Genetics Flashcards
What is the risk of carrier status in the unaffected sibling of a person affected by an AR disorder?
2/3 If someone is a child of 2 carrier parents, but is unaffected, their risk of carrier status is 2/3 (because they are not the ¼ that is affected).
What does Autosomal Recessive mean? What defines a pedigree showing AR inheritance?
Autosomal – ie. not germ line (not sex linked). AR: mutation in both copies of gene are needed to cause disease. Each time carrier parents have a child there is a 25% chance that the child will inherit the disease (roll the dice each time). AR pedigree: - affects either sex - An affected person usually has unaffected parents (carriers). An exception is very common AR conditions, which can show a “pseudo-dominant” pattern eg. C282Y gene and haemochromatosis. There is increased risk of AR disorders with parental consanguinity. An affected person can ONLY pass on an affected allele (as both copies affected) - in calculations their rate of carriage is 100% (or 1). NOTE: If it is called a “RARE” AR disorder (in the Q), usually assume that not both sets of grandparents are carriers (unless consanguineous).
Consanguinity increases the risk of genetic disorders: True or False?
Consanguinity increases the risk of an AR disorder, but not of an X-linked disorder, AD disorder or other disorder.
What does Autosomal Dominant mean? What are the features of AD inheritance?
Autosomal – ie. not germ line (not sex linked). M and F equally affected Dominant means only need to have one allele to have disease. Pedigree: - Affected person often has an affected parent - Risk to child of affected person is 50% - Look for disease occurring in every generation (less likley AR) - Affects either sex - Transmitted by either sex (LOOK FOR MALE-TO-MALE TRANSMISSION; This rules out both X-linked and mitochondrial traits).
What is an X-linked recessive disorder? An example? What are the features of an X-linked recessive pedigree?
Condition is X-linked. Boys inherit the condition from their mother (no X from father). Girls can inherit an affected allele from mother or father or both. An example is haemophilia A. X-linked recessive pedigree: - affects almost exclusively males - affected males born to unaffected parents; mother is asymptomatic carrier. - females may be affected, but less commonly [see other card] - NO male-to-male transmission
Why do women sometimes manifest x-linked conditions?
- Homozygous (rare): father is affected and mother is carrier. 2. Skewed X inactivation – unbalanced lyonisation 3. Only one X functioning eg. 45X (Turner’s) or 46XY females 4. X autosome balanced translocation: may interrupt gene or causes very skewed X inactivation. eg. translocation between X and Chr 2 → can’t “turn off” that X as would turn off Chr 2 function. Therefore get unbalanced lyonisation. 5. Maybe X-linked dominant (these conditions are often lethal in males - eg. Incontinentia pigmenti) 6. New mutation
What are the characteristics of X-linked dominant conditions? What is an example?
X-linked dominant inheritance: - any person (M or F) with a copy of the mutation (on X chr) will be affected - F > M (even if not male-lethal) - some are male lethal (b/c no second copy to partially compensate - ie. no protein produced) - females MAY be more variably and mildly affected than males (depends on disorder) - affected father: all daughters affected; all sons unaffected - affected mother: 50% chance of affected child (M or F); very rare for female to be homozygous for X-linked dominant condition. An example is incontinentia pigmenti, a disorder which presents in childhood and affects skin, teeth, nails and CNS.
These are some keys to spotting pedigrees: 1. Male to male transmission = AD 2. Affected males linked through unaffected females = XLR 3. All children affected of affected females = mitochrondrial 4. Siblings affected, with no FHx = AR 5. Sporadic can = anything (multigenic, AR, de novo, AD, XLR, mitochondrial, not genetic).
(from the lecture)
A person in whom a germline chromosomal translocation develops will exhibit which features?
None. Chromosomal translocation: - won’t affect person in whom it first develops - However, when having children, it will either result in MISCARRIAGE (because of unbalanced chromosomal translocation) or transmission of a CHROMOSOMAL DISORDER.
What is the difference between Non-penetrance (or incomplete penetrance) and Reduced Expression?
