Transcript Pattern of Inheritance2 - KSU Faculty Member websites

Objectives
Pattern of inheritance
Chromosomal Abnormalities
Polygenic or multifactorial inheritance
DNA analysis
Pre-symptomatic testing
Gene therapy
Genetic counselling
ABC of Genetics
Dr.AbdulRahman Alnemri, MD
PATTERN OF INHERITANCE
Genetic vs Familial Disorders:
A genetic disorder Mendelian inheritance
Altered genetic material could be sporadic/familial
A familial disorder
Either genetic / enviromental more common in
relatives of an affected individual.
PATTERN OF INHERITANCE
The Pedigree
The diagram of a family history
3 generation
Propand
PATTERN OF SINGEL GENE INHERITANCE
 Single mutant gene
 Genotype / phenotype
 Homozygous / Heterozygous
 Compound
 Mutation
 Recessive / Dominant
 Autosomal / X-linked
PATTERN OF AUTOSOMAL DOMINAT INHERITANCE
 > ½ of known mendelian phenotype.
 The incidence of some autosomal dominant disorder is
quite high at least in specific geographic area.
 An individual carries the abnormal gene in hetrozygous
state on one of a pair autosomes (1 -22 chromosomes)
 Male and female offspring have 50% chance of inheriting
the abnormal gene from affected parent
 Variable expressivity
 Reduced Penterance non-penetrance (asymptomatic) eg
Otosclerosis 40% of gene carriers have deffness
 Low – grade mosaicism, germ-line mosaicism. No family
history eg. Achondroplasia 80% have normal parents
HOMOZYGOTES FOR AD TRAITS
 Rare situation where both parents are affected
 much severe than heterozygous e.g. Achondroplasia and familial
hypercholesteremia, exception is Huntington disease.
 What is the risk for the child to be homozygous?
 A- 50% B- 25% C.100% D. Non risk
NEW MUTATIO IN AD TRAITS
Depend on fitness
Sever disorder – reduce reproductive capacity
ƒ  new mutation
CRITERIA FOR AUTOSOMAL DOMINANT INHERITANCE
1.
The pheotype appears in every generation “Vertical Pattern”,
exception:
o
o
fresh mutation
non-penrterant disease
2.
Any child of an affected parent has a 50% risk of inheriting
the traits, each pregnancy is “independent event”
3.
Phenotypically normal family member do not transmit the
phenotype to their children.
4.
Male and Female are equally likely to transmit the phenotype
to children of either sex.
5.
A significant proportion of cases are due to new mutations.
PATTERN OF AUTOSOMAL RECESSIVE INHERITANCE
 Less common than autosomal dominant conditions.
 Expressed only in homozygotes.
 Affected offspring inherited an abnormal alele from
each parent, both are unaffected hetrozygous carrier
 The risk of each child male or female being affected
is 1 in 4 (25%)
CONSANGUINITY IN AUTOSOMAL RECESSIVE INHERITANCE
 Baseline risk figures for any abnormality are up to
3% for any child for any parents and = 4.5 – 5% for
the offspring of the first cousins.
 Risk of recurrences is 25%
CRITERIA FOR AUTOSOMAL RECESSIVE INHERITANCE
1.
Seen only in the sibship of the proband
“Horizontal Pattern”
2. Recurrence risk for siblings of an affected
child is 25%
3. Males and Females are equally affected.
4. Parents of an affected child are
a symptomatic carriers of the genes.
MPS1
True or False
Autosomal recessive disorders often affect
metabolic pathways
Autosomal dominant disorders usually
affect structural proteins
X – LINKED recessive INHERITANCE
 More than 250 disorders have been described
 X – inactivation (Lyon Hypothesis)
 Males are hemizygous affected
 Female can be carrier, occasionally shows mild sings of the
disease
 Risk for sun % ?
 Daughters of affected males will all be carriers
 Sun of affected father ?
X – LINKED INHERITANCE
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The incidence of the trait is much higher in males than
in females.
The gene is transferred from an affected man to all of
his daughters. Any of his daughter’s sons has a 50%
chance of inheriting the gene.
The gene may be transmitted through a series of
carrier females.
The gene is never transmitted from father to son.
