Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
136 Cards in this Set
- Front
- Back
|
Unit Inheritance
|
- parental phenotypes do not "blend"
- i.e. one parent tall one parent with achondroplasia does not mean kid will be in the middle |
|
|
Segregation
|
- genes occur in pairs
- only one allele is transmitted |
|
|
Independent Assortment
|
- genes located at different loci transmit independently
|
|
|
Autosomal Dominant: are males or females affected more? Male to male transmission? Do unaffected individuals have affected children?
|
- equal
- yes - no risk almost 0 (except de novo mutations) |
|
|
What is the causative gene in achondroplasia? What mendalian pattern is it inherited in? All affected individuals have a substitution for ______ at AA 380 of protein
|
- FGFR3
- dominant - most common form of short-limbed dwarfism - glycine |
|
|
Variable expressivity
|
- seen in autosomal dominant disorders
- family members express to different degrees (some have more cardiac some more skeletal problems, etc) |
|
|
Penetrance, penetrant, non-penetrant
|
- seen in AD
- proportion of people who carry mutated gene who present with any of the known phenotypic effects of the gene - penetrant: have the gene & express the trait - non-penetrant: carry mutation but show no clinical expression |
|
|
Advanced paternal age increases the risk for what in AD disorders?
|
- de novo mutations
|
|
|
AR: are females or males affected more? how many alleles needed to express the trait? What is the example we talked about in class?
|
- the same
- two alleles - diastrophic dysplasia (gene = DTDST) |
|
|
X-linked Recessive: who is affected? Higher in males or females? male to male transmission?
|
- hemizygous males, heterozygous females unaffected (carrier females may show variable expression b/c of lyonization)
- males - no |
|
|
what is the lyon hypothesis?
|
- in somatic cells of females only one X is active
- inactivation occurs early in embryonic life - inactivation is random but fixed |
|
|
What are 5 reasons we could see X-linked recessive disorders in females?
|
1) lyonization
2) 45,X karyotye (turners syndrome) 3) deletion of normal gene & inactivation of normal X 4) affected female had carrier dad + mom 5) disorder is really AR |
|
|
X-linked dominant: more females or males? male to male transmission? more or less common then x-linked recessive?
|
- more females
- yes - less common than x-linked recessive |
|
|
Even though mito have their own _____, Most ________ are encoded by nuclear DNA: autosomal recessive inheritance
|
- DNA
- oxidative phosphorylative subunits |
|
|
Only mitochondria from ____contribute to zygote: _______ INHERITANCE
|
- oocyte
- MATERNAL |
|
|
On a pedigree what gives it away that it's maternal inheritance? (aka mito disease)
|
- mothers always pass it on
|
|
|
heteroplasmy vs homoplasmy
|
- mixture of normal & abnormal mtDNA
- homoplasmy is all mtDNA the same - either normal or abnormal - with replication they randomly segregate |
|
|
Percentage of abnormal DNA can change over time due to _______ as cells divide, or to a possible _______ of one type of mtDNA over another
|
- random drift
- replicative advantage |
|
|
what is the threshold effect
|
- certain percentage of abnormal mtDNA will be tolerated without symptoms
- when critical threshold reached symptoms appear - threshold differs between people |
|
|
what are the age effects with mtDNA? do they have repair enzymes?
|
- mito function decreases w/ age
- may be due to free radicals formed during ox phos - mutation rate is also 10x higher b/c lack repair enzymes |
|
|
what are the most likely tissues to be affected by mtDNA mutation?
|
- high energy requirements (ie skeletal muscle, brain, heart, smooth muscle)
|
|
|
how do you make a diagnosis of mitochondrial disorder?
|
- muscle bioposy to measure enzyme function & analyze mtDNA
|
|
|
for mitochondrial disorders, prenatal diagnosis is theoretically possible but prognosis difficult to predict due to __________
|
- heteroplasmy
|
|
|
MELAS is _______. LEON is ______
|
- heteroplasmic w/ high variability of expression
- homoplasmic & more penetrant in males |
|
|
Somatic Mosaicism
|
- caused by post-zygotic mutation which affects certain percentage of cells
|
|
|
Mosaic down syndrome, segmental neurofibromatosis and McCune-Albright syndrome are all examples of what?
