Delta Med - Genetics

Question 1

What proportion of the genome is transcribed and what portion codes for proteins?

Answer 1

60-70% of the genome is transcribed, but only 2% codes for proteins.

Question 2

What is the distribution of genes across the genome?

Answer 2

17, 19, 22 are gene dense chromosomes

4, 8 , 13, 18 and Y are gene poor

Question 3

What is the basic structure of a gene?

Answer 3

5’ - promotor region - transcription initiation - ATG (start codon) - Exon 1 Intron 1 etc - STOP codon - transcription termination - 3’

Question 4

What effect does splicing have upon protein expression?

Answer 4

Alternative splicing of mRNA can lead to different proteins from a single gene

Question 5

What are stages in gene expression?

Answer 5

DNA - RNA = transcription
mRNA - peptide = Translation
also post-trascriptional processing and post translational processing

Question 6

What are types of DNA changes?

Answer 6

Deletion - single to millions of base pairs
Frame shift mutation - DNA change than affects normal triplet reading frame of the DNA code (deletion or insertion)
Point mutation - single base change
Silent mutation - DNA sequence change that doesn’t change the protein product
Missense mutation - single base change resulting in a single AA change
Nonsense mutation - type of point mutation - single base change that change codon to a stop codon
Truncating mutation - causes premature stop codon and shortened protein product (may not be detectable) - usually either non-sense or frameshift mutation

Question 7

What is the cause of degeneracy in the genetic code?

Answer 7

Change of the 3rd nucleotide of a codon is less likely to alter the amino acid produced that if a 1st or 2nd is substituted.

Question 8

What are features or RNA vs DNA?

Answer 8

RNA vs DNA

• usually short and single stranded
• thymine replaced by uracil
• deoxyribose replaced by ribose

tRNA, rRNA involved in translation
small nuclear RNAs involved in splicing
small nucleolar RNAs (snoRNA) involved in modification of mRNA

Question 9

What are features of non-coding RNA?

Answer 9

previously thought that leftover non-coding RNA was junk
now recognised as a key regulator
genomes of simple organisms dominated by coding sequences
increased amount of non-coding sequences in more complex organisms

Question 10

What are characteristics of single gene conditions?

Answer 10

Most are uncommon!
Hereditary haemochromatosis (1/300)
Familial hypercholesterolaemia (1/500)
BRCA1/2 (1/1000)
A1AT (1/1700)
NHPCC (1/2000)
CF (1/3000)
Neurofibromatosis (1/3000)

Question 11

What are main features of Autosomal dominant inheritance?

Answer 11

1. no difference in males or females
2. 50/50 chance that a child will inherit the gene from a parent with it
3. may be incomplete penetrance or variable expressivity
4. a single affected person in a family may have a de-novo AD mutation in a gene

Question 12

What are features of Neurofibromatosis type 1?

Answer 12

100% penetrance by age 6
neurofibromas
cafe au lait spots
leish nodules
(hamartomas on slit lamp examination)

Question 13

What are features of marfan’s syndrome?

Answer 13

Autosomal dominant
FBN1 mutation
minority have TGFBRI mutation

Question 14

What are possible causes of disease in dominant gene mutations?

Answer 14

Haploinsufficiency (1/2 dose protein)
Dominant negative (abnormal protein)
Gain of function (protein product with increased activity or toxic effect)

Question 15

What are features of autosomal recessive conditions?

Answer 15

No gender difference
BOTH parents must carry gene mutations for children to be at risk
1/4 chance of inheriting condition if both parents carriers.
Usually only one sibship in a family is at risk (except consanguinous or high gene frequencies in general population)

Question 16

What are examples of autosomal recessive disorders?

Answer 16

Deafness
Albinism
Wilson's disease
Sickle cell disease
Thalassaemia
Cystic fibrosis
Homocysteinuria
Friedriech ataxia
Phenylketonuria
Haemochromatosis
Alpha-1-AT deficiency

Question 17

What are features of AD vs AR disorders?

Answer 17

AR disorders are often more severe than AD:
e.g. PCKD
Dominant - adulthood onset, slowly progressive, renal failure in later adult life
Recessive - onset in utero, oligohydramnios, death at birth from pulmonary insufficiency or later from renal failure

Question 18

What are features of x-linked inheritance?

Answer 18

x-linked recessive - female carriers show no phenotype (heteroxygous)
x-linked dominant - female carriers show a milder phenotype than males
affected males linked by unaffected or mildly affected females
no male to male transmission

Question 19

What are examples of x-linked recessive disorders?

Answer 19

Haemophilia A
G6PD deficiency
Fabry disease
Ocular albinism
Testicular feminisation
Chronic granulomatous disease
Fragile X syndrome
Colour blindness
Duchenne and becker muscular dystrophy

Question 20

What are examples of x-linked dominant disorders?

Answer 20

Vitamin D resistant rickets
Rett syndrome
Incontinentia pigmenti

Question 21

What accounts for more than 50% of miscarriages?

