Case 7: Mother and Child 1 Flashcards
Family Histories and Probabilities: What are the commonest patterns of inheritance?
1) Autosomal Dominant 2) Autosomal Recessive 3) X-linked recessive
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?
- 1 in 2 2. Transmitted from father to son usually 3. Affects females and males equally 4. Multiple generations affected
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?
- 1 in 4 2. Transmitted from 3. Affects females and males equally 4. Usually one generation affected
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?
- 1 in 2 for sons, 2. 50% asymptomatic carriers, 50% of sons affected 3. Usually only men affected 4. Multiple generations affected
Family Histories and Probabilities: Examples of autosomal dominant conditions:
Huntingtons, marphans syndrome, familial hypercholesterolaemia, spinocerebellar ataxia, hereditary breast and ovarian cancer, myotonic dystrophy, long QT syndrome
Family Histories and Probabilities: Examples of autosomal recessive conditions
Cystic fibrosis, phenylketonia, B-thalassemia, sickle cell anaemia, Tay-Sachs disease, Spinal muscular dystrophy
Family Histories and Probabilities: Examples of X linked recessive conditions
Duchenne muscular dystrophy, Haemophillia A, Red-green colour blindness
Family Histories and Probabilities: What is genomic imprinting?
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
Family Histories and Probabilities: What are the implications of genomic imprinting in terms of genetic disorders ie. How do these disorders come about?
- 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
Family Histories and Probabilities: What is uniparental disomy and why does it occur?
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
Family Histories and Probabilities: Give three examples of disorders linked with genomic imprinting
1 - Prader-Willi syndrome 2- Angelman syndrome 3- Beckwith-Weidmann syndrome
Family Histories and Probabilities: What is the cause of Prader-Willi syndrome and what are its features
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
- Neonatal hypotonia
- Obesity
- Excessive eating habits (hyperphasia)
- Short stature and hypogonadism
- Intellectual disability
Family Histories and Probabilities: What is the cause for Angelman’s Syndrome and what are its features?
**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
- Unusual facial appearance
- Developmental delay
- Intellectual diability
- Microcephaly
- Seizure
- Hand flapping
Family Histories and Probabilities: What is Bayes Theorem?
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.
Chromosomal Abnormalities:
Family Histories and Abnormalities: What is genomic imprinting?
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
Family Histories and Abnormalities: What is mosaicism?
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
Family Histories and Abnormalities: What is the common cause or mechanism for mosaicism?
Non-disjunction in the early post-zygotic mitotic division
Family Histories and Abnormalities: How are the characteristics of Mosaic down’s, and what about prevalence?
- 2-4% of down’s population are mosaic Down’s syndrome - The phenotype is very variable
Family Histories and Abnormalities: Where does Germline mosaicism occur most? What do you know about Germline mosaicism?
- 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
Family Histories and Abnormalities: What is Duchenne Muscular Dystrophy?
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
Family Histories and Abnormalities: what are the characteristics of mitochondrial inheritance?
- 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
