Unusual Genetics

Question 1

What is Genetic Imprinting?

Answer 1

-Differences in gene expression depending on whether a gene is maternally or paternally inherited
-Specific chromosomal regions contain imprinted genes
-Such regions usually contain both maternally and paternally imprinted genes
-Normal cellular process
-Leads to functional hemizygosity
=Only one pair of genes expressed
-Accounts for only a small number of genes

Question 2

What is the importance of genetic imprinting?

Answer 2

• Many developmental genes are imprinted
• Disruption of imprinting is implicated in several well known genetic disorders and many cancers (loss of biparental contribution)

Question 3

Describe Angelman Syndrome

Answer 3

• Severe global developmental
delay
• No speech
• Inappropriate laughter
• Drooling
• Seizures
• Cannot walk without help
• No family history
-Chromosome 15, 15q11-13 deletions

Question 4

Describe Prader Willi Syndrome

Answer 4

• Floppy at birth, poor feeding
• Short stature, small hands and feet
• Hyperphagia and obesity
• Hyponadism
• Mental retardation (mild to moderate)
-Chromosome 15, 15q11-13 deletions

Question 5

How does Angelman Syndrome and Prader Willi Syndrome demonstrate loss of heterozygosity?

Answer 5

-Both have 15q11-13 deletions
• Further analysis of these two patients show that
the deletion occurred on different chromosomes
• The chromosome that was deleted in Angelman
case was derived from Mother
• In the Prader-Willi case the chromosome was
derived from Father

Question 6

What are the mechanisms of loss of imprinting?

Answer 6

• Chromosome deletion of maternal/paternal chromosome (70% cases Angelman’s= maternal)
• Methylation abnormality= silencing (2% Angelman)
• Uniparental Disomy (2%)= actual maternal chromosome gone, replaced by paternal genome
• Mutation in UBE3A gene (2%)

Question 7

How can paternal uniparental disomy occur?

Answer 7

-Non-disjunction in paternal side (both chromosomes one cell)
-Mechanism= randomly kicked out to bet diploid number= trisomic rescue= loss of extra 15
So all paternal chromosome 15 as maternal contribution lost

Question 8

Describe a family pedigree of an imprinting disorder

Answer 8

-If paternally imprinted, only active/ expressed if inherited from mother

Question 9

Examples of the link between imprinting and cancer

Answer 9

Wilm’s tumour – maternal chrom 11p15
• Neuroblastoma – maternal chrom 1p36
paternal chrom 2
• Acute Myeloblastic Leukaemia – paternal chrom 7
• Rhabdomyosarcoma – maternal chrom 11p15.5
• Osteo-sarcoma – maternal chrom 13

Question 10

Describe mitochondrial DNA

Answer 10

• 16,559 base pairs
• Many copies in a cell, dependent on energy requirement of
cell/tissue
• Contains important genes for mitochondrial metabolic
pathways and ribosomal RNAs
• Maternally inherited
• High rate of mutations
– Point mutations and deletions occur (no repair mechanism)

Question 11

Describe the structure of mitochondrial DNA

Answer 11

• Double stranded
• Ring structure
• No Introns
• Genes are tightly packed together
• Few or no non-coding nucleotides between
genes
• Approx 92% of the mitochondrial genome has
coding function- the rest from nuclear DNA

Question 12

What are mitochondrial diseases?

Answer 12

-Disorder of high energy tissue
-Respiratory chain disorders
=Heart
=Eye
=Brain
-point mutations, deletions or duplications in the mitochondrial genome.
- if there is a mutation present, it may only be in a proportion of the mitochondria in a cell (Heteroplasmy) or in all the mitochondria (Homoplasmy).

Question 13

What signs can indicate mitochondrial disease?

Answer 13

• Raised serum lactate
• Mitochondrial DNA mutation
• Ragged red fibres on muscle biopsy

Question 14

Describe Kearns Sayre Syndrome

Answer 14

• Ophthalmoplegia
• Cardiomyopathy
• Myopathy with ragged red fibres
• Pigmentary retinopathy

Question 15

What are the multiple phenotypes of mitochondrial mutations (clinical heterogeneity)?