|
- somatic mosaicism
|
|
|
Gonadal mosaicism
|
- presence of more than one cell line in gonadal cells but not in rest of body
- mutation must have occurred in precursor sperm or egg cell & passed on to all derivatives |
|
|
child develops with OI & no PFM, is there a risk the parents have another baby with OI?
|
- risk is almost zero because don't know if it was gonadal mosaicism instead of de novo
|
|
|
_____________ is detected when 2+ offspring are present with an autosomal dominant disorder in the face of negative family history
|
- gonadal mosaicism
|
|
|
in __________ neither parent has the disorder, although one has ___________ for the mutation
|
- gonadal mosaicism
- gonadal mosaicism |
|
|
UPD
|
- presence of two homologous chromosomes inherited from only one parent
|
|
|
isodisomy vs heterodisomy
|
- isodisomy: parent passes on two copies of same gene (non disjunction in meiosis II)
- heterodisomy: parent passes on one copy of each homolog (non disjunction in meiosis I) |
|
|
what are the 3 posulated mechanisms in UPD?
|
1) trisomy rescue
2) fertilization of nullisomic gamete by disomic gamete (need two non disjunction events for this) 3) compensatory duplication of chromosome in monosomic cell |
|
|
trisomy rescue leads to ________, whereas nullisomic gamete duplication leads to ___________
|
- heterodisomy
- isodisomy |
|
|
when is UPD clinically significant?
|
- when there are imprinted genes or when there is a recessive allele
|
|
|
genomic imprinting
|
- differential modification of the maternal & paternal genetic contributions to the zygote
|
|
|
when can genomic imprinting be clinically significant?
|
- when patient has UPD or if there is heterozygous deletion of imprinted region
|
|
|
Imprinting is DNA _______. When does it occur? When is it reversible?
|
- methylation
- occurs before fertilization - reversible on passage through opposite sex (ie imprinting will be erased in gametes of male offspring) |
|
|
Prader willi is deletion of ________ allele from chromosome 15 or UPD of ______ 15, whereas angelmann is deletion of _________ allele or UPD of _______ 15
|
- paternal
- maternal - maternal - paternal |
|
|
In a normal individuals what angelman & parder willi genes are turned on/off for mom and dad?
|
- maternal: angelman on, praderwilli off
- paternal: angelman off, praderwilli on |
|
|
genetic amplification (anticipation)? occurs due to specific areas of ___________ in the genome
|
- increase in severity of phenotype with each successive generation
- instability |
|
|
in genetic amplification, the more severe the phenotype, the ______ the repeat copy number (of trinucleotides), Can see _______ in clinically asymptomatic individual
|
- bigger
- premutation |
|
|
Expansion in fragile X syndrome only occurs through what? Does the severity correlate with CGG repeats? When do you start seeing problems (how many bp)?
|
- female meiosis
- yes - 200 |
|
|
when does expansion in myotonic dystrophy occur? what about the congenital form?
|
- shows anticipation with each successive generation
- congenital form can only occur from maternal transmission |
|
|
does huntington disease show anticipation? what is the exception?
|
- no
- exception is juvenile-onset which can occur only through paternal transmission |
|
|
Missense mutation
|
replace one amino acid (due to single base pair substitution)
|
|
|
nonsense mutation
|
single base pair substitution causing amino acid to change to stop codon
|
|
|
splice site mutation
|
single base pair muttion that creates or destroys exon/intron splicing
|
|
|
microdeletion syndrome
|
constellation of findings due to specific large deletion in several genes
|
|
|
promoter mutation
|
- those that affect binding of RNA polymerase
|
|
|
how does a loss of function null mutation work? is it AR? AD?
|
- 50% of protein is sufficient
- inherited AR |
|
|
how does dossage effect work (aka mild vs severe disease)? mild disease dosage effect is also called ______
|
- mild disease: inherited as AD, one allele abnormal
- severe disease: inherited as AR condition, 2 abnormal alleles - incomplete dominance or haploinsufficiency |
|
|
how does loss of function dominant negative work?
