Med foundations 1 Flashcards
Constitutional/Congenital
Present at birth
Pathogenetic (definition)
Genetic alteration causing disease
Obligate Carrier (define)
Parent of a child with a recessive condition
Mosaic (define)
Two or more cell lines in one person
Chimera (define)
Mix of two cell lines, think of bone marrow transplant
Consanguinity
Individuals descended from common ancestor; second cousin or closer. .2% of US
Acquired
somatic change after birth, usually cancer related
SAB
spontaneous abortion
FTT
failure to thrive-doesnt put on weight
Two examples of autosomal dominant inheritance
Achondroplasia–GOT midget
Marfan’s Disease
Variable Expressivity (define) and give an example.
features of a disorder vary between individuals even in the same family. Usually autosomal dominant disorders have variable expressivity. Example: marfan syndrome
Marfan Syndrome
Tall lanky, disorder of connective tissue. Mortality: dilation of the aorta resulting in rupture.
Exhibits variable expressivity: people in same family may have to different degrees
also an example of dysplasia (defect in fibrilin)
Incomplete Penetrance (definition and example)
Not all individuals with a mutation have phenotypic effects. Ex: BRCA gene mutation
Explain the difference between variable penetrance, variable expressivity, and having both.
EX: BRCA gene. Only some people w/ gene get disorder (variable penetrance). And people who have the gene have different types of cancer (variable expressivity).
De novo mutation
New mutations can occur at “hot spots”.
Rate of new mutations increases with advancing paternal age.
Ex:: 80% of achondroplasia cases are de novo.
Examples of recessive inheritance
Cystic fibrosis
Sickle Cell
How is cystic fibrosis inherited?
recessively.
Is penetrance in autosomal recessive diseases complete or incomplete?
usually complete. if you have two copies, you have the disease.
Examples of recessive autosomal inheritance with ethnic correlations
Sickle Cell
Tay Sachs
Example of X-linked recessive inheritance and details of disease
Hemophilia: bleeding caused by factor 8 deficiency, life expectancy reduction by about 10 yrs.
Characteristics of X-linked diseases
Male to male transmission not observed. Males more likely than females to be affected. All daughters of an affected male are carriers. Female carriers may show milder version of trait
Lyonization (X-inactivation)
Explains why some female carriers of an x linked disorder might show some characteristics. One x chromosone is turned off in cells. A skewed ratio could lead to a phenotype. An example would be women exhibiting less severe symptoms of duchenne muscular dystrophy.
Duchenne Muscular Dystropy
X-linked recessive inheritance. skeletal muscle disease. life expectancy around 27 yrs
When could a female be affected by a recessive X linked disorder?
- Turners syndrome
- skewed x-inactivation
- she has an affected father and carrier mother
X-linked dominant inheritance (example)
Incontinentia Pigmenti; disorder of skin hair teeth etc. cognitive delays
X-linked dominant inheritance mechanism
Females are much more likely than males to be affected. male to male transmission not observed
How many genes on mitochondria?
37
MELAS
Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes; hearing loss, diabetes, seizures, intellectual disability
Heteroplasmy and Homoplasmy
mix of normal and abnormal mtDNA vs. all mt DNA is the same
Threshold effect in mtDNA
Threshold for symptoms showing
How does mitochondrial function vary with age?
Mt function decreases with age.
Anticipation (definition)
Increase in severity of phenotype in successive generations. Related to trinucleotide repeats
Example of disease with anticipation
Myotonic Dystrophy has a spectrum of severity depending on repeats. affects skeletal and smooth muscle; myotonia–sustained muscle contraction.
Fragile X syndrome
most common inherited cause of intellectual diability. Severity doesnt increase with repeats, but likelihood of having it does
Fragile X syndrome characteristics of carriers
female carriers have increased risk of early menopause
males are at risk for parkinsons syndrome
Mosaic Down syndrome
less severely affected. 1-2% of down syndrome.
Pallister Killian Syndrome
Mosaic tetrasomy 12p.
low muscle tone, characteristic facies, hypopigmentation
Only seen in mosaic form because the non mosaic form is lethal.
When should gonadal mosaicism be inferred?
When two offspring have an autosomal dominant disorder with no other family history.
Why are digynic triploidy and diandric triploidy evidence for imprinting?
Because depending on whether you get two copies from mom (digynic) or dad you get a different result.
Russell Silver Syndrome
small features, triangle face. about 10% of cases occur with uniparental disomy on chromosone 7.
Prader-Willi Syndrome
Hyperphagia; intellectual disability. “Prader no fader”
Angelman Syndrome
Severe disability. Caused by lack of genes on the maternal allele
Major anomalies vs. Minor anomalies
medical surgical intervention needed, cosmetically important.