Answer 15

– Pearson (Marrow-Pancreas) Syndrome
– Kearns Sayre Syndrome
– Myopathy
– Ataxia
– Cardiomyopathy
– Leighs encephalopathy
– Lieber's Hereditary optic neuropathy

Question 16

What is Heteroplasmy?

Answer 16

• Different daughter cells contain different proportions of mutant mitochondria
• Balance between normal vs mutant mitochondrial DNA
• Oocyte level (divides into different proportions) Only the oocytes contribute mitochondria to an individual, inheritance of mitochondrial disease is therefore always matrilinear
• Tissue level (pluripotent cell dividing)

Question 17

What does the severity and nature of phenotype depend on (mitochondrial disease)?

Answer 17

• Type of tissue involved
• Proportion of mitochondria carrying a mutation (Heteroplasmy)
• Type of mutation

Question 18

Describe the inheritance patterns in mitochondrial disorder

Answer 18

• Maternal inheritance only if affected gene is from
mitochondrial DNA
• Mitochondrial DNA does not code for all
mitochondrial protein
• If abnormal mitochondrial protein is coded from
genomic DNA then genetic disorders follow
mendelian patterns of inheritance

Question 19

What are Dynamic mutations?

Answer 19

• Mutations are evolving
• Not stably inherited
• Mutations are (usually) increasing in size with
successive generations
– But can also contract in size
=A large untranslated trinucleotide repeat expansion tends to be unstable during somatic cell division
• Has a threshold effect- disrupt translation
• Exhibit a relationship between severity and copy
number
– Explains the clinical phenomenon of Anticipation
• More severe in succeeding generations (expansion of mutation)

Question 20

What are the most common dynamic mutations?

Answer 20

• Most common are triplet repeats (other= hexonucleotide)
• Expansion of repeats usually has gender bias
– e.g. HD – expansion when transmitted from paternal
line
– Fragile X – expansion when transmitted from
maternal line
In the untranslated region of gene, for example the (CCG)n repeat in fragile X, or the (CTG)n repeat in myotonic dystrophy.
• Accounts for over 40 neurological,
neuromuscular and neurodegenerative disorder

Question 21

Describe Myotonic Dystrophy

Answer 21

• Frontal balding
• Cataracts
• Muscle weakness
• Myopathic facies
• Myotonia
• Dysphagia
• Intellectual deterioration

Question 22

Describe the genetics/aetiology of Myotonic Dystrophy

Answer 22

• CTG trinucleotide repeat in 3’ UTR of Myotonic
dystrophy gene.
• Normally 5-27 copies of repeat
• Disease alleles 50-2000 repeats
• Repeat expands on male or female transmission
• Disease shows anticipation
– More severe in succeeding generations

Question 23

Describe congenital Myotonic Dystrophy

Answer 23

• Severe neonatal muscle weakness
• Neonatal death from respiratory
failure
• Usually > 500 repeats
• Almost invariably mother is affected

Question 24

Examples of Trinucleotide Repeat Disease

Answer 24

• Myotonic Dystrophy (CTG)n
=Affects RNA Processing
• Fragile X (CCG)n Causes
=Methylation silencing of gene
• Huntington’s Disease (CAG)n
=Expression of mutant protein (gain of function) in coding region
• Friedreich Ataxia (GAA)n
=Affects RNA Processing, repeat in the frataxin gene is inherited as an autosomal recessive condition
• Spinocerebellar Ataxias
=Expression of mutant protein (polyglutamine tract) (gain of function) in coding region

Question 25

What is Digenic Inheritance?

Answer 25

First came to light in patients with Sensorineural
deafness
• >100 genes involved
• Usually conform to mendelian patterns of inheritance- mutations in two genes give rise to phenotype
• However a proportion of patients with deafness, were double heterozygotes for know deafness genes
– ie no hearing deficit were found in patients who were only carriers of a mutation in a single locus but deafness occurred where patients were carriers of mutations in 2 gene loci

Question 26

What is a contiguous gene deletion syndrome?

