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Genetic and chromosomal disorders
DR. MAHMOUD MOHAMED OSMAN
MBBCh, MSc (Pedia), MRCPCH
(UK), FRCP (Edinburgh) Consultant Pediatrician
Neonatologist Al Yammamah Hospital , MOH
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• Objectives
• Molecular Genetics
• Common Genetic Terminology
• Congenital Anomalies
• Genetic Diseases
• Chromosomal Aberrations
• Mitochondrial Disorders

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MOLECULAR GENETICS
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The DNA double helix.
The 5'
and 3' labels indicate the head-to-tail
organization of the DNA double helix. A, C, T,
and G are bases. S for sugar , P for phosphate.
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The life language DNA to RNA to Protein

• The "life cycle" of an mRNA in a
  eukaryotic cell. RNA is transcribed in the
  nucleus processing, it is transported to the
  cytoplasm and translated by the ribosome.
  Finally, the mRNA is degraded.

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Autosomes and Sex-chromosomes

• Autosomes are the first 22 homologous pairs of
  human chromosomes that do not influence the sex
  of an individual. Genes located on Autosomes
  control Autosomal traits and disorders.
• Sex Chromosomes are the 23rd pair of chromosomes
  that determine the sex of an individual.

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Homologous Chromosomes
and Sister Chromatids
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• Symbols guide for pedigree drawing

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COMMON GENETIC TERMINOLOGY
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Genetics Study of individual genes and their
effects includes studies of inheritance, mapping,
disease genes, diagnosis and treatment, and
genetic counseling.
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• Genes
• Genes are the individual pieces of coding
  information that we inherit from our parents (the
  blueprint for an organism).
• It is estimated that 30,000 to 40,000 genes are
  required to develop and operate a human being.
• Individual genes occur in pairs, one inherited
  from each parent.
• The balance of the expression of these genes is
  extremely delicate, with significant abnormality
  resulting when this balance is disturbed for some
  genes.

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• Genomics
• Study of conditions that are partly caused or
  prevented by mutation(s) in gene(s).
• Study is not just of single genes, but of the
  functions and interactions of all the genes in
  the genome.
• For instances the pathogenesis of diseases such
  as asthma, hypertension, diabetes, and
  psychiatric disorders

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• Syndrome
• The term syndrome is used to describe a broad
  error of morphogenesis in which the simultaneous
  presence of more than one malformation or
  functional defect is known or assumed to be the
  result of a single etiology.
• Its use implies that the group of malformations
  and/or physical or mental differences has been
  seen repeatedly in a fairly consistent and unique
  pattern.

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• Sequence
• The term sequence is used to designate a series
  of anomalies resulting from a cascade of events
  initiated by a single malformation, deformation,
  or disruption.
• A well-known example is the Robin sequence,
  in which the initiating event is small
  mandible (micrognathia).This precipitates
  glossoptosis with resultant incomplete fusion of
  the palatal shelves.

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• Association
• An association is a nonrandom occurrence in two
  or more individuals of multiple anomalies not
  known to represent a sequence or syndrome .
• These anomalies are found together more often
  than expected by chance alone, demonstrating a
  statistical relationship but not necessarily a
  known causal one.
• For example, the VATER (VACTERL) association
  represents a simultaneous occurrence of two or
  more malformations.

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• Alleles
• Variant forms of the same gene are known
  as alleles, and variation can have no apparent
  phenotypic effect or major consequences,
  depending on the specific gene and many other
  factors.
• Polymorphism
• When a variant has minimal phenotypic
  effect.
• Mutation
• Some syndromes are caused by a permanent
  structural or sequence change (mutation) in a
  single gene.

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Congenital anomalies
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Congenital anomalies
Four types of structural defects that can result
in a chain of defects (sequence) by the time of
birth.
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Congenital anomalies

• Malformations sequence
• Single, local tissue morphogenesis
  abnormality that produces a chain of subsequent
  defects (Robin sequence).
• Malformation syndrome
• Appearance of multiple malformations in
  unrelated tissues without an understandable
  unifying cause with enhanced genetic
  investigation, a single etiology may become
  identified. (Trisomy 21,and Teratogens)
• Disruptions
• Destruction of normally developted organ -
  amniotic bands

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Congenital anomalies

• Deformations Compression of the fetus with
  malformed uterus, Oligohydramnous,
  multiple fetuses.
• Agenesis Complete absence of organ.
• Hypoplasia Incomplete development of organ.
• Dysplasia Poor organization of cells into
  tissues or organs.
• Atresia Absence of opening, e.g. GIT, bile
  ducts.

