Case 7: Mother and Child 1

Question 1

Family Histories and Probabilities: What are the commonest patterns of inheritance?

Answer 1

1) Autosomal Dominant 2) Autosomal Recessive 3) X-linked recessive

Question 2

Family Histories and Probabilities: What are the features of an autosomal dominant pattern? 1. Chance of inheritance 2. transmission 3. Affect males/females? 4. Multiple generations affected?

Answer 2

1. 1 in 2 2. Transmitted from father to son usually 3. Affects females and males equally 4. Multiple generations affected

Question 3

Family Histories and Probabilities: What are the features of an autosomal recessive pattern? 1. Chance of inheritance 2. transmission 3. Affect males/females? 4. Multiple generations affected?

Answer 3

1. 1 in 4 2. Transmitted from 3. Affects females and males equally 4. Usually one generation affected

Question 4

Family Histories and Probabilities: What are the features of an X-linked recessive pattern? 1. Chance of inheritance 2. transmission 3. Affect males/females? 4. Multiple generations affected?

Answer 4

1. 1 in 2 for sons, 2. 50% asymptomatic carriers, 50% of sons affected 3. Usually only men affected 4. Multiple generations affected

Question 5

Family Histories and Probabilities: Examples of autosomal dominant conditions:

Answer 5

Huntingtons, marphans syndrome, familial hypercholesterolaemia, spinocerebellar ataxia, hereditary breast and ovarian cancer, myotonic dystrophy, long QT syndrome

Question 6

Family Histories and Probabilities: Examples of autosomal recessive conditions

Answer 6

Cystic fibrosis, phenylketonia, B-thalassemia, sickle cell anaemia, Tay-Sachs disease, Spinal muscular dystrophy

Question 7

Family Histories and Probabilities: Examples of X linked recessive conditions

Answer 7

Duchenne muscular dystrophy, Haemophillia A, Red-green colour blindness

Question 8

Family Histories and Probabilities: What is genomic imprinting?

Answer 8

So normally, you inherit two working alleles. However, in genomic imprinting, certain genes are IMPRINTED, meaning they are marked as having come from the mother or father and one of them is SILENCED during fertilisation. - This means with imprinited genes you only have one working copy - It is as if you have a haploid as there is no ‘substitute allele’ - imprinted genes more vulnerable to the negative effects of mutations

Question 9

Family Histories and Probabilities: What are the implications of genomic imprinting in terms of genetic disorders ie. How do these disorders come about?

Answer 9

• If the imprinted gene is the faulty gene then there is no manifestation of a disorder. - However, if the imprinted gene is the normal gene and the active gene is faulty, this is a problem and could lead to a genetic disorder - Thus the expression of the disease phenptype depends on whether the mutant allele has been inherited from the mother or father

Question 10

Family Histories and Probabilities: What is uniparental disomy and why does it occur?

Answer 10

Uniparental disomy is a type of trisomy rescue where the chromosome that is lost is not one of the duplicates and thus the cell ends up with 2 maternal or 2 paternal alleles. So the person receives two copies of the chromosome from one parent and none from the other! * Duplicates means coming from the same parent here

Question 11

Family Histories and Probabilities: Give three examples of disorders linked with genomic imprinting

Answer 11

1 - Prader-Willi syndrome 2- Angelman syndrome 3- Beckwith-Weidmann syndrome

Question 12

Family Histories and Probabilities: What is the cause of Prader-Willi syndrome and what are its features

Answer 12

PW syndrome results from absence of the paternally expressed gene due to (most common causes:

• Deletion of the proximal long q arm of Ch.15 (15q11.2-q13 (**70%)
• Uniparental disomy (thus having two copies of the maternal chromosome and no copies of the paternal)(30%)

Features

1. Neonatal hypotonia
2. Obesity
3. Excessive eating habits (hyperphasia)
4. Short stature and hypogonadism
5. Intellectual disability

Question 13

Family Histories and Probabilities: What is the cause for Angelman’s Syndrome and what are its features?

