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MTHistoTech LEC M8: GENETIC DISORDERS
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Ramirez
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John Patrick B. – BSMT 3-B
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BASIC CLINICAL GENETICS CONCEPTS
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STRUCTURAL ORGANIZATION OF THE
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CHROMOSOME
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ETIOLOGY OF DISORDERS
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Hereditary Congenital Derived from one’s parents –
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transmitted in the gametes
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through generations (familial)
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Present at birth
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MUTATIONS IN PROTEIN-CODING GENES
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➢ Permanent changes in the DNA.
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Germ cell
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mutation
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Transmitted to the progeny and
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give rise to inherited diseases
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Somatic cell
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mutation
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Not transmitted to the progeny;
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important in the causation of
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cancers and some congenital
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malformations
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- DNA
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- Nucleosomes
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3. Chromatin fiber
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4. Chromatid
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5. Chromosome
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HISTONES
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• Major class of chromosomal proteins.
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• Largely responsible for the structure of chromatin.
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• Contains 20% lysine and arginine (positive
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charge amino acids) – enables DNA binding.
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• 5 major types: H1. H2A
H2B
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NUCLEOSOME
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• Beadlike units within the chromatin fiber.
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Each consists of:
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• 2 molecules each of H2A
H2B
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• Segment of DNA
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• 1 molecule of H1
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CHROMATIN
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Heterochromatin Euchromatin Dense
inactive
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Disperse
active
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Silent Does not alter the amino acid
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Conservative
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missense
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Substitution of one amino acid for
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another with similar chemical
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properties
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Non-
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conservative
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missense
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Substitution of one amino acid for
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another with different chemical
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properties
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Nonsense Creates a stop codon – leading to
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premature termination
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POINT MUTATIONS
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• Substitution of a single nucleotide base by a
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different base.
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FRAMESHIFT MUTATIONS
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• Insertion of one or two base pairs (non-multiples
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of 3).
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• Alteration of reading frame of the DNA strand.
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TRINUCLEOTIDE REPEAT MUTATIONS
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• Amplification of a sequence of three nucleotides.
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• All affected sequences share the nucleotide
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guanine and cytosine.
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• These mutations are dynamic – have a tendency
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to get worse as they are passed down.
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OTHER ALTERATIONS IN PROTEIN-CODING
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GENES
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➢ Coding genes can also undergo structural
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variations (amplifications
deletions) or
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translocations that result in aberrant gain or loss
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of protein function.
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➢ Structural changes may occur in the germline or
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be acquired in somatic tissues.
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MTHistoTech LEC M8: GENETIC DISORDERS
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Ramirez
John Patrick B. – BSMT 3-B
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MAJOR CATEGORIES OF GENETIC DISORDERS
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MENDELIAN DISORDERS
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➢ Resulting from mutations in single genes.
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Pleiotropy Single gene mutations may
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have phenotypic effects
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Genetic
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Mutation at several loci may
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heterogeneity
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produce same trait
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Modifier genes Genes in other loci that
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influenced manifestations of a
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single gene – can affect
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penetrance
dominance
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expressivity
and pleiotropy
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Modifier gene
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Introduces a functional gene to
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therapy
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modify the expression of many
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genes
gene networks
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reset homeostasis
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Phenotypic manifestations:
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Complete
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penetrance
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Every individual with the mutant
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genotype shows the expected
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phenotype.
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Incomplete
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Some individuals with the mutant
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penetrance
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genotype do not show the
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expected phenotype
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Variable
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expressivity
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All affected individuals show the
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phenotype with varying degrees
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of severity or features
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Incomplete
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Not all carriers of the mutant
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penetrance
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genotype show the phenotype;
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& variable
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those who do may show it with
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expressivity
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different levels of severity
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AUTOSOMAL RECESSIVE INHERITANCE
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o Manifested in the homozygous state.
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o Occurs when both alleles at a given locus are
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mutants.
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o Parents are usually not affected – carriers.
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o 25% chance of offspring being affected.
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o Common in consanguineous marriage.
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o Make up the largest group of mendelian dso.
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o Expression of defect tends to be more uniform
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than autosomal dominant disorders.
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o Complete penetrance is common.
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o Onset is frequently early in life.
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o Rarely due to new mutations.
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o Enzymes are affected in many cases.
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CONSANGUINITY
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▪ “Founder effect”
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– common ancestor.
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▪ Most commonly associated with inborn
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errors of metabolism.
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Increases the incidence of multifactorial
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disorders:
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▪ Diabetes
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▪ Cardiovascular disorders
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▪ Obesity
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▪ Certain types of cancer
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Reasons for human inbreeding avoidance on
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siblings:
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▪ Witnessing an infant being taken care of
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by one’s mother
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▪ Growing up in close proximity to a child
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(Westermarck effect)
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X-LINKED INHERITANCE
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o Most are X-linked recessive.
