Day 10.3 Genetics Flashcards
What is the purpose of PCR
Amplify a desired fragment of DNA (eg an allele)
What are the steps of PCR?
- Denaturation - heat the DNA to separate the 2 strands
- Annealing- During cooling, premade DNA primers anneal to a specific seq on the strand to be amplified
- Elongation - heat-stable DNA polymerase replicates the DNA seq after each primer –> then have 2 copies
- Repeat a lot for amplification.
Agarose gel electrophoresis
Used to separate PCR products of different sizes. Negative end (cathode) has wells, and DNA is negatively charged, so it runs toward positive end (anode). Smaller molecules (low molecular weight) travel further bc it is easier for them to get through the gel Results are compared to (known) DNA ladder.
What is unique about the primers used in PCR?
They’re DNA primers (vs the normal RNA primers)
How is PCR for proteins different?
Proteins can be positive or negative, so the wells are in the middle, so that they can travel in either direction. So, PCR identifies both charge and size (smaller travels further)
Southern blot
Southern = DNA sample (and DNA probe)
DNA sample is electrophoresed on gel and txfrd to a filter. Filter is soaked in a denaturant, and then exposed to a labeled DNA probe.
Labeled probe binds to the DNA, making double stranded DNA.
Double strand is seen when the filter is exposed to film.
Northern blot
Northern = RNA (and DNA probe)
RNA is electrophoresed on a gel and then transferred to a filter.
Filter is soaked in denaturant and exposed to DNA probe. DNA binds to RNA and double stranded RNA-DNA hybrid is seen when filter is exposed to film.
Western blot
Western = protein sample (Ab probe)
Sample protein is separated via electrophoresis and transferred to a filter. Labeled Ab is used to bind to the protein.
Southwestern blot
Southwestern - DNA binding proteins (transcription factors) are the sample. They are idenitified using labeled oligonucleotides as the probes.
What is an oligonucleotide?
A short sequence of nucleic acids (single stranded)- e.g. a primer is an oligonucleotide.
What blotting procedure is used to determine gene expression?
Northern (so you can look at the RNA sequence that is transcribed) Northern = RNA
What is a microarray?
Lots of nucleic acid seq’s are arranged in a certain order in grids on a glass/silicon chip.
RNA or DNA probes are hybridized to the chip, chip is scanned to detect the relative amts of binding.
What is microarray used for?
To look at gene expression lvls or to detect SNPs- single nucleotide polymorphisms
For genotyping, forensics, predisposition to dz, cancer mutation, genetic linkage analysis
ELISA
Rapid test for Ag-Ab reactivity.
2 ways to do it:
1. Use a labeled test Ag to see if the pt’s immune system recognizes it (e.g. use HBsurfAg to see if pt has Ab against it; HIV Ag to see if pt has anti-HIV Ab)
2. Use a labeled test Ab to see if the pt has Ag present
The test substance (either Ag or Ab) is coupled to a color-generating enz, so if the target substance is present in the sample, the solution will have an intense color rxn, indicating a positive result.
What is the sensitivity and specificity of the ELISA test?
Both are 100%
But both FP and FN results do occur.
FISH
Fluorescent DNA or RNA probe binds to specific gene site of interest.
Used for specific localization of genes and direct visualization of anomalies (like microdeletions) at a molecular level
Used when deletion is too small to be visualized by karyotyping.
Fluorescence - gene is present. (If no fluor, it is not)
Karyotyping
Done in Metaphase.
Chromosomes are stained, ordered, numbered by morphology, size, arm-length ratio, banding pattern.
Can be performed on sample of blood, bone marrow, amniotic fluid, placental tsu.
Used to dx chromosomal imbalances- autosomal trisomies, sex chr disorders
Cloning methods
- Isolate eukaryotic mRNA of interest
- Expose the mRNA to a reverse transcriptase, to make cDNA
- Insert the cDNA fragments into bacterial plasmids w abx-resistant genes
- Put the bacteria on Abx plate- the ones that survive have the cDNA. Make a cDNA library.