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Genetic diseases
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Types of Genetic Diseases

1. Mendelian disorders
2. Multifactorial inheritance Disorders
3. Chromosomal Aberrations
4. Mitochondrial

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I. Mendelian disorders

• Mendelian disorders currently are more than 5,000
  disorders .
• Autosomal dominant
• Autosomal recessive
• Sex-Linked Traits
• Co-dominant (Incomplete)

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1. Autosomal Dominant Traits

• If dominant allele is present on the autosome,
  then the individual will express the trait (AA or
  Aa).
• Heterozygotes are affected (Aa).
• Affected children usually have affected parents.
• Two affected parents can produce an unaffected
  child. (Aa x Aa - aa )
• Two unaffected parents usually will not produce
  affected children. (aa x aa) (except in case of
  new mutation)
• Both males and females are affected with equal
  frequency.
• Pedigrees show no Carriers.

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• Autosomal Dominant Pedigree
• Genotypes of Affected and Unaffected
• AA and Aa Affected aa Unaffected

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Why patients with an AD disorder may have no
affected parent ?

• New mutation The patient may represent a new
  mutation that occurred in the DNA of the egg or
  sperm.
• Incomplete penetrance Meaning that not all
  individuals who carry the mutation have
  phenotypic manifestations. In a pedigree this can
  appear as a skipped generation.an unaffected
  individual links two affected persons.
• Variable expression Individuals with the same
  autosomal dominant mutation can manifest the
  disorder to different degrees.
• Somatic mutations Some mutations occur in a cell
  in the developing embryo, and because not all
  cells are affected, the change is said to
  be mosaic. (The phenotype caused can be
  varied, but it is usually milder than if all
  cells contain the mutation.)
• Germline mosaicism The mutation occurs in cells
  that populate the germline that produce eggs or
  sperm. (A germline mosaic might not have any
  manifestations of the disorder but might produce
  multiple eggs or sperm that carry the mutation.)

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2. Autosomal Recessive Traits

• In order to express the trait, two recessive
  alleles must be present (aa).
• Heterozygotes are Carriers with a normal
  phenotype (Aa).
• Most affected children have normal parents.
  (Aa x Aa)
• Two affected parents will always produce an
  affected child. (aa x aa)
• Two unaffected parents will not produce affected
  children unless both are Carriers.(AA x AA - Aa x
  Aa)

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• Affected individuals with homozygous unaffected
  mates will have unaffected children. (aa x AA)
• Close relatives who reproduce are more likely to
  have affected children.
• Both males and females are affected with equal
  frequency.
• Pedigrees show both male and female carriers.

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• Autosomal Recessive Pedigree
• Genotypes of Affected and Unaffected
• AAUnaffected AaCarrier Unaffected
  aaAffected

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3. Sex-Linked Traits

• Sex-linked traits are produced by genes only on
  the Ch.X .
• They can be Dominant or Recessive. (Most are
  Recessive!)
• More males than females are affected.
• An affected son can have parents who have the
  normal phenotype. (XAY x XAXa)
• An affected daughter, her father must be
  affected, and her mother must be affected or a
  carrier.(XaY x XaXa or XAXa)
• The trait often skips a generation from the
  grandfather to the grandson.
• If a woman has the trait (XaXa), all her sons
  will be affected.
• Pedigrees show only female carriers but no male
  carriers.

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• Sex-Linked Recessive Pedigree
• Genotypes of Parents
• Male XR Y Female XR Xr

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Pedigree of an X-linked dominant disorder with
male lethality,
such as incontinentia pigmenti.
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Y - linked inheritance

• Y chromosome carries genes involved in male
  development and spermatogenesis.
• In Y linked inheritance, only males would be
  affected, with transmission being from a
  father to all his sons via the Y
  chromosome.
• This pattern of inheritance was previously
  suggested for conditions as hairy ears, and
  webbed toes.
• In most conditions in which Y linked inheritance
  has been postulated the actual mode of
  inheritance is probably autosomal dominant with
  sex limitation.

