Transcript Genetic Disordersx

Genetic Disorders
Genomics
• Study of all genes in the genome and their
interactions
• Two most common DNA variations
▫ Single-nucleotide polymorphisms
▫ Copy number variations
Epigenetics
Heritable changes in gene expression that are
not caused by alterations in DNA sequence
Classification
• Disorders related to mutations in single genes
with large effects (Mendelian disorders)
• Chromosomal disorders
• Complex multigenic disorders
Mutations
• Permanent change in the DNA
• Interfers with protein synthesis at various levels
• Point mutation
▫ Within coding sequences
▫ Within noncoding sequences
• Frameshift mutation
▫ Deletions
▫ Insertions
• Trinucleotide-repeat mutations
▫ Amplifications, dynamic
Mendelian Disorders
• Autosomal dominant
• Autosomal recessive
• X-linked
Autosomal Dominant
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Manifested in the heterozygous state
Some proportion due to a new mutation
Incomplete penetrance
Variable expressivity
Influence of environmental factors
Age of onset delayed in many conditions
Most are loss-of-function mutations
Table 5-1 common disorders
Autosomal Recessive
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Largest category of mendelian disorders
Trait does not usually affect the parents
Siblings have a ¼ chance of having the trait
Think about consanguinity if mutant gene is rare
Expression of the defect tends to be more
uniform
Complete penetrance is common
Onset is frequently early in life
New mutations are rarely detected clinically
Many of the mutated genes encode enzymes
Table 5-2 common disorders
X-linked Disorders
• Most are recessive
• Few X-linked dominant ( e.g. vitamin Dresistant rickets)
• Affected male does not transmit the disorder to
his sons, but all daughters are carriers
• The heterozygous female usually does not
express the full phenotypic change because of
the paired normal allele
• Table 5-3 common disorders
Biochemical and Molecular Basis of
Mendelian Disorders
• Enzyme defects and their consequences
▫ Accumulation of substrate
▫ Decreased amount of end product
▫ Failure to inactivate a tissue-damaging substrate
• Defects in membrane receptors and transport
systems
• Alterations in the structure, function, or quantity
of nonenzyme proteins
• Mutations resulting in unusual reactions to
drugs
Disorders associated with Defects in
Structural Proteins
• Marfan syndrome
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Disorder of connective tissues
Defect in fibrillin-1
Skeletal abnormalities
Ocular changes
Cardiovascular lesions – life-threatening
• Ehlers-Danlos syndromes
▫ Defect in the synthesis or structure of fibrillar
collagen
Disorders associated with Defects in
Receptor Proteins
• Familial hypercholesterolemia
• Mutation in the gene encoding the receptor for
LDL, which is involved in the transport and
metabolism of cholesterol
Disorders associated with Defects in
Enzymes
• Lysosomal Storage diseases
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Tay-Sachs
Niemann-Pick DiseaseType A,B,C
Gaucher disease
Mucopolysaccharidoses
• Gycogen storage diseases
▫ Hepatic forms
▫ Myopathic forms
▫ Miscellaneous forms
• Alkaptonuria
Disorders associated with Defects in
Proteins that Regulate Cell Growth
• Proto-oncogenes
• Tumor-suppressor genes
• Important in the pathogenesis of tumors
Complex Multigenic Disorders
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Polymorphism
Common disease/common variant hypothesis
Environmental factors
Difficult to distinguish from mendelian disease
at times
Chromosomal Disorders
• Normal karotype
▫ G banding
▫ Terminology
• Structural abnormalities
▫ Aneuploidy
 Nondisjunction
 Anaphase lag
▫ Mosaicism
▫ Deletion
 Ring chromosome
▫ Inversion
▫ Isochromosome
▫ Translocation
 Balanced reciprocal
 Robertsonian
Cytogenic Disorders involving
Autosomes
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Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome
Chromosome 22q11.2 Deletion syndrome
Trisomy 21
• 1/700 incidence in US
• Maternal age
• Flat facial profile, oblique palpebral fissures,
epicanthic folds, intellectual
disability,hypotonia
• 40% congenital heart disease
• Increased risk of leukemia
• Abnormal immune responses
• Alzheimer disease after 40 years of age
• Figure 5-21 clinical features of trisomies
Chromosome 22q11.2 Deletion
Syndrome
• DiGeorge syndrome
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Thymic dysplasia  immunodeficiency
Parathyroid hypoplasia  hypocalcemia
Cardiac malformations
Facial anomalies
• Velocardiofacial syndrome
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Facial dysmorphism
Cleft palate
CVS anomalies
Learning disabilities