Answer 13

**Note Prader-Willi and Angelman’s are syndrome where you get the same area of deletion, however the deletion is on either the maternal or the paternal chromosome

• In Angelman’s, the deletion of the log q arm of Ch15 is on the maternal chromosome (70% of cases)
• Only 7% is due to Uniparental Disomy where one has two copies of the paternal chromosome and none of the maternal

Features

1. Unusual facial appearance
2. Developmental delay
3. Intellectual diability
4. Microcephaly
5. Seizure
6. Hand flapping

Question 14

Family Histories and Probabilities: What is Bayes Theorem?

Answer 14

P (A|B) = P(B|A) X P(A)

________________

P(B)

Bayes theorem describes how the conditional probability of each of a set of possible causes for a given observed outcome can be computed from knowledge of the probability of each cause and the conditional probability of the outcome of each cause.

Question 15

Chromosomal Abnormalities:

Question 16

Family Histories and Abnormalities: What is genomic imprinting?

Answer 16

Expression of certain genes determined by whether gene is inherited from the mother of father - inactivation of a gene from the mother or father occurs by adding methyl groups

Question 17

Family Histories and Abnormalities: What is mosaicism?

Answer 17

The presence in an individual or tissue of at least two cell lineages that differ genetically, derived from a single zygote. There are two types; * Somatic mosaicism: involving any tissues or cells * Germline mosaicism: Involving Germline cells producing eggs or sperm

Question 18

Family Histories and Abnormalities: What is the common cause or mechanism for mosaicism?

Answer 18

Non-disjunction in the early post-zygotic mitotic division

Question 19

Family Histories and Abnormalities: How are the characteristics of Mosaic down’s, and what about prevalence?

Answer 19

• 2-4% of down’s population are mosaic Down’s syndrome - The phenotype is very variable

Question 20

Family Histories and Abnormalities: Where does Germline mosaicism occur most? What do you know about Germline mosaicism?

Answer 20

• Occurs most commonly in autosomal dominant and X linked conditions - Affected person does not have any features of the disease - Children are at risk of being affected

Question 21

Family Histories and Abnormalities: What is Duchenne Muscular Dystrophy?

Answer 21

Pathogenesis

DMD is X linked progressive myopthy

Phenotype

Males usually present at 3-5 years

Muscle degeneration

Muscle weakness

Gowers manouver by 5 years

Confined to a wheelchair by 12 years

Scoliosis and contractures

Females with DMD

Age of onset and severity

If X chromosome carrying mutant allele is active, females develop the above signs

Cardiac abnormalities

Genetics

DMD gene encodes dystrophin, intracellular protein expressed in smooth/skeletal/cardiac muscle and brain neurones

If a mother is apperently not a carrier she still has up to 15% for having a boy with DMD due to germline mosaicism

1/3 of boys have a new de novo mutation

Question 22

Family Histories and Abnormalities: what are the characteristics of mitochondrial inheritance?

Answer 22

• 1. Maternally inherited
• (sperm mitochondria not present in the zygote, this mtDNA only passed down from the mother)
• If mother has a mutation in her mtDNA - her daughters can pass it on, but children of any sons will not inherit the mutation as they will only inherit their mtDNA from the son’s partner
• Peridgrees of mitochondrial inheritance are quite distinct - (affected males will not pass down mutation, affected females will have some offspring with mutations)

2. Replicative segregation

At cell division, multiple copies of mtDNA in each mitochondria in each cell replicate and sort randomly among newly synthesised mitochondria. Then the mitochondria distribute randomly between daughter cells - leads to variability in mitochondrial disorders when there is a mutation

3. Homoplasmy and heteroplasmy

Daughter cells that receive a pure population of just the mutant mitochondrial DNA/ Daughter cells that receive a mixture of normal and mutant DNA