|
- mutant protein is producing from one allele and interfering with the normal protein function
|
|
|
how does gain of function work? how is it inherited?
|
- causes new/gain of function of protein product
- AD |
|
|
genetic heterogeneity
|
- different genes can cause the same diseases
|
|
|
allelic disorders
|
- different mutations in the same gene may produce different clinical phenotypes
|
|
|
variable expression
|
- sometimes people express different types and sometimes they don't (knowing mutation does not predict phenotype)
|
|
|
what does FISH look for?
|
- can look at microdeletion
- can only be done if you are looking for a specific gene |
|
|
methylation specific RT PCR
|
- uses RT PCR to figure out what DNA is methylated
|
|
|
chip technology (microarray)
|
- looks for small missing or extra pieces of DNA
|
|
|
allele specific oligonucleotide testing
|
- looks at common mutations
|
|
|
what do short tandem repeat polymorphisms tell you?
|
paternity test
- in non coding regions |
|
|
multiple ligation dependent probe amplification
|
- allows multiple exons to be amplified at once & run on gel to look at presence of a region
|
|
|
difference between microarray and multiple ligation-dependent probe amplification?
|
- microarray looks at lots of genes
- MLPA looks at exons within one gene |
|
|
indirect mutation testing
|
- what was done before knew what genes corresponded to what dieseases --> study of families
|
|
|
what are the 3 trisomies compatible with life? what about sex chromosomes?
|
- 13, 18, 21
- can have +X & +Y or lose a sex chromosome |
|
|
______ is useful because it allows identification of small changes that cannot be identified by karyotyping (ie you can probe for certain chromosomes or regions on the chromosome)
|
- FISH
|
|
|
47, XX, +18 means what?
|
- female, one extra chromosome (18)
|
|
|
when does chiasmata occur?
|
- before meiotic division
|
|
|
what is the only monosomy reported?
|
- turner syndrome
|
|
|
triploidy
|
- three sets of chromosomes (ie 69)
|
|
|
what is the difference between constitutional numerical vs. structural changes?
|
- numerical is change in number of chromosomes
- structural is exchange of info b/w chromosomes, deletion, duplication, inversion, insertion, etc. |
|
|
what is the most likely origin of single chromosome changes? triploidy?
|
- single is non-disjunction
- triploidy is two sperm fertilizing one egg |
|
|
exchange of material between two or more chromosomes
|
- translocation
|
|
|
_______ translocations show no phenotype
|
- balanced
|
|
|
what does t(10;11)(p15;q21) mean?
|
- translocation b/w short arm 10 & long arm 11
|
|
|
if daughter is 46,XX,t(10;11)(p;q) what does that mean? if daughter is 46,XX,der(11)t(10;11)(p;q) what does this mean?
|
- daughter has balanced translocation from mother
- daughter got the derivative 11 from translocation b/w 10 & 11 meaning she will have trisomy for part of 10 & monosomy for part of 11 |
|
|
_______ translocations will impact the phenotype due to mixture of monosomy (deletion) & trisomy (duplication) regions
|
- unbalanced
|
|
|
familial translocations
|
- present at birth in some or all cells & are unique to family
|
|
|
robertsonian translocations occur between what chromosomes?
|
- 13/14/15/21/22
- regions in loss of non-critical genes in short arm regions involved |
|
|
what does 45,XY,der(13;14)(q10;q10) mean? what does 46,XX,+14,der(14;21)(q10;q10) mean? are both of these robertsonian translocations?
|
- male w/ robertsonian translocation b/w 13 & 14
- female w/ unbalanced translocation got robertosonian chromosome & 14 from parent - because it has 46 chromosomes it is NOT A ROBERTSONIAN TRANSLOCATION? |
|
|
46,XX,t(10;11)(p15;q21) is a _________ translocation. 46,XX,der(10)t(10;11)(p15;q21) is __________. 45,XX,der(13;14)(q10;q10) is __________.
|
- balanced
- unbalanced - robertsonian |
|
|
_______: Loss of material tends to result in more severe phenotype than duplication of material. On the other hand, ______ are relativey rare and more likely to be picked up later in life.
