Gene disorder (autosomal, chromosomal, X-linked, mitochondrial) + Genetic Testing

Question 1

What is the definition of a mutation?

Answer 1

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

Question 2

What is polymorphism?

Answer 2

Natural variations in genomic DNA sequence that usually have no obvious adverse affects.

Question 3

How can mutations be expressed?

Answer 3

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

Question 4

What are single gene disorders?

Answer 4

mutations in one gene, can be autosomal, X-linked or Y-linked

Question 5

Autosomal dominant

Answer 5

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

Question 6

Autosomal recessive

Answer 6

Disease mainfests when both alleles affected
Carriers are heterozygous for that gene
affected usually born to unaffected
If both carriers, 25% of affected

Question 7

X-linked recessive

Answer 7

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

Question 8

X-linked dominant

Answer 8

Affects either sex

Female heterozygotes more mildy affected than male due to lyonisation

Question 9

What are some examples of autosomal dominant inheritance?

Answer 9

Huntingtons, Achondroplasia and Marfans

NB most proteins are non enzymatic

Question 10

What is achondroplasia?

Answer 10

Dwarfism, limb shortening
there is altered cartilage ossification
mutation in FGFR3 gene
80% have de novo mutation in germ cells

Question 11

What is marfans?

Answer 11

Mutation of fibrilin 1
Dom neg affect
allelic heterogeneity
variable expressivity

Question 12

What is phenylketonuria?

Answer 12

AR inheritnace
mutation in phenylalanine hydroxylase gene
no conversion to tyrosine
increased phenylalanine in blood, leading to mental convulsions, mental retardation

Question 13

Haemochromatosis

Answer 13

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

Question 14

How would you get a karyotype?

Answer 14

Biopsy cells that are dividing eg bone marrow or amniotic cells. Can analyse chromosomes for stuctural or numerical disorders

Question 15

What is aneuploidy?

Answer 15

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)

Question 16

What is mosacism?

Answer 16

Can be structural or numerical, but is post zygotic. Eg post zygotic mitotic non disjunction

Question 17

What is a reciprocal translocation?

Answer 17

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.

Question 18

What are inversions?

Answer 18

An intra chromosomal structural rearrangement
invlves same chromosome
can be pericentric (middle portion inverts) or paracentric (telomeric region inverts)

Question 19

What is G banding?

Answer 19

Karyotype analysis, need to find dividing cells.

Will detect gross numerical and structural abnormalities

Question 20

What is FISH?

Answer 20

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

Question 21

What and when will pre natal screenings take place?

Answer 21

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

Question 22

What are prenatal diagnostic tests?

Answer 22

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.

Question 23

How can cells who’s DNA we have be analysed?

Answer 23

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)

Question 24

What are some features of mDNA?

Answer 24

Maternally inherited
Diseases affecting will affect respiratory chain, leading to low ATP and apoptosis
Will affect high energy demand organs eg brain, muscle