Non-penetrance = No phenotypic features, despite carrying genotype. Also = Incomplete Penetrance. - a feature of dominantly inherited disorders - influenced by: other genes, environment, epigenetic modification of alleles - an issue in genetic counselling. Reduced (or Variable) Expression = some features of the condition, but not full phenotype (eg. some subtle features of phenotype). - also most common in dominant disorder (only one copy faulty).
What is a normal karyotype?
23 pairs of chromosomes: 22 pairs of autosomes, and one pair of sex chromosomes.
What is Klinefelter Syndrome?
Karyotype 47XXY The person is MALE (NOT an intersex condition / disorder of sexual development). Present in 3 age groups: 1. antenatally (detected on amniocentesis – usually for advanced maternal age) 2. puberty – may have some breast development and delayed /decreased secondary male sex characteristics 3. adults with primary infertility
What is aneuploidy?
Aneuploidy: abnormal number of chromosomes
What is Euploidy?
Euploidy: normal number of chromosomes
What is triploidy?
Triploidy: 3 copies of all chromosomes
What is trisomy?
Trisomy: 3 copies of a chromosome (same chromosome). Usually due to non-disjunction (failure of chromosome pairs or sister chromatids to separate properly during meiosis). Survivable if it is Chr 13, 18 or 21. Trisomy 13: Patau syndrome Trisomy 18: Edwards sydnrome Trisomy 21: Downs syndrome
What is the implication of 47XYY karyotype?
47XYY karyotype: Usually normal male. May have some poor attention and lower IQ than siblings (about 15 points). There was a study showing high rates of imprisonment in this population, but probably flawed. More likely to be normal child than behavioural abnormality (eg. ADHD / autism / conduct disorder / OCD etc).
What is uniparental disomy?
Inheritance of both copies of chromosome from one parent.
Probably occurs as a response to triploidy (cell disposes of one copy, but manages to keep two copies from one parent).
Imprinting
.
Mosaicism
.
What is Prader-Wili Syndrome? What is the underlying genetic abnormality?
Prader-Wili syndrome: - neonatal hypotonia, FTT in infancy - small hands and feet - cryptorchidism - developmental delay, MR - syndromic features - hyperphagia, obesity In adulthood: Mild MR, obese and non-obese, osteoporotic, high body fat / lean mass ratio, delayed / incomplete pubertal function, controversies about ongoing Tx (GH, testosterone) Loss of region of chromosome 15: either delete one copy (paternal) of chromosome and imprint other copy (maternal) OR uniparental disomy with imprinting
What is genetic imprinting?
Imprinted genes are silenced. This occurs to certain genes (we know it happens on chr 7, 11, 15). Depending on the gene, either the maternal copy or the paternal copy is epigenetically silenced (maternally imprinted or paternally imprinted). An individual will thus have one active copy of the gene. Silencing usually happens through the addition of methyl groups during egg or sperm formation. The epigenetic tags on imprinted genes usually stay put for the life of the organism. But they are reset during egg and sperm formation. Regardless of whether they came from mom or dad, certain genes are always silenced in the egg, and others are always silenced in the sperm. Individuals with an imprinted copy of a defective gene will not express the phenotype; However, they may pass on a copy that is not imprinted, and thus their offspring may suffer the phenotype. This phenomenon explains why the offspring of a tiger and lion cross-breed pair will be different (mainly in terms of size) depending on whether the father was a tiger or a lion.
How can imprinting cause disease? What would make you suspect imprinting on a pedigree?
Mechanisms of disease due to imprinting:
(1) Deletion of active allele (other copy silenced).
Example: Prader-Willi syndrome. The gene 15q11-q13 is maternally imprinted. Deletion of 15q11-q13 in the paternal chromosome accounts for 75% of cases. Disease occurs because the [normal] maternal copy is silenced.
(2) Uniparental disomy (of imprinted copy)
Example: 25% of cases of Prader-Willi Syndrome are due to maternal UPD.
(3) Mutation at imprinted allele.
This will alter the observed pattern of Mendelian inheritance. For example, a mutated gene can be silenced if inherited from one parent, but expressed if inherited from the other gender parent.
If both mothers and fathers are passing on the PHENOTYPE (not just carriage of the genotype), then it cannot be due to an imprinted gene.