|
- deletions
- duplications |
|
|
cancer associated translocations like _________ are not unique to the individual and are diagnostic
|
- t(9;22) --> philadelphia chromosome present in CML
|
|
|
acquired changes
|
- cancer associated with genetic change
- not present at birth - phenotype is unchanged by cancer associated translocation |
|
|
in acquired changes, why do translocations recur? what genes can they affect?
|
- breakpoints may be locations of oncogenes (genes that drive cell cycle)
- lose regulation / overproduce normal protein |
|
|
where do deletions in cancer usually happen?
|
- tumor supressors
- removes cell cycle control |
|
|
constitutional vs. acquired: trisomy? meiosis mitosis? monosomy? translocation balanced impact on phenotype? unalanced impact on phenotype? where do they occur (what cell lines)?
|
- const: 13, 18, 21 vs. acquired: any
- C: meiosis vs. A: mitosis - C: X vs. A: any - C: no impact on phenotype usually within families vs. A: diagnostic recurrent - C: abnormal phenotype vs. A: normal phenotype - C: majority of cells vs. A: site of cancer |
|
|
what are 9 clinical features of down syndrome?
|
1) Flat midface/facial profile
2) abnormal auricles 3) nuchal skin fold (increased thickness of neck) 4) single palmar crease 5) poor moro reflex 6) upslanted palpebral fissures 7) clinodactyly (5th fingure curvature) 8) hypotonia 9) hyperflexibility of joints - another commonly seen feature is wide gap b/w 1-2 toes |
|
|
what are 7 associated findings of down syndrome?
|
1) congenital heart disease
2) atlantoaxial instability 3) GI abnormatilities (duodenal atresia) 4) Leukemia 5) Intellectual disability 6) strabismus (one eye drifts out) 7) thyroid abnormalities |
|
|
trisomy 18, what is the prognosis
|
edwards syndrome
- very poor prognosis, only 5% survive beyond 1 year |
|
|
what are 4 clinical findings associated with trisomy 18 (edwards syndrome)?
|
1) small size & small head
2) congenital heart defects 3) overlapping fingers (2nd over 3rd & 5th over 4th) 4) rocker bottom feet |
|
|
trisomy 13, what is the prognosis
|
- patau syndrome
- very poor prognosis, only 5% survive 6 months |
|
|
what are 8 clinical findings associated with patau syndrome (trisomy 13)?
|
1) scalp defects (cutis aplasia)
2) holoprosencephaly 3) microcephaly 4) micropthalmia 5) cleft palate/lip 6) CHD 7) polydactyly 8) renal anomalies |
|
|
what are 6 clinical features associated with turner syndrome?
|
1) lymphedema
2) gonadal regression 3) bicuspid aortic valve 4) short stature 5) webbed neck 6) horseshoe kidney |
|
|
klinefelter syndrome & some clinical description
|
- 47, XXY
- learning disabilities, immaturity, relatively tall w/ long legs, hypogonadism (infertility associated with this), gynecomastia (enlargement of breast tissue) |
|
|
47, XXX
|
- speech delay, IQ 10-15 below siblings
- increased risk for infertility - most offspring chromosomally normal |
|
|
47, XYY
|
- IQ 10-15 points below siblings
- may be at increased risk for behavioral problems (impulsivity) - most offspring chromosomally normal |
|
|
contiguous gene syndromes
|
- clinical symptoms defined before genetic causes known
- submicroscopic deletion of a chromosome containing more than one gene - phenotype correlated with specific genes involved |
|
|
DiGeorge syndrome
|
- deletion on chromosome 22
- prominent nose, long face, small mouth |
|
|
Williams syndrome
|
- deletion on 7q
- happy pleasant social kids - overly friendly, "cocktail party" personality |
|
|
Miller Dieker syndrome
|
- deletion on 17p
- lissencephaly |
|
|
_______: a condition present at birth which requires medical, surgical or cosmetic intervention.
|
- birth defect
|
|
|
Congenital heart disease, polydactyly, neural tube defect are all examples of what?