Cloning: what is cDNA
DNA that lacks introns
Cloning: how is the DNA able to be inserted into plasmids?
Restriction enz cleave DNA at 4bp to 6bp palindromic sequences, which allows them to be inserted.
What is Sanger DNA sequencing?
Dideoxynucleotides halt DNA polymerization at each base, so sequences of various lengths are generated (and overall, all of the sequences cover the entire original sequence)
Terminated fragments are electrophoresed and the original sequence is deduced from matching up the overlaps.
What is knock-in?
Inserting a gene.
Constitutive: Gene insertion is random (into any place in the genome) so it could be inserted in the middle of something important and make it non-fnl
Conditional: insertion is targeted thru homologous recombination w the mouse gene. This is better.
What is knock-out?
Removing a gene
Conditional: targeted deletion of gene thru homologous recombination w the mouse gene.
In mouse model systems, how can the gene be manipulated at a specific devtl point?
Inducible cre-lox system w an abx-controlled promoter.
Eg to study a gene whose deletion causes embryonic lethality.
What is RNAi?
dsRNA that is complementary to a mRNA seq of interest is synth’d.
When it’s transfected into cells, the dsRNA separates and promotes degredation of the target mRNA, knocking down gene expression. (no mRNA means no proteins)
Codominance
Neither of 2 alleles is dominant, each has an effect
Ex: Blood groups A, B, AB
Variable expression
The nature and severity of a phenotype can vary from one individual to another even if they both have the same dz mutation
Ex: 2 pts w neurofibromatosis or tuberous sclerosis can have different dz severity
Pleiotropy
One gene has more than one effect on an individual’s phenotype
Ex: PKU causes seemingly unrelated sx - MR, hair and skin changes
Incomplete penetrance
Not all individuals with mutant genotype show the mutant phenotype
THis is why a dz can “skip generations”- mutant gene is always there, but may not show in phenotype.
Imprinting- how does it affect phenotype?
Differences in phenotype depend on whether mutation is in paternal or maternal gene.
Ex: Prader-Willi and Angelman’s syndromes are both d/t inactivation or deletion on Chr 15.
What is imprinting?
Imprinting is silencing of one allele (inactivated by methylation). Therefore, at that locus, only the other allele that is not imprinted is active. If the one active allele (the one that is not imprinted) is defective/deleted, then there is dz.
Prader-Willi syndrome
Ex of imprinting. Mom’s allele was imprinted (silenced), and the normally active Paternal allele is deleted.
Prader = Paternal deletion on Chr 15
Px in infancy w hypotonia, poor feeding, almond eyes and downward mouth.
Sx: MR, obese and hyperphagic, hypotonia, short stature (partial GH deficiency), bhvr disorders, and hypogonadotrophic hypogonadism –>genital hypoplasia, childhood osteoporosis, and delayed menarche
Angelman’s syndrome
Ex of imprinting. Dad’s allele was imprinted (silenced), and the normally active Maternal allele is deleted.
angelMan’s = Maternal deletion on Chr 15
Sx: MR, seizures, ataxia, inappropriate laughter (happy puppet)
What is the difference bt variable expression and pleiotropy?
Variable exprsn means the nature and severity of phenotype can vary bt individuals
Pleiotropy means that one gene can have more than one affect on the phenotype (eg can affect both brain and skin)
Anticipation
Severity of disease worsens w successive generations
Or, age of onset is earlier in successive generations
Ex trinucleotide repeat dz like huntington’s
Loss of heterozygosity
Must lose both alleles before there is an effect.
Eg if a pt inherits a mutation in a tumor suppressor gene, the pt is fine- unless there is also a mutation/deletion in the complementary allele –> then, cancer. (Two-hit hypoth)
Ex: retinoblastoma, p53 mutations
Note: this is NOT true for oncogenes- they have a gain of fn mutation, so only need one mutated.
