Recessive Inheritance

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Recessive Inheritance

• Diane Stirling
• Department of Clinical Genetics
• Edinburgh

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Recessive Inheritance
Carriers have ONE abnormal copy of the gene pair
Affected individuals have TWO abnormal copies of
the gene pair
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Carrier

• Healthy person who possesses one copy of a mutant
  gene for an inherited disorder
• Term is restricted to people at risk of
  transmitting Mendelian disorders
• Can be used in autosomal dominant, autosomal
  recessive and X linked recessive disorders
• Does not apply to parents whose children have a
  chromosomal or congenital malformations e.g.
  neural tube defect

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Autosomal Recessive Inheritance

• one or more affected children
• with unaffected parents
• usually only one generation affected
• males and females affected with
• equal frequency and severity
• a higher incidence of consanguinity

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Autosomal Recessive Inheritance
1
1
Risk of being a carrier
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Autosomal Recessive Inheritance
1/2
1/2
1
1
Risk of being a carrier
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Autosomal Recessive Inheritance
1/2
1/2
1
1
1/2
Risk of being a carrier
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Autosomal Recessive Inheritance
1/2
1/2
1/4
1
1
1/2
Risk of being a carrier
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Autosomal Recessive Inheritance
1/2
1/2
1/4
1
1
1/2
Risk of being a carrier
2/3

• Not ½ as homozygous affected
• state can be excluded

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Autosomal Recessive Inheritance
1/2
1/2
1/4
1
1
1/2
Risk of being a carrier
Population risk
2/3
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Autosomal Recessive Inheritance
1/2
1/2
1/4
1
1
1/2
Risk of being a carrier
Population risk
2/3
1 1 1
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Obligate carriers
In families with an autosomal recessive condition
some individuals will be OBLIGATE CARRIERS
because of the way the condition is
inherited OBLIGATE CARRIERS are identified by
drawing the family pedigree
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Obligate carriers
In families with an autosomal recessive condition
some individuals will be OBLIGATE CARRIERS
because of the way the condition is
inherited OBLIGATE CARRIERS are identified by
drawing the family pedigree
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Calculating risk of having child with disorder
(no family history)

• Example - Cystic Fibrosis
• population carrier frequency is 1/22
• recessive condition
• therefore chance of an affected child is
• 
  

1/22 1/22
1/22 X 1/22 X 1/4 1/1936
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Calculating risk with a family history
Risk of being a carrier
2/3 1/20
Risk of an affected child
2/3 x 1/20 x ¼ 1/120
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Calculating risk with a family history
The rarer the AR disorder the lower the risk of
an affected child
Risk of being a carrier
2/3 1/60
Risk of an affected child
2/3 x 1/60 x ¼ 1/360
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Consanguinity-mating between individuals who
share at least one common ancestor

• Marriage between first cousins
• 3-5 increased risk of severe abnormality and
  mortality in offspring compared with that in the
  general population
• Marriage between 1st and 2nd degree relatives is
  almost universally illegal
• Marriage between Uncles and Nieces occur in some
  Asian countries
• Closer the degree of relationship the higher the
  risk to offspring
• Only ½ the children born to incestuous
  relationships are normal
• (Kingston 1994)

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Calculating risk - Consanguinity
Risk of being a carrier
1/2
1/2
Risk of an affected child
½ x ½ x ¼ 1/16
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Heterogeneitysimilar phenotype from different
genotypes
AA AA
AA BB
AA AA AA
AB AB AB
All children affected
All children unaffected
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Screening in Autosomal Recessive Conditions

• Aims
• Identify affected individuals
• Identify couple at risk of having an affected
  child

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Requirements of Screening Programmes

• Sensitive enough to avoid false negatives
• Specific enough to avoid false positives
• Safe, simple and inexpensive
• Needs to confer benefits to the individual as
  well as to society to avoid stigmatisation

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Types of Screening Programmes

• Population Screening
• Whole populations or
• At Risk Populations (for example)
• Taysachs
• common in Ashkenazi Jews
• significant reduction in birth prevalence
• Couple Screening
• Antenatal testing in Cystic Fibrosis
• Cascade Screening
• Families with a known AR disorder

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Population Screening

• Need to know
• The incidence of the disorder
• The prospect of altering prognosis
• Example
• National neonatal programme e.g. Phenylketonuria
• Guthrie test
• 1 in 10 000
• Early detection and treatment avoids the
  development of mental retardation

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Cascade Screening

• Advantages
• High pick up rate
• Fewer tests needed to identify one carrier
  compared to population testing
• Disadvantages
• Unlikely to pick up most couples at 1 in 4 risk
  since most couples will not have a family history

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Couple Screening in Cystic Fibrosis