|
- birth defects
|
|
|
clinical dysmorphology
|
- evaluation for mild dysmorphic features
- ex. single palmar crease |
|
|
what is the correlation between minor and major malformations?
|
- as the # of minor malformations, there is a bigger % of major malformations
|
|
|
________: a recognizable pattern of multiple anomalies thought to be pathogenetically related
|
- syndrome
|
|
|
down syndrome and neurofibromatosis type I (cafe ole spots) are examples of what?
|
- syndrome
|
|
|
_____: a non-random occurence in two or more individuals of multiple anomalies
|
- association
- usually pathogenesis unknown |
|
|
VATER (VACTERL) association
|
- vertebral
- anal anomalies - cardiac - trachio-esophageal fistula - renal anomalies - limb anomalies |
|
|
CHARGE association (now considered a syndrome)
|
- Colobomas of the eye
- Heart defects - Atresia choanae - retarded growth/development - genital hypoplasia - ear anomalies |
|
|
_________: pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor (ie jaw deforms and causes cascade of other events)
|
- sequence
- in pierre robin = malformed jaw, palate malformation due to jaw not developing properly |
|
|
pierre robin & potter are examples of what
|
- sequences
|
|
|
_______ is due to genetic factor. _______ is due to mechanical factor cascading to other problems. ______ is due to unknown factors.
|
- syndrome
- sequence - association |
|
|
poor formation of tissue or part of organ resulting from intrinsically abnormal process
|
- malformation
|
|
|
unusual forces on tissue
|
- deformation
|
|
|
breakdown of normal tissue
|
- disruption
|
|
|
abnormal organization of cells in tissue
|
- dysplasia
|
|
|
cleft lip & webbed feet are examples of ______
|
- malformation
|
|
|
congenital dislocation of the hip & club foot are examples of what _______
|
- deformation
|
|
|
amniotic band syndrome resulting in amputation of finger is example of ________
|
- disruption
|
|
|
hemangioma and skeletal dysplasia such as OI are examples of _______
|
- dysplasia
|
|
|
The effect of ________ on the fetus is highly dependent on the gestational age at time of exposure and dose
|
- tetratogens
|
|
|
when does the first ultrasound occur?
|
- 8 - 10 weeks after conception
|
|
|
what is the first trimester sonographic screening test for down syndrome?
|
- nuchal translucency screening (NT)
|
|
|
nuchal translucency
|
- normal fluid-filled space b/w back of fetal neck and overlying skin
- increased in fetuses with down syndrome |
|
|
what are the first trimester measures for maternal serum screening? What do you look for with down syndrome?
|
- PAPPA-A (pregnancy associated protein - A): low
- beta hCG: high |
|
|
what are the second trimester measures of maternal serum screening? What do you look for with down syndrome?
|
- PAPP-A (normalizes = not a good test)
- beta hCG - high - inhibin A - high - AFP & U E3 are slightly lower than average |
|
|
to interpret the results of a maternal serum screen what do you have to know?
|
- gestational age, maternal weight/diabetes/race, smoking status
|
|
|
when is CVS performed? what does it do? how long does the karyotype take?
|
- performed around 11 weeks (1st trimester)
- sample chorionic villi - rapid karyotype (2-7) days |
|
|
what is the risk of miscarriage with CVS? what are other risks?
|
- 1%
- elevated risk of maternal infection - limb malformation syndrome - confined placental mosaicism in 1% of cases - amniotic fluid alpha-fetoprotein not assayed |
|
|
when is amniocentesis performed? what is it? how long does cell culturing take?
|
- performed 15-17 weeks of gestation (2nd trimester)
- aspirate amniotic fluid - culture takes 7-10 days |
|
|
who has a higher risk of miscarriage: CVS or aminocentesis?
|
- CVS (1%)
- amniocentesis (0.5% or lower) |
|
|
"early" amniocenesis (11-13 weeks) associated with ___________
|
- fetal club foot
|
|
|
PGD? what does it require?
|
- process of screening embryos for genetic abnormalities prior to transfering into the uterus
- requires IVF |
|
|
what is the incidence of birth defects?
|
- 3% in children at birth
- 4% children at 1 year age |