Heterozygous female are usually unaffected
Sporadic cases are ? Consequence of new gene
mutations.
FEMALES AFFECTED WITH X-LINKED RECESSIVE CONDITIONS
If both parents carry an x-linked recessive allele
“consanguineous”
Turnur Syndrome – hemizygous for X
chromosome genes.
Skewed X inactivation pattern.
HEMOPHILIA
PATTERN OF X-LINKED DOMINANT INHERITANCE
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Affected males with normal mates have no affected
sons and no normal daughters.
Both males and females offspring of carrier have a
50% risk of inheriting the phenotype.
For rare phenotype, affected females are about
twice as common as affected males.
E.g. Vitamin D- resistant rickets
MULTIFACTIONAL INHERITANCE
 Normal traits (e.g. Ht, IQ) and developmental
disorders and many common disorders of adult life.
 Liability genes [has a normal distribution curve] AND
Environmental factors.
CHARACTERISTICS INCLUDES
1.
Although the disorder is obviously familial there is
no distinctive pattern of inheritance within a single
family.
2.
The recurrence risk is higher when more than one
family member is affected.
3.
The more sever the malformation, the greater the
recurrence risk.
CHARACTERISTICS INCLUDES (Cont.)
4.
There is a similar rate of recurrence (typically 3 – 5%) among all
first degree relatives, And risk is much higher for first degree
relatives compared to second degree relatives and so on.
5.
If a multifactorial trait is more frequent in one sex than in the
other, the risk is higher for relatives of patient of the less
susceptible sex .
6.
The risk of recurrence is related to the incidence of the disease.
7.
Increased recurrence risk when the parents are consanguineous.
8.
The frequency of concordance for identical twins ranges from
21% - 63%.
INCIDENCE IN SIBS
Unilateral CL, no CP
Unilateral CLP
Bilateral CL, no CP
Bilateral CLP
4
4.9%
6.7%
8.0%
NON-TRADITIONAL PATTERN OF INHERITANCE
Mitochondrial Inheritance:
 MDNA encodes 13 proteins in respiratory chain of
the organelle.
 Mitochondrial DNA mutations (deletion), always
shown maternal transmission though Paternal
Inheritance may occur!
 High mutation rate.
 Heteroplasmy  variable expression.
Sex–limited AND Sex ---influenced traits
 Sex- Limited  due to anatomic difference e.g.
uterine or testicular defects.
 Sex- Influence  more in one sex.
Y – LINKED INHERITANCE
IMPRINTING
 Genomic Imprinting – phenotype expression depends on
the parents of origin for certain genes. And
chromosomes segments are inactivated (imprinted)
during gamete formation and remain so in the resulting
zygote.
 Parader – willi syndrome and Angleman syndrome.
UNIPARENTAL DISOMY (UPD)
 Inheriting both homologous chromosomes from
a single parent.
 Three types of phenotypic effects are seen.
1)
Imprinted Genes
2)
Autosomal Recessive
3)
Mosaicism
CHROMOSOMEAL DISORDERS
 Estimated in 0.7% of live
births
 In ≈ 2% of all pregnancies in
woman over 35yrs. of age.
 And In 50% of all spontaneous
first trimester abortion.
 Numerical / Structural.
CLINICAL INDICATION FOR CHROMOSOMAL ANALYSIS
1)
Problems of early growth and development, FTT
developmental delay, dysmorphic features, short
stature,
ambiguous
genetilia
retardation.
2)
Recurrent abortions
3)
Fertility problems
4)
Family history of translocations.
and
mental
APPROACH TO THE DYSMORPHIC CHILD
Gathering information:
1.
2.
3.
4.
5.
Constructing the pedigree and analysis of the
pedigree.
Reviewing Past records and Prenatal history.
Clinical assessment
a. Visual assessment
b. Measurement
c. Extended Family
Counselling
Follow-up
APPROCH TO THE DYSMORPHIC CHILD
Counselling:
1. Counsel the parents together
2. Remove distractions
3. Be prepared to repeat
4. Use visual aids
5. Ascertain what the family needs
APPROACH TO THE DYSMORPHIC CHILD
Follow – up:
Lack of diagnosis
Counselling other family members
New diagnostic technique
Natural history