progeni enrollment actual vs...
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MENDELIAN
INHERITANCE
Mohammed El - Khateeb June 30th . 2014
MGL- 6
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Genetic Diseases (GD)
Chromosomal Abnormalities
Single Gene Defects
Non-Traditional Inheritance
Multifactorial Disorders
Cancer Genetics
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Topics of Discussion
• Basic concepts of formal genetics
• Autosomal dominant inheritance
• Autosomal recessive inheritance
• Factors that may complicate
inheritance patterns
• Probability
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Mendelian Inheritance
Single Gene Defects
Most common ♦ Autosomal recessive
♦ Autosomal dominant
♦ Factors complicating Mendelian inheritance
♦ X-linked recessive
♦ X-linked dominant
♦ Y-linked
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Pedigree The family tree
Representation of the ancestry of an
individual’s family.
Symbolic representations of family
relationships and inheritance of a trait
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Goals of Pedigree Analysis
• Determine the mode of inheritance:
dominant, recessive, partial
dominance, sex-linked, autosomal,
mitochondrial, maternal effect.
• Determine the probability of an
affected offspring for a given cross.
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Obtaining a pedigree
A three generation family history should be a standard component of medical practice. Family history of the patient is usually summarized in the form of a pedigree
Points to remember:
• Ask whether relatives have a similar problem
• Ask if there were siblings who have died
• Inquire about miscarriages, neonatal deaths
• Be aware of siblings with different parents
• Ask about consanguinity
• Ask about ethnic origin of family branches
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Pedigree
Symbols
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Pedigree Analysis
Normal
Female Normal
Male
Mating
1st born
Siblings
Affected
I
II
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2 3
I
II
III
IV
2
1 2
1 2 3 4 5 6
1 2 3 4 5 6
1 2 3 4 5 6
Founders
Proband IV - 2 V
1 2
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Autosomal dominant
inheritance
• D abnormal gene
• d normal gene
• Each child of an
affected person has
a 50% chance of
being affected
• Affected persons
are usually
heterozygous
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Characteristics of autosomal dominant inheritance: 1. A gene is dominant if it is expressed when heterozygous
2. An affected individual has a 50% chance of having an affected child. 3. An affected child will have one affected parent
4. The affected parent can be either the mother or the father
5. Autosomal dominant traits have low frequencies in the population 6. Autosomal dominant traits are usually lethal when homozygous
7. No skipping of generations
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Autosomal Dominance
Example: Waardenburg Syndrome
Hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes.
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• Hemizygous: Having half the number
of alleles
• Expressivity: The severity or intensity
of the phenotype of an allele.
• Penetrance: The degree to which a
gene expresses any observable
phenotype
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Pitfalls in Recognizing AD
Inheritance Incomplete Penetrance. Some people who have the
gene mutation do not show the clinical effects.
Penetrance Limited to one gender. For example,
when prostate cancer risk is inherited in an autosomal
dominant manner, women who inherit the mutation are
not affected; they can, however, pass the mutation on to
their sons
Variable Expressivity. The gene mutation has variable
clinical manifestations: the disorder may range from mild
to severe; or a range of different complications may
occur among people with the mutation.
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Pitfalls in Recognizing AD
Inheritance
New Mutation. An affected person may
be the first person in the family with the
condition, due to a mutation arising for
the first time in sperm, egg, or embryo
Germline Mosaicism. A new mutation
may arise in testis or ovary, resulting in
an unaffected parent transmitting the
condition to two or more children
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AD Disorders
Marfan’s Syndrome
Huntington’s Chorea
Osteogenesis imperfecta
Neurofibromatosis
Retinoblastoma
Tuberous sclerosis
Apert’s Syndrome
Multiple polyposis of colon
Achonroplacia
Brachydactylyl
Ehlers-Dalton Syndrome
Familial
Hypercholeserolemia
Porphyria
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GENETIC TRAITS IN HUMANS CAN BE TRACKED
THROUGH FAMILY PEDIGREES
• Recessive traits are often
more common in the
population than dominant
ones.
• E.g. absence of freckles
more common than
presence.
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Polydactyly
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Polydactaly
Autosomal Dominant Inheritance
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Apparent sporadic cases
Possible explanations
• Variable expressivity
• New mutation
• Non-penetrance
• Gonadal mosaicism
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Autosomal Recessive
Carrier parents are
Heterozygotes carry the
recessive allele but exhibit
the wild type phenotype.
Normal parental phenotype
75% chance for normal
offspring
25% chance for affected
offspring
Males & females equally
affected
“Inborn errors of
metabolism”
Associated with specific
ethnic groups
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Autosomal Recessive
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Heterozygote Advantage in Recessive Conditions
Condition Carriers protected against
1. Thalassaemia falciparum malaria
2. Sickle cell falciparum malaria
3. (G-6-PD deficiency
falciparum malaria)
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Examples of AR conditions
• Beta thalassemia
• Sickle cell anemia
• Congenital adrenal hyperplasia
• Familial Mediterranean fever
• Cystic fibrosis
• Phenylketonuria
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Factors that may complicate
Inheritance Patterns
• Codominance
• Epistasis
• New mutation
• Germline Mosaicism
• Delayed age of onset
• Reduced penetrance
• Variable expression
• Pleiotropy and Heterogeneity
• Genomic Imprinting
• Anticipation
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Pitfalls in Providing Genetic
Counseling for AR Inheritance
• Misassigned paternity. If the biologic father of an affected individual is someone other than the person assumed
to be the father, misleading carrier test results might occur (the
apparent father would usually not be a carrier) and risk of
additional affected children could be misstated.
