Non-Mendelian Inheritance Flashcards
(39 cards)
Anticipation
triple repeat disorders
Mosaicism
more than one cell type contained in an individual
uniparental disomy
individual inherits both alleles or homologous chromosomes from one parent
Genomic imprinting
expression of phenotype depends on the parent of origin
mitochondrial
inheritance is from the mother
Myotonic dystrophy shows what genetic phenomenons? What is its inheritance and triple repeat codon?
anticipation, penetrance, triple repeat, pleiotropic
Autosomal dominant 19q13.32
CTG repeats
Normal alleles - 5-34 CTG repeats
Premutation alleles - 35-49 CTG repeats
Full penetrance alleles - >50 CTG repeats.
skeletal and smooth muscle, eye, heart, endocrine system, CNS
Huntington Disease shows what genetic phenomenons? What is its inheritance and triple repeat codon?
Genotype-phenotype correlation
adult-onset form = 40 to 50 CAG repeats
Juvenile-onset form = form > 60 CAG repeats.
mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset.
Symptoms:
-Progressive motor disability featuring chorea (uncontrolled movement)
-Mental disturbances including cognitive decline
changes in personality, and/or depression
abnormal body postures
incomplete and complete penetrance
autosomal dominant
CAG repeats
Normal allele. p.Gln18, –>36 or more CAG repeats.
Intermediate allele: incomplete-penetrance HD-causing alleles - 36-39
HD-allele: Full-penetrance HD-causing alleles. p.Gln18 –> 40 CAG repeats development of HD.
CAG repeats = at risk for HD
Cancer is mosaic genetic disorder. What are the 3 main types?
somatic, gonosomal, and germline
What are the different mechanisms of getting Beckwith Wiedemann syndrome which behaves as AD?
Maternal transmission = high penetrance
Paternal transmission = low penetrance
Paternal UPD chr 11p15: Beckwith- Weidemann syndrome (overgrowth syndrome/macrosomia)–> both chromosome from dad
OR
One chromosome from dad and one from mom but abnormal methylation of the mom’s –> Beckwith- Weidermann Syndrome
OR
Hemophilia A can occur where there is father to son
What are the different mechanisms of getting Angelman Syndrome?
Normal Imprinting: dad is imprinted in this region, mom is usually expressed
- If you have a deletion in the mother’s chromosome for genes related to AS (only dad will be expressed) –> AS
- Abnormally imprint mom, dad will be expressed –> AS
- two chromosome from dad and nothing from mom –> AS
- genetic mutation in the region for AS genes–> AS
What are the different mechanisms of getting Prader Willi syndrome?
Normal Imprinting: mom is imprinted in this region, dad is usually expressed
- If you have a deletion in the father’s chromosome for genes related to Prader-willi syndrome (only mom will be expressed) –> PWS
- Abnormally imprint dad, mom will be expressed –> PWS
- two chromosome from mom and nothing from dad –> PWS
can only be transmitted through mothers only
Affected males do not pass on the genes
Often non-homogeneity to phenotype because of heteroplasmy
female has a mitochondrial trait, all of her offspring inherit it
only 1 allele is present in each individual, so dominance is not an issue
Mitochondrial inheritance
What disorder display allelic heterogeneity?
same gene: different phenotypes
Dystrophin gene – outcome of mutation effects
Duchenne Muscular Dystrophy – frameshifts, null allele
Becker Muscular Dystrophy – non-frameshifts , abnormal but present protein
X-linked Dilated Cardiomyopathy
Paired Box 3 transcription factor (Pax3) gene - Loss-of-function and gain-of- function mutations mutations Waardenburg syndrome (LOF) Alveolar rhabdosarcoma (GOF) –chromosomal translocation creates a novel chimeric gene, fusing PAX3- FKHR fusion.
Androgen receptor gene – LOS and GOF
Testicular feminization (AIS) - inactivation , null allele
Spinal and bulbar muscular atrophy (Kennedy disease) – Triplet Repeat
Expansion (CAG) leads to >38 Gln tract
The mitochondria has its own genome.
Variable expressivity in mitochondrial inheritance is due to what?
heteroplasmy
The mitochondria has its own genome.
Variable expressivity in mitochondrial inheritance is due to what?
heteroplasmy
levels of heteroplasmy increases with aging
Leber’s hereditary optic atrophy
Mitochondrial encephalopathy, lactic acidosis, and
stroke like syndrome (MELAS)
Maternal Inherited Diabetes and Deafness (MIDD)
Polygenic inheritance involves what and consist of what 3 types?
This involves the inheritance and expression of a phenotype being determined by many genes at different loci, with each gene exerting a small additive effect.
Polymorphic – combinations of polygenic alleles
Continuous (quantitative) – traits that
exhibit a range of values
Discrete (qualitative) – traits that are converted to a dichotomous or bimodal phenotypic distribution
Several human characteristics show a continuous distribution in the general population. Give examples.
Height
Intelligence
Blood Pressure
Skin Color
What’s the recurrence risk of hypertension that has 3 genes involved that all act dominantly? What about if they all acted recessively?
Loci X, Y, and Z
0.1 x 0.1 x 0.1= 0.001 or 1/1000 frequency will have genotype x-/y-/z-.
Multifactorial diseases that show familial clustering, have no recognized Mendelian pattern of inheritance.
They are determined by the additive effects of many genes at different loci together with the effect of environmental factors.
These conditions show familial incidence in close relatives of affected ~ 2-4%, instead of mutations rate seen in Mendelian (25-50%).
What is the empiric risk in familial aggregation?
Parents who have several affected children have higher risk alleles than parents with only one affected child.
Relative Risk - The rule of Thumb (1st degree)
- one affected → chance of a 2nd ~ 3-4%
- two affected→ Chance for 3rd ~ 5-8%
- three affected → chance of 4th ~ 9-12%
recurrence risk = √ (population incidence)
The recurrence risk is greatest among close relatives of the index case and decreases rapidly in more distant relatives. Give an example
spina bifida the risks to first -, second-, and third - degree relatives approximately 4%, 1% and < 0.5%, respectively.
If the condition is more common in individuals of one particular sex, recurrence risk varies according to sex of index case. Give an example
Pyloric stenosis shows a male to female ratio of 5 to 1. Offspring (relatives) of an affected girl has higher susceptibility
Offspring of male proband - sons risk 6.4% and
daughters risk 2.5% .
Incidence increases among relatives of the most severely affected patients. Give an example.
index patient has bilateral cleft lip and palate, risk to future sibling is 6 %.
index patient has unilateral cleft lip, risk to future
sibling is 2 %.
Recurrence risk increases with increasing number of
previously affected children. Give an example.
neural tube defect, recurrence risk is about 2 - 4%.
2 children with NTD, recurrence risk rises to 10%.
The rule of Thumb
- one affected → chance of a second ~ 3-4%
- two affected→ Chance for third ~ 5-8%
- three affected → chance of fourth ~9-12%
