What does alteration in the genetic code cause?
Mutations
How does permanent damage in the DNA affecting germ cells come to be?
Can be inherited
What does Permanent DNA damage in Somatic cells cause?
May result in tumor or developmental abnormality
__________ is a a single base substitution.
Point mutation
_______ is an insertion or deletion of 1-2 base pairs.
Frameshift
____ is an amplification of a 3-nucleotide sequence.
Trinucleotide repeat
What other 3 factors can impact protein coding Gene function?
- Polymorphisms
- Epigenetic changes
- Alterations in Non-coding RNA’s
What are the types of Genetic disorders?
- Mendelian Disorders
- Autosomal Dominant
- Autosomal Recessive
- Sex-linked (x-linked) disorders
- Disorders with multifactorial (polygenic inheritance)
- Cytogeneic Disorders (chromosomal aberrations) (autosomes and Sex chromosomes)
Tell me about autosomal dominant disorders….
- Mutated gene on ONE of the autosomes
- Expressed in heterozygous state, one parent usually affected.
- Often present with outward physical changes, but these may have delayed age of onset (Huntingtons disease)
What is reduced or incomplete Penetrance?
An autosomal dominant occurrence where a person has a mutant gene but either doesn’t, or only partially expresses it phenotypically.
What is Variable expressivity?
If the expression can be identified in all affected persons but to differing extents.
What is New or De novo mutation?
If neither parent is affected/no family history.
_______ is an Autosomal disease with nearly 1000% penetrance yet variable expressivity.
Neurofibromatosis (Bumps all over face)
Which is the larges group of Medelian disorders?
Autosomal Recessive
Tell me about Autosomal recessive disorders…
- Affect patients are homosygous; Parents appear unaffected.
- 25% of offspring are affected; 50% of offspring are carriers
- If the Recessive gene is rare in the population, disorder may be the result of consanguinity.
Many AR conditions are _________ defects leading to ______.
Enzyme defects leading to Metabolic dysfunction.
* Heterozygous patients are unaffected clinically as they typically have reduced but still adequate levels of the normal functional enzyme.
When is age of onset with AR disorders?
Early, complete penetrance is also common
Tell me about X-linked Disorders….
- all are not the X Chromosome
- Most are recessive
- Females having two x chromosomes are usually unaffected heterosygous carriers
- Males being hemizygous, will express the disorder.
- Y chromosome only carries one significant gene SRY (sex determining region)
What is an example of x-linked disorder?
Hemophilia A
What is lyonization?
16 days post conception most of one X chromosome in the female zygote is inactivated randomly resulting in the formation of a Barr Body in each cell.
*All progeny of that cell will carry the same inactivated X chromosome
What are the Diseases caused by Mutations in Structural proteins?
- Marfan Syndrome
- Ehlers-danlos syndromes
Tell me about Marfan Syndrome….
- Autosomal dominant
- Prevalence 1 in 5000
- Mutation of FBN1 gene resulting in abnormal fibrin, a glycoprotein necessary for normal elastic fiber production.
What are the characteristics of Marfan Syndrome?
- Tall thin body
- Abnormally long legs
- Arachnodactyly
- dislocation of lens of eye
- aortic aneurysm and dissection leading to heart failure and aortic rupture.
Tell me about Ehlers-Danlos Syndromes..
- At least 6 clinical variants of disease
- Problem with collagen synthesis, among 30 distinct types of collagen.
- Variable tissue distribution of these collagens may explain clinical heterogeneity of EDS’s
What are some examples of Diseases caused by mutations in Gene Encoding Receptor proteins or Channels?
- Familial Hypercholesterolemia (LDL receptor)
- Cystic fibrosis (Chloride channel protein)
Tell me about Familial Hypercholesterolemia..
- Its one of the more common inherited disorders (autosomal dominant)
- Frequency 1 in 500
- Mutation of the gene that encodes the LDL receptor
- Results in impaired metabolism and increased LDL cholesterol in the plasma
What are manifestations of Familial Hypercholesterolemia?