• Uniparental disomy. If a couple in which only one partner is a
carrier has an affected child, it may rarely be due to uniparental
disomy: in this case both gene mutations are inherited from the
parent who is a carrier, due to an error in the formation of sperm
or ovum.
• De novo mutations. Although also rare, de novo mutations can
account for ~1% of gene mutations in some disorders and thus
provide another explanation for the birth of an affected child
when only one parent is a carrier.
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ceramide
fucose
N-acetylglucosamine (GlcNAc)
galactose
A-transferase
N-acetylgalactosamine (GalNAc) transferase
galactose
B-transferase
Galactose transferase
A
B H (type O)
BLOOD GROUPS
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Co-domiance
• Has three alleles: A, B & O • AB co-dominant, O recessive • Genotype represented using
IA, IB & i
Phenotype Genotype
Type A IAIA or IAi
Type B IBIB or IBi
Type AB IAIB
Type O ii
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Epistasis
• hh genotype = no H protein.
All ABO genotypes appear as type O.
when one gene affects the expression of a second gene.
H gene is epistatic to the ABO gene.
• H protein attaches the A or B protein to the cell surface.
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Pleiotropy
• The appearance of several apparently unrelated phenotypic effects caused by a single gene
• Refers to a Mendelian disorder with several symptoms
• Different subset of symptoms in different individuals.
• Usually means that a genes is involved in multiple processes
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PLEIOTROPY
• MARFAN SYNDROME: AD. Affects
EYE, Skeleton and Cardiovascular
• CF. AR, Sweat glands, Lungs and
Pancrease
• OI: , Bones, Teeth, and Sclera
• Albinism, Pigmentation and Optic Fiber
development
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Genetic heterogeneity
Individuals with identical phenotypes may reflect
different genetic causes.
• Deafness
• Albinism
• Cleft palate
• Poor blood clotting
Different genes can produce identical phenotypes.
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HETEROGENEITY A disease that can be caused by mutations at a different loci in
different families.
Disease Description Chromosomes on which
known loci is located
• Retinitis pigmentosa Progressive retinopathy and > 20 chromosome regions
loss of vision identified
• Osteogenesis imperfecta Brittle bone disease 7, 17
• Charcot-Maric-Tooth diseas Peripheral neuropathy 1, 5, 8, 11, 17, X
•
• Familial Alzheimer disease Progressive dementia 1, 14, 19, 21
• Familial melanoma Autosomal dominant melanoma 1, 9
(skin cancer)
• Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p, 2q, 3, 7
colorectal cancer
• Autosomal dominant breast Predisposition to early-onset breast and 13,17
cancer ovarian cancer (chromosome 17 form)
• Tuberous sclerosis Seizures, facial angiofibromas, hypopig- 9,16
mented macules, mental retardation
• Adult polycystic kidney Accumulation of renal cysts leading to 4,16
disease kidney failure
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VARIABLE EXPRESSION Penetrance is complete, but severity of the
disease is variable, • Environmental effects,
• Modifier genes, Different expression in different families
• Allelic heterogeneity- Beta-Thal, Sickle Cell
• Osteogenesis imperfecta, Mutations at COOH terminal more sever than NH2 terminal,
Accidental fracture Complecations,
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DELAYED AGE OF ONSET
Observed in many genetic diseases. It
complicate the interpretation of
inheritance patterns in the families.
Huntington Disease – AD
Hemochromatosis – AR FATAL
Familial Alzheimer Disease
Familial Breast Cancer
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REDUCED PENETRANCE
Diseases genes in which an
individual may have the disease
genotype without expressing of the
disease.
Phenotype
• Retinoplastoma. Autosomal Dominant
• 10% of gene carriers do not show the
disease = OBLIGATE CARRIERS:
Penetrance = 90%
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Anticipation
Myotonic dystrophy
Number of CTG repeats
phenotype
5 normal
19 - 30 premutant
50 - 100 mildly affected
2,000 or more severely affected
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GERMLINE MOSAICISM
Occurs when all or part of a Parent’s
germ line is affected by a disease
mutation but the somatic cells are not. It
elevates the recurrence risk for future
offspring of the mosaic parent
Osteogenesis Imperfecta
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NEW MUTATION
• New mutations are frequent cause of the
appearance of a genetic disease in an
individual with no previous family history of
the disorder. The recurrence risk for the
individual’s sibling is very low, but it may be
substantially elevated for the individual’s
offspring
• Achnondroplasia = 7/8 are new mutations,
• 1/8 inherited