• Advantages
• High uptake for testing
• Identifies couples at 1 in 4 risk
• Disadvantages
• Possible lack of informed consent
• Need appropriate information and counselling
  available
• Need to be aware of the implications of a
  positive test

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Homozygotes / Heterozygotes

• Heterozygotes
• Individuals with 2 different alleles at a
  particular locus
• Homozygotes
• Individuals with identical alleles at a
  particular locus

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Homozygous

• Affected individuals are referred to as
  homozygous if they carry the same mutation in
  both copies of the same gene
• Example
• Cystic Fibrosis Homozygous for F508

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Heterozygous

• Carriers are referred to as heterozygous
• Example
• Cystic Fibrosis Heterozygous for 508
• However affected individuals can also be
  heterozygous if they possess two different
  mutations within the same gene
• Example
• Cystic Fibrosis Heterozygous for F508 and
  R117H

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Cystic Fibrosis -most common single gene
disorder in Caucasians

• Birth prevalence in UK 1 in 2400
• Carrier frequency 1 in 22
• Characterised by progressive respiratory and
  gastrointestinal problems
• Associated with impaired fertility
• Diagnostic test - sweat test
• Treatment delays disease progression
• Physio, antibiotics and enzyme supplements
• survival rates predicted to exceed 40 years

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Cystic Fibrosis

• CFTR gene identified in 1989
• chromosome 7q31
• gt800 different mutations identified to date
• not all found to be disease causing
• delta F508 first CFTR mutation described and it
  is by far the most common mutation world-wide
• Specific mutations vary in frequency among
  carriers in different ethnic groups
• delta F508 in Northern European
• W1282 in Ashkenazi Jews

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Cystic Fibrosis

• Severity of phenotype may be related to the
  presence of mild or severe mutations either in
  the homozygous state or in combination with each
  other

Mild Mutations R117H R347H R334H A455E
Severe Mutations delta F508 W1282X G542X N1303K
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Screening for Cystic Fibrosis

• Direct Gene Test
• Carrier rate detection depends on which CF
  mutation system is used
• CF4 - detects 81.20 (Antenatal)
• CF9 - detects 83.55
• CF20 - detects 86.05

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Direct Gene Test
Heterozygous delta F508
Heterozygous delta F508
Prenatal testing available as both causative
mutations are identified
?
Homozygous delta F508
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Linkage Analysis
Heterozygous delta F508
?
Prenatal testing not available by direct gene
testing as both causative mutations cannot be
identified
?
Heterozygous delta F508/ ?
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Cystic Fibrosis -Linkage Analysis

• Used when the causative mutations cannot be
  identified in an affected individual or obligate
  carrier
• Polymorphic markers ( occurring as more than one
  normal variant )
• Allows the discrimination between the two copies
  of the chromosomal region within which it lies
• Needs DNA from both affected and unaffected
  individuals in the pedigree

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Linkage Analysis
Heterozygous delta F508
?
Heterozygous delta F508/ ?
?
Affected
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Linkage Analysis
Affected
?
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Linkage Analysis
Affected Normal
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Linkage Analysis
Affected Normal
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Linkage Analysis
Affected Normal Carrier
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Linkage Analysis
Affected Normal Carrier
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Linkage Analysis
Affected Normal Carrier Carrier

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Linkage Analysis
Affected Normal Carrier Carrier

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Linkage Analysis
Affected Normal Carrier Carrier
Affected
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Sickle Cell Disease

• Variable disease severity
• chronic haemolytic anaemia
• recurrent infarction episodes
• susceptibility to infection
• cerebrovascular accidents
• Associated with African-Caribbean population
• Diagnosis blood film, electrophoresis, direct
  gene test

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Sickle Cell Trait - Carriers

• Can be diagnosis on blood film - sickling
• asymptomatic
• protection against malaria

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Sickle Cell Trait - US

• Early 70s
• mandatory screening for SCT in all people who
  were not of Caucasian, Indian or Oriental race
• in some states carrier status was mandatory for
  issuing of marriage licence/ condition of entry
  to school
• Presence of SCT could lead to - loss of
  employment, increased insurance
  premiums,revelation of non paternity, delays in
  adoption, ban from flying

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Sickle Cell Trait - Greek Village

• Vigorous education program
• Whole village screened
• Purpose was to reduce number of affected births
• Outcome
• Carriers were rejected by non-carriers
• Carriers married carriers and continued to have
  children

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Summary

• one or more affected children with unaffected
  parent
• usually only one generation affected
• males and females affected with equal frequency
  and severity
• a higher incidence of consanguinity
• 1 in 4 risk of an affected child
• 1 in 2 risk of a carrier child

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