all his      male
                                      daughters will    transmission
                                      be affected       in the
  3/4/2010                                              pedigree 77

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