Answer 26

A syndrome caused by a microdeletion that spans two or more genes tandemly positioned along a chromosome

Question 27

Examples of well-known contiguous gene deletion syndromes

Answer 27

• Williams-Beuren syndrome 7q11.23
• DiGeorge syndrome 22q11.2
• Wolf-Hirschhorn syndrome 4p16.3
• Smith-Magenis syndrome 17p11.2

Question 28

Describe genotype-phenotype correlations in contiguous gene deletion syndromes

Answer 28

• Is the clinical manifestations due to the genes which have been deleted
• If so can we attribute particular phenotype to the
particular genes which has been deleted
• Or is the syndrome due to just one of the genes that has been deleted

Question 29

Describe the genetic cause of William Beuren Syndrome

Answer 29

-Common 1.5Mb deletion spanning 24-28
genes
• 320-500Kb highly repetitive sequence
flanking the Williams critical region
• Due to defective homologous non-allelic
recombination

Question 30

How does Williams Beuren Syndrome present?

Answer 30

• Dysmorphic facial features
• “Cocktail party” demeanour
• Excessive non-social anxiety
• Preserved vocabulary
• Cardiovascular problems
• Supravalvular aortic & renal stenosis
• Transient hypercalcaemia (paediatric)

Question 31

What genes are associated with WBS?

Answer 31

• ELN
• CLIP2
• LIMK1

Question 32

Describe the role of ELN in WBS

Answer 32

Elastin gene. 90-100 % of the WBS patients have hemizygous
deletion of ELN
=> Cause of supravalvular aortic stenosis (SVAS)
=> ? Cause of facial features

Question 33

Describe the role of CLIP2 in WBS

Answer 33

Encodes cytoplasmic linker protein subunit 2 / 115 (CLIP115);
implicated in membranous organelles / microtubules interaction
=> ? A cause of neurological features of Williams syndrome

Question 34

Describe the role of LIMK1 in WBS

Answer 34

Encodes LIM Kinase; strongly expressed in brain

=> some neurological features of WBS

Question 35

Why focus on telomeres in sub telomeric chromosomal rearrangements?

Answer 35

• Majority of translocations involve chromosome ends (shared
telomere-associated repeats)
• Gene rich adjacent regions (rearrangements likely to have
phenotypic consequences)
• Moderate-severe MR
•=for sporadic cases (7%)
•=for familial cases (25%)

Question 36

What is Mosaicism?

Answer 36

When an individual is made up of populations of
cells with different genetic constitutions.
Can be mosaic for
– Chromosomal Aneuploidy
– Molecular Mutations

Question 37

Describe Somatic Mosaicism

Answer 37

• All cells suffer mutations as they divide
= At meiosis and at mitosis
= Approximately 10-6 per gene per cell division
• Repair Mechanisms Exist
= Can give rise to reversion
• Given the numbers of cells in the body
= everybody will have some cells which has a mutation of some sort
An autosomal dominant mutation can arise during somatic cell division, after formation of the zygote. Only a proportion of cells in the body will therefore carry a mutation, and the indivdual may show no features of disease, the features may be milder, or the features may affect only one body area. The mutation may only be present in gonadal tissue.

Question 38

When is mosaicism clinically important?

Answer 38

• If mutant cells has tendency to grow and replace
normal cells (cancer cells)
• If the mutation arose early in embryonic
development, so becomes a large proportion of the
whole body
• If the mutation occurred in the germ line

Question 39

Describe Gonadal Mosaicism

Answer 39

• Commoner in some diseases
– Duchenne Muscular Dystrophy
– Osteogenesis Imperfecta
• Can offer pre-natal diagnosis for a second child, even
when parents are unaffected (if a mutation is
identified)
• Causes recurrence risk for fatal dominant conditions
If a child is the first in a family to be affected with a dominant disease, this may be because of a new mutation or there may be gonadal mosaicism in the parent. This gives a higher recurrence risk than expected.

Question 40

How might mosaicism present?

Answer 40

• Differential growth pattern from one side to the next
• Mutations in skin= patches
• Pallister Killian syndrome mosaic tetrasomy 12p- can only exist in mosaicism (would be lethal if pure)

Question 41

How can Angelman syndrome arise?

Answer 41

Angelman syndrome can arise as a result of paternal uniparental disomy, deletion of the critical region at 15q12 in the maternally inherited chromosome, or point mutation in the maternally inherited copy of the UBE3A gene. This can be detected by analysis of DNA markers from both parents and the affected child.