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o Heterozygous female carriers rarely express
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the full phenotypic change; transmit them only
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to sons.
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o Affected male does not transmit the disorder
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to sons
but all daughters are carriers.
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Specific genetic disorders:
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INHERITANCE PATTERNS
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AUTOSOMAL DOMINANT INHERITANCE
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o Manifested in heterozygous state – at least
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one parent in an index case usually is affected
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o Both males and females can be affected.
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o Both sexes can transmit the condition.
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o Some patients do not have affected parents –
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new mutations.
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o Clinical features can be modified by reduced
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penetrance and variable expressivity.
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o The age of onset is delayed (late onset) –
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symptoms and signs do not appear until
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adulthood.
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A 50% reduction in the normal gene product is
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associated with:
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o Proteins involved in regulation of complex
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metabolic pathways
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o Key structural proteins (collagen
cell
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membrane skeleton)
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MTHistoTech LEC M8: GENETIC DISORDERS
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Ramirez
John Patrick B. – BSMT 3-B
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GENETIC DISORDER INHERITANCE PATTERN GENE AFFECTED
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Marfan syndrome Autosomal dominant Fibrillin-1 (FBN1)
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Ehlers-Danlos syndrome Autosomal dominant
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COL3A1
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Autosomal recessive
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COL5A1
COL5A2
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Cystic fibrosis - CF transmembrane conductance
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regulator (CFTR)
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Phenylketonuria - Phenylalanine hydroxylase (PAH)
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Galactosemia Autosomal recessive MARFAN SYNDROME
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• Disorder of connective tissues.
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• Fibrillin-1 (extracellular glycoprotein) – Required
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for structural integrity of connective tissue .
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• Major tissues affected are skeleton
eyes
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cardiovascular system.
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PHENYLKETONURIA (PKU)
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• Inability to convert phenylalanine to tyrosine
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• Mutations that cause a severe lack of enzyme
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phenylalanine hydroxylase (PAH).
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• Classic PKU (most common form) is common in
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persons of Scandinavian descent.
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Clinical
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features
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Galactose-1-phosphate
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uridyltransferase (GALT)
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Clinical
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features
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Tall stature
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Long fingers
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Bilateral subluxation of the lens
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Mitral valve prolapse
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Aortic aneurysm
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Aortic dissection
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Severe mental retardation
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Seizures
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Decreased skin pigmentation
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EHLERS-DANLOS SYNDROME
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• Defects in collagen synthesis or structure.
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Clinical
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features
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Fragile and hyperextensible skin
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vulnerable to trauma
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Hypermobile joints
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Ruptures (colon
cornea
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arteries)
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Poor wound healing
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Molecular
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Type III collagen synthesis
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bases for
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(COL3A1 mutation)
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GALACTOSEMIA
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• Disorder of galactose metabolism.
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• Most commonly affects the liver
eyes
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• Can be prevented or ameliorated by removal of
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galactose from the diet for at least the first two
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years of life.
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Progression:
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1. 2. Lactose splits into glucose and galactose.
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Galactose cannot be converted to glucose due to
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transferase deficiency.
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3. Galactose-1-phosphate and other metabolites
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(galactitol) accumulates in many tissues.
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common
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Lysyl hydroxylase deficiency
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variants
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Type V collagen synthesis
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(COL5A1
COL5A2 mutations)
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CYSTIC FIBROSIS
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• Disorder of epithelial ion transport affecting fluid
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secretion in exocrine glands and the epithelial
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linings of the respiratory
gastrointestinal
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reproductive tracts (tissue-specific).
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• A high level of sodium chloride in the sweat –
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characteristic biochemical abnormality.
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• Reduced production or abnormal function of an
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epithelial chloride channel protein.
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Progression:
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1. Ion transport defects.
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2. Abnormally viscid mucous secretion.
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3. Blockage of airways and pancreatic ducts.
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4. Recurrent and chronic pulmonary infections and
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pancreatic insufficiency.
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COMPLEX MULTIGENIC DISORDERS
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➢ Multifactorial polygenic disorders.
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➢ Caused by interactions between genetic variants
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and environmental factors.
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➢ Environmental influences significantly modify the
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phenotypic expression of complex traits.
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➢ E.g.
Type 2 diabetes mellitus.
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CYTOGENETIC (CHROMOSOMAL) DISORDERS
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➢ Results from alterations in the number or
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structure of chromosomes
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➢ May affect autosomes or sex chromosomes.
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➢ May be associated with the absence
excess
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abnormal rearrangements of chromosomes.
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➢ Result from de novo changes in most cases.