Minor: no major surgery
22q11 deletion syndrome
Piece of long arm of 22nd chromosone missing.
74% of kids have a heart defect. palette anomalies, nasal voice.
Looks phenotypically different, have to look at patients carefully.
Malformation (definition+ex)
Defect from an intrinsically abnormal deveopment process; occurs at 8-10 weeks. ex: heart defect, cleft lip,
Deformation (definition +ex)
abnormality from mechanical forces; occurs AFTER 8-10 weeks, ex: clubbed foot, overlapping toes. Squished against side of placenta.
Disruption (definition+ex)
environmental disturbance, think of tunnel being completely blocked wheras in deformation tunnel is only partially blocked.
Ex: oligodactyly–amniotic band compression. cleft palate
Dysplasia
Abnormal organization of cells into tissues. Ex: polycystic kidney disease. dented chest
Syndrome (definition and example)
multiple anomalies thought to be pathogenically related
Sequence (definition and example)
cascade from single known anomaly or MECHANICAL factor.
Ex: Pierre robin sequence.
micrognathia–>glossoptosis–>cleft palette
Potter sequence :
lack of fetal urine–>anhydamnios–> fetal compression–>hypoplasia
Field Defect (definition and example)
derived from the disturbance of a single developmental field.
Ex: a midline development issue
Ex: OEIS (external bowels)
or holoprosencephaly spectrum
Association (definition and example)
Non random occurrence of multiple anomalies that cannot be explained by chance. UNKOWN factor.
Ex: VATERAL (Vertebral anomalies, anus, cardiac, TEF, renal, limb
Teratogen (definition)
exposure in pregnancy with a harmful effect
ex: infection, medications, drugs, heavy metals, procedures
Characteristics of teratogens
dose response relationship
period of greatest sensitivity
Examples of teratogens
thalidomide
warfarin (coumadin)
acutane
Where are men placed on a pedigree?
to the left of females
Three principles of mendellian inheritance
- unit inheritance
- segregation
- independant assortment
What organ systems are most likely to be affected in mitochondrial disorders?
Systems w. large ATP requirements. CNS, skeletal muscle, eye muscle, heart muscle (muscles +brain)
Heterodisomy vs. isodisomy
in heterodisomy, the parent provides one copy of each homologous chromosone. In isodisomy, the parent passes on two IDENTICAL copies of hte same chromosone
dysmorphic features
variants of physical features that are present in less than 2-3% of population
What percent chance is there that a person has a syndrome if they have….
1 anomaly?
2 anomaly?
3 anomaly?
1 anomaly: 3% chance
2 anomalies: 10% chance
3 anomalies: 20% chance
More examples of teratogens
ace inhibitors, androgens, cocaine, vitamin A, some antibiotics
Hardy Weinberg and what p and q stand for
p^2+2pq+q^2=1
q^2 is incidence of homozygotes=incidence of AR disease
2pq=heterozygotes=incidence of carriers
How would you calculate if “at least 1” child will have a disease?
At least 1= 1-none
Multifactorial genetics (definition)
combined contribution of genes and environmental factors in the causation of a particular disease or trait
What are the two types of multifactorial traits?
quantitative and threshold
What is liability in multifactorial inheritance?
liability is the total combined genetic and environmental factors that influence the development of a multifactorial disorder or trait
can liability be measured?
no
Examples of liability differences between males and females
cleft lip and palate: M>F
congenital hip dysplasia F>M
Pyloric stenosis: M>F
Recurrence risk rules
Recurrence risk is greater if….
- greater severity
- more than one family member is affected
- more closely related family members
- if proband is of less commonly affected sex
- recurrence risk of 1st d relative is equal to square root of population incidence
heritability (definition)
How much of a phenotypic variance is caused by genes vs environment?
Genetic risk factors of AD
Apolipoprotein E (APOE) : if you have a copy of the e4 allele, your risk increases 2-5x; if you have 2 copies your risk increases 5-10x
What is recurrence risk rate for birth defects?
4%
polygenic trait
results from the combined influence of multiple genes
Signs of multifactorial inheritance
familial concentration
absence of clear biochemical defects from 1 gene
variation in severity and expression
gender differences
What percent of breast cancer is due to an inherited change? (BRCA, p53, etc)
about 5-10%
If you see a pedigree with only affected women, what is the mode of inheritance?
X linked dominant
What percent of children are diagnosed with a birth defect at birth? after 1 year?
3%, 4%
Concurrence of minor and major anomalies
If a child has 3 or more minor anomalies, 20-90% more likely to have a major malformation
