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Objectives
Pattern of inheritance Chromosomal AbnormalitiesPolygenic or multifactorial inheritanceDNA analysisPre-symptomatic testingGene therapyGenetic counselling
ABC of Genetics
Dr.AbdulRahman Alnemri, MD
Genetic vs Familial Disorders:
A genetic disorder Mendelian inheritanceAltered genetic material could be sporadic/familial
A familial disorderEither genetic / enviromental more common in relatives of an affected individual.
PATTERN OF INHERITANCE
The PedigreeThe diagram of a family history
3 generation
Propand
PATTERN OF INHERITANCE
Single mutant gene
Genotype / phenotype
Homozygous / Heterozygous
Compound
Mutation
Recessive / Dominant
Autosomal / X-linked
PATTERN OF SINGEL GENE 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
PATTERN OF AUTOSOMAL DOMINAT INHERITANCE
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
HOMOZYGOTES FOR AD TRAITS
Depend on fitness
Sever disorder – reduce reproductive capacity ƒ new mutation
NEW MUTATIO IN AD TRAITS
1. The pheotype appears in every generation “Vertical Pattern”, exception:
o fresh mutation o 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.
CRITERIA FOR AUTOSOMAL DOMINANT 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%)
PATTERN OF 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%
CONSANGUINITY IN 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.
CRITERIA FOR AUTOSOMAL RECESSIVE INHERITANCE
MPS1
True or False
Autosomal recessive disorders often affect metabolic pathways
Autosomal dominant disorders usually affect structural proteins
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 recessive INHERITANCE
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.
X – LINKED INHERITANCE
If both parents carry an x-linked recessive
allele “consanguineous”
Turnur Syndrome – hemizygous for X
chromosome genes.
Skewed X inactivation pattern.
FEMALES AFFECTED WITH X-LINKED RECESSIVE CONDITIONS
HEMOPHILIA
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
PATTERN OF X-LINKED DOMINANT 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.
MULTIFACTIONAL INHERITANCE
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
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%.
CHARACTERISTICS INCLUDES (Cont.)
INCIDENCE IN SIBS
Unilateral CL, no CP 4Unilateral CLP
4.9%Bilateral CL, no CP 6.7%Bilateral CLP 8.0%
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.
NON-TRADITIONAL PATTERN OF INHERITANCE
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
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.
IMPRINTING
Inheriting both homologous chromosomes from
a single parent.
Three types of phenotypic effects are seen.
1) Imprinted Genes
2) Autosomal Recessive
3) Mosaicism
UNIPARENTAL DISOMY (UPD)
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.
CHROMOSOMEAL DISORDERS
1) Problems of early growth and development,
FTT developmental delay, dysmorphic
features, short stature, ambiguous genetilia
and mental retardation.
2) Recurrent abortions
3) Fertility problems
4) Family history of translocations.
CLINICAL INDICATION FOR CHROMOSOMAL ANALYSIS
Gathering information:
1. Constructing the pedigree and analysis of the pedigree.
2. Reviewing Past records and Prenatal history.3. Clinical assessment
a. Visual assessmentb. Measurement
c. Extended Family4. Counselling5. Follow-up
APPROACH 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
APPROCH TO THE DYSMORPHIC CHILD
Follow – up:
Lack of diagnosis
Counselling other family
members
New diagnostic technique
Natural history
APPROACH TO THE DYSMORPHIC CHILD