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MTHistoTech LEC M8: GENETIC DISORDERS
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Ramirez
John Patrick B. – BSMT 3-B
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Chromosome
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loss
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Produces more severe defects
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than chromosomal material gain
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Translocation A segment of one
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chromosome is transferred to
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another
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Excess
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May come from a complete
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material
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chromosome or from a part
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Isochromosome Identical arms are formed by
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Autosome
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chromosome
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imbalance
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Less tolerated than imbalances
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of sex chromosomes
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abnormal division through the
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centromere
resulting in
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duplication of one arm and
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loss of the other.
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Sex
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Often produces subtle
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Deletion chromosomal
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abnormalities
sometimes not
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disorders
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detected at birth
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A loss of a chromosomal
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segment causing missing
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genetic material
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Inversion A chromosomal segment
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Karyotype Photographic representation of a
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stained metaphase spread in which
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the chromosomes are arrange in
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order of increasing length
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breaks and reattaches in
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reverse orientation – altering
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gene order
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Banding
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Allows identification of each
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techniques
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chromosome – can detect and
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Forms when its ends break
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and fuse together
often
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losing genetic material
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localize structural abnormalities
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NUMERIC ABNORMALITIES
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46 Normal human chromosome ct.
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Euploid Any exact multiple of the haploid
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number (n)
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Polyploid Chromosome numbers
e.g.
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Aneuploid Any number that is not an exact
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multiple of n
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Ring
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chromosome
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Specific disorders:
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DOWN SYNDROME
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• Characterized by extra copy of genes on Chr 21.
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• Most common chromosomal disorder.
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• Maternal age has a strong influence on incidence
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• Meiotic nondisjunction of Chr 21 in the ovum.
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• Leading cause of mental retardation.
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Flat facial profile
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Oblique palpebral fissures
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Epicanthic folds
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Clinical features ANEUPLOIDY
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Is due to:
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o Nondisjunction of a homologous pair of
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chromosomes at the first meiotic division; or
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o Failure of sister chromatids to separate during
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the second meiotic division.
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MOSAICISM
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o Presence of two or more populations of cells
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with different complements of chromosomes
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in the same individual.
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STRUCTURAL ABNORMALTIES
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• Due to chromosomal breakage followed by loss
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or rearrangement of material.
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Genetic basis:
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Trisomy 21 (4%) Chromosome count is 47 –
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most commonly caused by
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meiotic nondisjunction
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Translocation
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Long arm of Chr 21 to Chr 14
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-0.04
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or 22
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22q11.2 DELETION SYNDROME
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• Encompasses a spectrum of disorders that result
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from a small interstitial deletion of band 11 on the
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long arm of chromosome 22.
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Mixture of 46 and 47
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chromosomes
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DiGeorge
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syndrome
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Velocardiofacial
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syndrome
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Mosaicism T cell immunodeficiency
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Hypocalcemia
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Mild immunodeficiency
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Pronounced dysmorphology
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Cardiac defects
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Clinical features Congenital heart defects
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Palate abnormalities
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Facial dysmorphism
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Developmental delay
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Thymic hypoplasia
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Impaired T cell immunity
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Parathyroid hypoplasia
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Hypocalcemia
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MTHistoTech LEC M8: GENETIC DISORDERS
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Ramirez
John Patrick B. – BSMT 3-B
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KLINEFELTER SYNDROME
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• Defined as male hypogonadism (most common).
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• Develops when there are at least two X
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chromosomes and one or more Y chromosomes.
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• Most have karyotypes of 47
XXY karyotype.
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• The extra chromosome may be of either maternal
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or paternal origin.
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TURNER SYNDROME
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• Characterized by primary hypogonadism in
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phenotypic females
results from partial or
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complete monosomy of the short arm of the X
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chromosome.
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Clinical features Growth retardation
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Swelling of the nape
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Low posterior hairline
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Primary amenorrhea
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SINGLE GENE DISORDERS WITH ATYPICAL
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PATTERNS OF INHERITANCE
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➢ Caused by triplet repeat mutation.
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➢ Caused by mutations in mitochondrial genes.
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➢ Associated with alteration of imprinted regions of
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the genome.
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TRINUCLEOTIDE REPEAT MUTATION
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• Occurs when the number of triplets present in a
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mutated gene is greater than the number found
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in a normal gene.
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• The number of triplets in the disease gene
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continues to increase as the disease gene is
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inherited.
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• E.g.
fragile X syndrome
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MITOCHONDRIAL DISORDERS
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• Associated with maternal inheritance.
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• Diseases caused by mutations in genes
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(mitochondrial DNA) that encode enzymes
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involved in oxidative phosphorylation.
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• Affects CNS
skeletal muscles
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liver
and kidney.
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• E.g.
Leber hereditary optic neuropathy
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IMPRINTING
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• Epigenetic process whereby certain homologous
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genes are differentially inactivated during
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paternal and maternal gametogenesis.
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• Refers to transcriptional silencing.
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• Only one copy of the functional gene exists in the
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individual.
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• Loss of the functional allele (not imprinted) by
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deletions give rise to disease.
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