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• X-linked disorders in summary
• NO Y-linked disorders known
• (Allele for hairy ears is Y-linked)
• X-linked recessive
• Heterozygous female is a carrier
• Only sons are affected
• Daughters are carriers
• X-linked dominant rare
• vitamin D - resistant rickets

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4. Incomplete and Co-dominance

• Some alleles do not show a dominance
  hierarchy.
• Incomplete dominance
• The phenotype of a heterozygous genotype is
  intermediate in appearance
• Co-dominance
• More than 2 alleles for a given trait.
• Each allele in the genotype for a particular gene
  will be expressed in the phenotype.
• Some versions of the gene are dominant over
  others. But they are not dominant over all of the
  alleles.
• Both dominant alleles are expressed in
  heterozygotes.

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ABO blood types are an example of
co-dominance inheritance
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II. Disorders with multifactorial inheritance

• Disorders with multifactorial inheritance
• Diabetes mellitus type II
• Essential systemic hypertesion
• Gout
• Schizophrenia, bipolar disorders
• Congenital heart defects
• Skeletal abnormalities

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III. Chromosomal Aberrations (Abnormalities)

• What are Chromosomal Aberrations?
• - Damage to chromosomes due to physical or
  chemical disturbances or errors during meiosis.
• - Two Types of Chromosome Mutations
• Aberrations in Chromosome Number
• Aberrations in Chromosome Structure

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A- Autosomes Number Abnormalities

• 1- Monosomy
• Only one of a particular type of chromosome
  (2n-1)
• 2-Trisomy
• Having three of a particular type of
  chromosome (2n1)
• 3- Polyploidy
• Having more than two sets of chromosomes
• - Triploids (3n 3 of each type of chromosome),
  - Tetraploids (4n 4 of each
  type of chromosome).
• 4- Mosaicisim
• Nondisjunction during mitosis may lead to
  clonal cell lines with abnormal chromosome counts
• - No known autosomal monosomies (100 lethal)
• - Autosomal aneuploidies highly detrimental and
  rare
• - Polyploids are extremely rare. In general,
  polyploids are more nearly normal in
  
  appearance
  than having monosomy or trisomy,

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B- Sex Chromosome Number Abnormalities

• Possible outcomes
• Sex chromosome aneuploidies less rare,
  perhaps due to dosage compensation and few genes
  on Y
• Klinefelter Syndrome (XXY)
• Phenotypically male but with Barr bodies
• Tend to be tall with female-like breasts and
  reduced testes
• May show signs of mental retardation
• XYY
• Phenotypically male but often very tall
• May have severe acne
• XXX
• Phenotypically normal female
• Turner Syndrome (XO)
• Phenotypically female with no Barr bodies
• Usually with undeveloped reproductive structures

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Chromosome Structure Abnormalities

1. Deletion during cell division, especially
   meiosis, a piece of the chromosome breaks off,
   may be an end piece or a middle piece (when two
   breaks in a chromosome occur).
2. Inversion a segment of the chromosome is turned
   180, same gene but opposite position
3. Translocation movement of a chromosome segment
   from one chromosome to a non-homologous
   chromosome.
4. Duplication a doubling of a chromosome segment
   because of attaching a broken piece from a
   homologous chromosome, or by unequal crossing
   over.

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Trisomy 21 (Down Syndrome)

• The incidence
• Down syndrome in live births is approximately
  1 in 733. It is the most common genetic cause
  of moderate mental retardation.
• Clinical Manifestations
• Down syndrome is associated with characteristic
  dysmorphic features (Flat facial profile,
  epicanthal folds low set ears, short stature,
  hypotonia, lax joints, simian palmar crease).
• Moderate to severe mental retardation

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• Congenital heart defects in 40 such as
  atrioventricular septal defects, ventricular
  septal defects, atrial septal defects, patent
  ductus arteriosus, and tetralogy of Fallot.
• Congenital and acquired gastrointestinal
  anomalies.
• Hypothyroidism, leukemia, immune dysfunction,
  diabetes mellitus, and problems with hearing and
  vision are common.
• Alzheimer disease like dementia is a known
  complication that occurs as early as the 4th
  decade.
• Most males are sterile, but some females
  reproduce, with a 50 chance of having trisomy 21
  pregnancies.

