Gene disorder (autosomal, chromosomal, X-linked, mitochondrial) + Genetic Testing Flashcards
What is the definition of a mutation?
any permanent heritable change in the sequence of genomic DNA or any alteration of DNA from its natural state
Silent; missense; nonsense; frameshift ( insertions/deletions); splice donor
What is polymorphism?
Natural variations in genomic DNA sequence that usually have no obvious adverse affects.
How can mutations be expressed?
Gain of function mutation
Loss of function:-
-usually minimal phenotypic affect, unless both alleles
-No product or function is a null allele (can cause haploinsufficiency)
-Some heterozygous loss of function is the dominant negative effect
What are single gene disorders?
mutations in one gene, can be autosomal, X-linked or Y-linked
Autosomal dominant
Disease manifests when heterozygous (one allele is affected)
Passing on is 50 percent (heterozygote x normal)
Affected person usually one affected parent
affects either sex
Autosomal recessive
Disease mainfests when both alleles affected
Carriers are heterozygous for that gene
affected usually born to unaffected
If both carriers, 25% of affected
X-linked recessive
Are carried by females and passed on to sons
No male to male transmission
Affects mainly males
Assuming carrier female x male, 25%of affected son, 50% have the mutated gene
X-linked dominant
Affects either sex
Female heterozygotes more mildy affected than male due to lyonisation
What are some examples of autosomal dominant inheritance?
Huntingtons, Achondroplasia and Marfans
NB most proteins are non enzymatic
What is achondroplasia?
Dwarfism, limb shortening
there is altered cartilage ossification
mutation in FGFR3 gene
80% have de novo mutation in germ cells
What is marfans?
Mutation of fibrilin 1
Dom neg affect
allelic heterogeneity
variable expressivity
What is phenylketonuria?
AR inheritnace
mutation in phenylalanine hydroxylase gene
no conversion to tyrosine
increased phenylalanine in blood, leading to mental convulsions, mental retardation
Haemochromatosis
AR inheritance
Iron overload causing organ and tissue damage
late onset
Diff types eg HFE (6) , hepcidin, ferroportin or transferrin receptor.
Diagnose on iron studies plus gene tasting
Treat with vensection
How would you get a karyotype?
Biopsy cells that are dividing eg bone marrow or amniotic cells. Can analyse chromosomes for stuctural or numerical disorders
What is aneuploidy?
A different number of chromosomes caused by a meiotic non disjunction
eg is downs syndrome (trisomy 21), Klinefelters (XXY, breast development) and Turners (XO poor female development)
What is mosacism?
Can be structural or numerical, but is post zygotic. Eg post zygotic mitotic non disjunction
What is a reciprocal translocation?
a two way exchange of material between two NON homologous chromosomes. Normally no phenotype will develop as they are balanced. However during gamete segregation this can cause issues and unbalanced versions.
What are inversions?
An intra chromosomal structural rearrangement
invlves same chromosome
can be pericentric (middle portion inverts) or paracentric (telomeric region inverts)
What is G banding?
Karyotype analysis, need to find dividing cells.
Will detect gross numerical and structural abnormalities
What is FISH?
Fluorescence in situ hybridisation Fluorescent DNA markers bind to specific part of DNA. Can use dividing and non dividing cells only good for a particular chromosome eg HER-2
What and when will pre natal screenings take place?
Ultrasound- 8 weeks, no harm.
Nuchal translucency- for DS, 10-13 weeks. No harm, can be combined with a serum test. Measure fluid
Serum testing- 15-17 weeks, look for feto placental proteins. good for downs syndrome eg increased maternal age
What are prenatal diagnostic tests?
Chorionic Villus: 10-12 weeks; fetal cells from placenta; small risk of miscarriage; preferred as earlier
Amniocentesis: 15-16 weeks; fibroblasts from amniotic cells; might need to culture cells
PGD: when IVF is used, DNA removed from single cell. Can be analysed.
How can cells who’s DNA we have be analysed?
DNA analysis includes PCR based approach.
Direct mutation analysis is used when the gene and mutation is known in a family
Indirect (LINKAGE), using a polymorphic marker (SNPs) to track the abnormal gene. (eg haemophilia)
What are some features of mDNA?
Maternally inherited
Diseases affecting will affect respiratory chain, leading to low ATP and apoptosis
Will affect high energy demand organs eg brain, muscle