Answer 21

aneuploidy.

trisomy and monosomy lead to genes in either 150% or 50% of normal amounts

Trisomies 13, 18 and 21 are most common in live births

Question 22

What are sex chromosome aneuploidy?

Answer 22

47,XXY - klinefelter syndrome
47,XYY
45,X Turner syndrome
47,XXX

Tend to have less severe phenotypes due to most genes on X being subject to X inactivation
Few important genes on Y

Question 23

What are features of Klinefelter syndrome?

Answer 23

47,XXY
Tall stature
Slightly feminised physique
Loss of chest hair
female type pubic hair pattern
Frontal baldness absent
Poor beard growth
Breast development
Osteoporosis
Infertility
mild low IQ

Question 24

What are features of turner syndrome?

Answer 24

Short stature
ovarian dysgenesis
infertility
heart and renal defects
normal intellect

Question 25

What are features of Cri du chat syndrome?

Answer 25

5p- syndrome - loss of part of a chromosome. ``` Leads to high pitched cry feeding problems low birth weight cognitive speech and motor delays abnormal face skin tags in front of eyes ```

Question 26

What are features of reciprocal translocations?

Answer 26

1/600 newborns de novo or inherited Balanced translocations - no loss of genetic material Somatic mutations also common - e.g. philadelphia chromosome

Question 27

What are robertsonian translocations?

Answer 27

common in 1:1000 involves 2 acrocentric chromosomes 13, 14, 15, 21, 22 only 45 chromosomes present in karyotype - hybrid chromosome

Question 28

What are features of microdeletion syndromes?

Answer 28

caused by deletion of small sections of chromosome, too small to be detected by std cytogenetics effects due to monosomy of several contiguous genes usually detected by FISH

Question 29

What is the mechanism of imprinting?

Answer 29

parental specific methylation of CpG rich domains and biochemical modification of histone proteins, reset during gametogenesis

Question 30

What are 8 currently recognised imprinting syndromes?

Answer 30

``` Prader-Willi syndrome 11q11-13 Angelman syndrome 11q11-13 Transient neonatal diabetes 6q24 Beckwith-Wiedemann syndrome 11p15.5 Russell silver syndrome 11p15.5, matUPD7 mat UPD14 14q32 patUPD14 14q32 pseudohypoparathyroidism 20q13 ```

Question 31

What is uniparental disomy?

Answer 31

when both copies of a chromosome pair are derived from the same parent. One cause of abnormal imprinting patterns. Typically result of trisomy rescue in early embryonic life

Question 32

What is the cause of prader-willi syndrome?

Answer 32

inheritence of Deletion on paternal gene on chromosome 15 - leading to lack of paternally functioning genes. voracious appetite, obesity, poor muscle tone and feeding as child. 70% due to paternally derived deletion of 15q12 25% mat UPD15

Question 33

What is the cause of angelman syndrome?

Answer 33

inheritence of deletion of maternal 15 epilepsy, tremors and smiling expression 70% are due to maternally derived deletion of 15q12. 5-10% UBE3A mutation 5% pat UPD15

Question 34

What are 4 examples of trinucleotide repeat diseases?

Answer 34

Fragile X syndrome - CGG Friedreich ataxia - GAA Huntington disease - CAG Myotonic dystrophy - CTG

Question 35

What are features of myotonic dystrophy?

Answer 35

Muscle weakness, cataracts, myotonia, infertilisty Progressive CTG repeat 50 = disease, 50-100 - generally mild congenital form often >1000 Congenital form almost always maternally inherited worse with succeeding generations.

Question 36

What are features of fragile X syndrome?

Answer 36

CGG repeat 200 = full mutation - males have intellectual diability, but intellect is variably affected in males premutation - females are shy, 20% premature ovarian failure, males - ataxia, tremor, FAXTAS

Question 37

What are features of huntington disease?

Answer 37

Progressive neurodegenerative condition 1:10,000 AD CAG repeat - polyglutamine intergenerational instability - >29 repeats undable much greater for male than female transmission Protin = huntingtin likely that expansion confers a toxic gain in function mean onset 40y invariably fatal no treatment 15 years from onset to death chorea, cognitive impairment, psychiatric symptoms (depression, personality changes) reduced penetrance from 36-39, HD from 40

Question 38

What are features of mitochondrial inheritance?

Answer 38

affected mothers pass on mutation to all children (varying mutant loads) males cannot pass on the disorder variable expressivity E.g. Lebers Hereditary Optic Neuropathy

Question 39

What are features of mitochondrial DNA?

Answer 39

Maternal inheritance Multiple copies (2-10 per mitochondrion) High mutation rate heteroplasmy mtDNA bottleneck (small subset of genomes selected to populate oocyte - leading to rapid shifts in heteroplasmy) thershold effect - minimum critical number of mutant mtDNAs needed for each tissue to become dysfunction

Question 40

What are classical mitochondrial diseases?

Answer 40

MELAS - mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes MERRF - myoclonic epilepsy with ragged red fibres Leber hereditary optic neuropathy External ophthalmoplegia - kearns sayre syndrome, chronic external ophthalmoplegia NARP - neurogenic weakness ataxia with retinitis pigmentosa