XLinked Inheritance

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X-Linked Inheritance

• Dr. Jonathan Berg

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• www.cee.hw.ac.uk/genisys/

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X Linked Inheritance
Mother
Father
X X
Y X
Little Girl
Little Boy
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X Linked Disease
Mother (Carrier)
Father
X X
X Y
Normal Female Carrier Female Affected
Male Normal Male
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X-Linked Inheritance
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X-Linked Inheritance
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X InactivationIn Female Cells only One X
chromosome is active
Female Zygote
Person
Random X inactivation
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X InactivationWhat happens in a carrier female
Female Zygote
Person
Random X innactivation
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X Inactivation

• To provide gene-dosage compensation in females
• Some genes on the pseudoautosomal region escape
  innactivation
• The XIST gene at Xq13 is essential for X
  inactivation
• Methylation is one mechanism of X inactivation

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Skewing of X inactivation

• Occurs when one X chromosome carries a
  cell-lethal mutation
• When There is a mutation in one XIST gene
• With balanced XAutosome translocations
• By Chance

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X InactivationSkewed X Inactivation
Female Zygote
Person
Random X innactivation
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Duchenne Muscular Dystrophy
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George age 3

• Mild developmental delay
• Slow to walk
• Difficulty standing
• Unable to run
• On examination
• Hypertrophy of calf muscles
• Proximal muscle weakness
• Creatine Kinase 10,000iu

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Muscle Biopsy
Normal
Henry
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Dystrophin Staining
Normal
Henry
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Henry has Duchenne Muscular Dystrophy

• Diagnosis has been confirmed on Biopsy
• No deletion or duplication detected on mutation
  testing.
• A deletion or duplication is found in
  approximately 60-70 of affected patients
• Henry is likely to have a point mutation in the
  gene

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Rose D.

• Wishes to know risk of having an affected child
• Risk of being a carrier from pedigree 25
• Can modify risk further without molecular testing

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Creatine Kinase

• Breakdown product of muscle
• Greatly elevated in affected males
• Elevated in 2/3 of female carriers
• Both Jane D and Rose D have normal CK

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Bayes Risk Calculation

• Actual Probability (Posterior Probability)
• Determined from
• Prior Probability (Pedigree Risk)
• and
• Conditional Probability (other factors)

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Risk That Jane D. is a Carrier

• Jane D Carrier
• 1/2
• 1/3
• 1/4
• 1/24
• 1

• Jane D Not Carrier
• 1/2
• 1
• 1
• 1/2
• 12

• Prior Risk
• Normal CK
• 2 Normal Sons
• Posterior Probability

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Prior Risk for Rose D.

• half of mothers carrier risk
• 1/13 X 1/2 1/26

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Risk That Rose D. is a Carrier

• Rose D Carrier
• 1/26
• 1/3
• 1/78
• 1

• Rose D Not Carrier
• 25/26
• 1
• 25/26
• 75

• Prior Risk
• Normal CK
• Posterior Probability

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Risk That Rose D will have affected Child
Risk of being a carrier X Risk of transmission

• 1/76 X 1/4 1/304

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Use of Linkage
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Linkage for DMD
X Chromosome
A
DMD
3
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Use of Linkage
7
3
1
1
7
7
3
1
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Use of LinkageFlanking Markers
A
A
D
D
B
7
7
3
1
1
D
A
B
A
1
7
3
7
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Use of LinkageFlanking Markers
A
D
B
7
3
1
A
B
A
7
3
7
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Use of LinkageUndesirable crossover
A
A
D
D
B
7
7
3
1
1
D
D
B
A
?
1
7
3
7
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Risk Analysis in X linked Pedigrees

• From pedigree structure
• Use unaffected males in Bayes Risk Calculation
• Females may show laboratory evidence of carrier
  status (because of X-Inactivation)
• Use of linkage
• Use of mutation analysis

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Charles

• Age 10
• Developmental Delay from early infancy
• Behavioural problems
• On examination
• Long face
• Prominent ears
• Slightly Coarse Features

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Charles
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Charles Family History
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Fragile X syndrome

• Males
• Developmental delay, IQ lt50
• Macrocephaly
• Facial features
• Prominent ears
• Long face
• Macro-orchidism
• Females
• Many have developmental delay

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Charles Family History
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The Fragile X geneFMR1
CGGCGGCGGCGGCG
Tyrosine Kinase Important in brain development
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The Fragile X geneFMR1
CGG lt50 repeats Normal CGG 40-200 repeats
Pre-mutation No Phenotype CGG 200 repeats
Full expansion switches gene off
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Fragile X expansion

• Occurs in female transmission only

Male with pre-mutation (40-200 repeats)
Female with pre-mutation
Female or male children with pre-mutation or full
expansion
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Female Full Expansion Carriers

• More subtle facial features
• Variable developmental delay
• 50 to 80 have IQ lt 85
• May well be unaware they are affected

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HindIII/Eag1 Digestof Fragile X Gene
EagI Site Cuts Unmethylated DNA
CGG.............CGGCGGCGG
HinDIII (Always Cuts)
HinDIII (Always Cuts)
5.2kb
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The Fragile X full expansion causes Methylation
of surrounding DNA
M
CGG.............CGGCGGCGG
M
This inactivates the FMR1 gene
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Fragile X analysis
Normal Premutation
Full Mutation
Male Female Male Female
Male
Full Expansion 5.2kb 2.6kb
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HindIII/Eag1 Digest
Grandfather
Mother
Brother
Charles
Sister
5.2kb
2.6kb
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Pre
Pre
Pre
Pre
Pre
Full
Full
Full
Pre
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Diagnosis

• Chromosome analysis (historic)
• DNA analysis - sensitive and specific
• Pre-natal diagnosis possible
• But
• Mother may be affected
• Apparently well daughter may already be
  affected
• Cannot predict severity of affected daughter

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K.A.
Pictures on WWW.rettsyndrome.org
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Rett Syndrome

• Prevalence approximately 1/10,000 to 1/20,000
• Usually only females affected
• Characteristic profile of psychomotor development
• Some skeletal and growth effects

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Progression of DiseaseAfter Hagberg and
Witt-Engerstrom

• Normal development
• Early onset deceleration onset 6-18 months
• Rapid Destructive stage onset 1-3 years
• Pseudostationary stage onset 2-10 years
• Late motor deterioration From age 10

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Diagnostic Criteria - required1988

• Normal prenatal and perinatal period
• Normal psychomotor development for first 6 months
• Deceleration of head growth
• Loss of purposeful hand skills between 6 and 30
  months
• Communication loss and social withdrawal
• Impairment of language and severe psychomotor
  retardation
• Stereotypic hand movements
• Gait apraxia and truncal ataxia from age 1 to 4

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Retts Syndrome is caused by mutations in MECP2
Me
Me
CGCGCG
CGCGCG
Me
Me
MECP2
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Rett SyndromeX-Linked Dominant

• Phenotype usually only seen in females
• Mutations in the MECP2 gene on X chromosome
• Presumed early embryonic lethal in males
• Seen in affected males with klinefelters syndrome
• Usually sporadic
• Recurrence is reported if mother is a gonadal
  mosaic