- Multiple xanthomas of the skin
- Premature atherosclerosis
- Heterozygotes = 2-3x increased LDL
- Homozygotes = over 5x increased LDL
- Homozygotes often die of MI before age 20
- Lomitapide used to treat homozygous form.
What are the diseases caused by mutations in Enzyme Proteins?
Phenylketouria
Galactosemia
Lysosomal storage diseases
Tell me about Phenylketonuria….
- AR disorder
- 1:10,000 White infants
- lack of phenylalanine hydroxylase
- Leads to hyperphenylalaninemia and PKU
- Affected infants are normal at birth but increased phenylalanine levels impair brain development = mental retardation by 6 months of age. (restricting dietary sources of Phenylalanine will prevent retardation in these individuals thus screening is mandatory in US.
What are Storage diseases?
Autosomal recessive transmission that commonly affects infants and young adults = accumulations of large insoluble molecules in macrophages leads to hepatosplenomegaly.
*Frequent CNS involvement leads to neuronal damage, mental retardation and or early death.
What are the 4 lysososomal storage diseases?
- Tay-sachs disease
- Niemann-pick disease
- Gaucher disease
- Mucopolysaccharideoses
Tell me about Mucopolysaccharide storage diseases….
Most are Ar
- Due to lack of any one of several enzymes necessary to degrade mucopolysaccahrides
- affected patients often have coarse facial features, coding of cornea, joint stiffness and mental retardation.
Tell me abut Hurler Disease (MPS type 1)?
AR disease caused by deficiency of alpha-L-iduronidase.
- Life expectancy 6-10 years
- Bone marrow transplant may improve outlook but cost 300K a year.
What is Hunter Syndrome?
A chronic X-linked intolerance to sitting in lecture from late september through late november…….okay it is x-linked but is due to a deficiency in L-iduronate sulfates and is similar to Hurler disease without the corneal clouding.
What are Multifactorial disorders?
2 or more genes responsible plus environmental influences:
- BP
- Hair color
- Height and weight
What is normal chromosome count?
46
1 in _____ newborns has a chromosomal abnormality.
200 *Thought to contribute to 50% of 1st trimester spontaneous abortions.
what is a Euploid?
a normal chromosome count (46)
What is a Polyploidy?
an increased chromosome count that generally results in spontaneous abortion.
Euploid, polyploidy, monosomy, trisomy aneuploidy are both examples of ______.
Numeric Autosomal aberrations
What is monosomy?
Missing chromosome
What is Trisomy?
Extra chromosome
What is aneuploidy?
any number that is not an east multiple of the normal chromosome count.
What are some examples of Structural Autosomal Aberrations?
Translocations = transfer of a part of one chromosome to another nonhomologus chromosome. *reciprocal translocation is where fragments are exchanged between two chromosomes.
Deletion = loss of a portion of a chromosome
Inversion = chromosome breaks in two point, then released fragment is reunited after a complete turnaround.
What are cytogenetic disorders involving autosomes?
Trisomy 21 (down syndrome) = most common one. - Due to meiotic nondisjunction of chromosome 21 during ovum formation.
Mental retardation
Epicanthic folds
Flat facial profile
Cardiac malformation
Down syndrome increased risk of Leukima by ______ times.
10-20 times
What are cytogenetic disorders involving sex disorders?
Klinefelters syndrome = male hypoganthism when there are at least 2 X chromosomes and one or more Y chromosomes *Phenotypically patients are males.
Turner syndrome: partial or complete absence of one of the X chromosomes.
What are the manifestations of klinefelters syndrome?
- increased length of lower limbs; reduced body hair; gynecomastia; hypogonadism- most common cause of male sterility.
Dentally = increased frequency of taurodontism.
What are manifestations of turners syndrome?
- short stature
- webbing of neck
- “shield like” chest
- high arched palate
- failure to develop secondary sex characteristics (primary amenorrhea)
What are indications for genetic analysis?
Prenatal:
Mothers age >34yrs
Parent is carrier of a chromosomal translocation or x-linked disorder.
History of previous child with chromosomal abnormality
Postnatal:
- Multiple congenital anomalies
- unexplained mental retardation or developmental delay
- suspected aneuploidy (downs)
- infertility
- Multiple spontaneous abortions.