Cytogenic Disorders involving Sex
Chromosomes
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Lyon hypothesis
Klinefelter syndrome
Turner syndrome
Hermaphroditism
Pseudohermaphroditism
Lyon Hypothesis
• Only one of the X chromosomes is genetically
active
• The other is rendered inactive at random at
about day 16 of embryonic life
• Inactivation of the same X persists in all cells
derived from each precursor cell
• Barr body
• Not all of the genes on the inative X are switched
off
• Both Xs are required for normal oogenesis
Klinefelter Syndrome
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Male hypogonadism
Two or more X and one or more Y
Elongated body, gynecomastia
Reduced spermatogenesis and male infertility
Increased risk of breast cancer, extragonadal
germ cell tumors, autoimmune disorders
• Longest CAG repeat X chromosome remains
active
Turner Syndrome
• Complete or partial monosomy of the X
chromosome
• Hypogonadism in phenotypic females
• Single most important cause of primary
amenorrhea
• Figure 5-23 Clinical features
Hermaphroditism and
Pseudohermaphroditism
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Genetic sex
Gonadal sex
Ductal sex
Phenotypic or genital sex
True hermaphrodite – presence of both ovarian
and testicular tissue
• Pseudohermaphrodite – disagreement between
phenotypic and gonadal sex
▫ Female – excess androgen
▫ Male – complete androgen insensitivity syndrome
Single-Gene Disorders with Nonclassic
Inheritance
• Diseases caused by trinucleotide-repeat
mutations
• Disorders caused by mutation in mitochondrial
genes
• Diseases associated with genomic imprinting
• Diseases associated with gonadal mosaicism
Fragile X Syndrome
• Prototype of mutation with long repeating sequence
of three nucleotides
• Second most common genetic cause of intellectual
disability after Down syndrome
• Macro-orchidism
• Normal carrier males
• Affected females –much higher than in other xlinked recessive disorders
• Risk of phenotypic effects depends upon position in
pedigree
• Anticipation – worsens with each successive
generation
Leber Hereditary Optic Neuropathy
• Prototype of mitochondrial inheritance disorder
• Maternal inheritance
• mtDNA complement of the zygote is derived
entirely from the ovum
• Genes incode for enzymes involved in oxidative
phosphorylation
• Threshold effect
• Neurodegenerative disease – progressive loss of
central vision
Genomic Imprinting
• Imprinting selectively inactivates either the maternal or
the paternal allele
• Uniparental disomy
• Angelman
▫ Deletion of maternally-derived chromosome 15
▫ “Happy puppet” – intellectual disability, ataxia,
inappropriate laughter, seizures
• Prader-Willi
▫ Deletion of paternally-derived chromosome 15
▫ Intellectual disability, hypogonadism, hypotonia,
hyperphagia, short stature, obesity, small hands and feet
Molecular Diagnosis of Genetic
Diseases
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Indications for analysis of germ line genetic alterations
Indications for analysis of acquired genetic alterations
PCR and detection of DNA sequence alterations
Polymorphic markers and molecular diagnosis
Molecular analysis of genomic alterations
▫ Southern blot
▫ FISH
▫ Array CGH
• Epigenetic alterations – do not alter the DNA sequence
• RNA analysis- RNA viruses – HIV, HCV
Indications for Germline Alterations
• Prenatal genetic analysis
▫ Amniocentesis, chorionic villus sample, or umbilical
cord blood
▫ Mother of advanced age
▫ Parent who is a carrier of a translocation or inversion
▫ Parent with a previous child with a chromosomal
abnormality
▫ Fetus with ultrasound-detected abnormalities
▫ Parent who is a carrier of an X-linked disorder
▫ Abnormal levels of triple markers (AFP. BetaHCG,
estriol)
Indications for Germline Alterations
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Postnatal genetic analysis
Peripheral blood lymphocytes
Multiple genetic anomalies
Unexplained intellectual disability and/or
developmental delay
Suspected aneuploidy
Suspected unbalanced autosome
Suspected sex chromosome abnormality
Suspected fragile-X
Infertility
Multiple spontaneous abortions
Indications for Acquired Alterations
• Diagnosis and management of cancer
▫ Detection of tumor-specific alterations
▫ Determination of clonality
▫ Identification of specific alterations that can direct
treatment
▫ Determination of treatment efficacy
▫ Determination of Gleevec-resistant forms of
tumors
Indications for Acquired Alterations
• Diagnosis and management of infectious
diseases
▫ Detection of microorganism-specific genetic
material for diagnosis
▫ Identification of alterations that are associated
with drug resistance
▫ Determination of treatment efficacy