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• Genetics of trisomy 21
• This risk of having a child with trisomy 21 is
  highest in women who conceive at gt35 yr of age.
  Younger women have a lower risk.
• In approximately 95 of the cases of Down
  syndrome there are 3 copies of chromosome 21
  (Non-disjunction).
• The origin of the extra chromosome 21 is
  maternal in 97 of the cases as a result of
  errors in meiosis.
• Approximately 1 of trisomy 21 are mosaics, with
  some normal cells.
• Another 4 have a translocation that involves
  chromosome 21.
• The translocations can be de novo or inherited.
• It is not possible to distinguish the phenotypes
  of persons with Non-disjunction trisomy
  21 and those with a translocation.

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Nondisjunction of chromosome 21 leading to
Down syndrome
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Trisomy 18 (Edwards syndrome)

• INCIDENCE 1/6,000 births   
• CLINICAL MANIFESTATIONS
• Microcephaly, prominent occiput, micrognathia,
• Low birthweight,
• Short sternum,
• Closed fists with index finger overlapping the
  3rd digit and the 5th digit overlapping the 4th,
  narrow hips with limited abduction,
• Rocker-bottom feet,
• Cardiac and renal malformations, and
• Mental retardation
• 95 of children die in the 1st year

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Trisomy 13 (Patau syndrome)

• INCIDENCE 1/10,000 births
• CLINICAL MANIFESTATIONS
• Microcephaly cerebral malformation, especially
  holoprosencephaly
• Ocular hypotelorism, microphthalmia,
• Bulbous nose cleft lip often midline
• Low-set, malformed ears
• Flexed fingers with postaxial polydactyly
• Cardiac malformations visceral and genital
  anomalies
• Scalp defects hypoplastic or absent ribs
• Early lethality in most cases, with a median
  survival of 7days 91 die by 1 year

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Clinical Features of Common Autosomal Trisomies
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Turner syndrome

• Turner syndrome is caused by the loss of one X
  chromosome (usually paternal) in
  fetal cells, producing a female with 45 chrom.
• This results in early loss of the fetus in over
  95 of cases.
• Severely affected fetuses who survive to the
  second trimester can be detected by
  ultrasonography, which shows cystic hygroma,
  chylothorax, asictes and hydrops.
• The incidence of Turner syndrome in live born
  female infants is 1 in 2500.
• Phenotypic abnormalities vary considerably but
  are usually mild.
• In some infants the only detectable abnormality
  is lymphoedema of the hands and
  feet.

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• The most consistent features of the syndrome are
  short stature and infertility from streak gonads,
  neck webbing, broad chest, cubitus valgus.
• Coarctation of the aorta, renal anomalies and
  visual problems may also occur.
• Intelligence is usually within the normal range,
  but a few girls have educational or behavioural
  problems.
• Associations with autoimmune thyroiditis,
  hypertension, obesity and non-insulin dependent
  diabetes reported.
• Growth can be stimulated with androgens or
  growth hormone, and oestrogen replacement
  treatment is necessary for pubertal development.

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• Mitochondrial disorders

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IV. Mitochondrial disorders
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• Mitochondrial disorders
• Not all DNA is contained within the cell nucleus.
  Mitochondria have their own DNA consisting of a
  double-stranded circular molecule.
• This mitochondrial DNA consists of 16 569 base
  pairs that constitute 37 genes.
• Mutations within mitochondrial DNA appear to be 5
  or 10 times more common than mutations in nuclear
  DNA.

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• As the main function of mitochondria is the
  synthesis of ATP by oxidative
  phosphorylation, disorders of mitochondrial
  function are most likely to affect tissues such
  as the brain, skeletal muscle, cardiac muscle and
  eye, which contain abundant mitochondria and rely
  on aerobic oxidation and ATP production.
• Disorders due to mitochondrial mutations often
  appear to be sporadic.
• When they are inherited, however, they
  demonstrate maternal transmission. This is
  because only the egg contributes cytoplasm and
  mitochondria to the zygote.

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