Dominant negative mutation
Mutation exerts a dominant effect- so a heterozygote will make a non-fnl altered protein that also prevents the normal gene product from fn’g
Ex: mutation of Tx factor in its allosteric site. The non-fn’g mutant can still bind DNA, preventing the wild-type Rx factor from binding. (i don’t think this is the best ex)
Linkage disequilibrium
Tendency for certain alleles in the same gene to occur together more often than they would by chance.
Measured in an entire population (not in a family) and often varies in different populations.
Mosaicism
Occurs when cells in the same body have different genetic makeups.
If it’s germ-line mosaic, it will not affect the adult which has the mosaicism, but can produce dz in that person’s offspring.
Examples of mosaicism
Lyonization- random X inactivation in some cells in females
Mutation in the embryonic precursor of the bone marrow stem cell –>hematologic mosaicism
Chimeric pt- 2 zygotes that fuse, so 2 DNAs in one pt
Locus heterogeneity
Mutations at different loci can produce the same phenotype
Ex: several different things produce marfan’s habitus:
marfan’s syndrome
MEN 2B
homocystinuria (can’t metabolise methionine)
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited dz
Uniparental disomy
Offspring gets 2 copies of chromosome from 1 parent, and no copies from other parent
Can look like imprinting.
Hardy-Weinberg eqlbm
Disease prevalence:
p^2 + 2pq + q^2 = 1
Allele prevalence:
p + q = 1
2pq = heterozygote prevalence p^2 = pp prevalence, q^2 = qq prevalence (so p^2 + q^2 is the prevalence of ALL homozygotes)
What is the prevalence of an X-linked recessive dz in males and in females, using Hardy-Weinberg?
Males: q
Females: q^2
What are the assumptions of Hardy-Weinberg law?
- No mutations at the locus
- No selection for any of the genotypes at the locus
- Completely random mating
- No migration
If 1% of all individuals have an auto-recessive dz, what % of alleles are not mutant?
Auto-recess means that only pp will have it. So prevalence of pp is p^2 = 1%.
So, p is sq rt of 0.01, which is 0.1
Since p = 0.1,
q = 0.9 (since p + q = 1 is allele prevalence)
So, 90% of alleles are NOT mutant
(and 10% are)
Also, 1 % are pp, 18% are pq, and 81% are qq
Autosomal dominant inheritance
Only one allele needs to be mutated to cause dz
Often d/t defects in structural genes
Many generations, both male and female affected
50% of offspring affected (either sex)
Often pleiotropic (meaning the one gene has more than one effect on phenotype), and often present after puberty. (Huntington’s)
Fam hx is crucial to dx.
Autosomal recessive inheritance
Phenotype only present when you have both copies of the allele.
Often d/t enz deficiencies
Usu only seen in one generation (unless incest)
Commonly more severe than auto-dom, pts often px in childhood
If both parents are carriers (Rr), then 25% chance that offspring will get it.
X-linked recessive
Males are affected more severely bc they only have one X
Sons of heterozyg mom get it 50% of the time
Females of heterozyg mom are carriers 50% of time.
Homozyg females are affected (dad had it and mom was a carrier)
X-linked dominant
Transmitted thru both parents
ALL female offspring of an affected father have it.
An affected mother can pass it on to either male or female offspring.
Hypophosphatemic rickets
(aka vit d resistant rickets)
X-linked dom
Increased phosphate wasting at proximal tubule
Results in rickets-like presentation
Mitochondrial inheritance
Inheritance is thru mother ONLY.
ALL offspring of affected females have dz.
There is variable exprsn in the population d/t heteroplasmy (presence of both normal and mutated mito DNA)
List 3 mitochondrial inheritance defects
- Mitochondrial myopathy - see ragged-red musc fibers on biopsy
- Leber’s hereditary optic neuropathy - degeneration of retinal ganglion cells and axons, leads to acute loss of central vision
- Leigh syndrome - subacute sclerosing encephalopathy
Females have a 50% chance of being a carrier
X-linked recessive
Usu only seen in one generation
Auto-recessive
If a male is affected, all of his daughters will be affected
X-linked dom
If a female is affected, all of her offspring will have the dz
Mitochondrial inheritance
No male-to-male transmission
X-linked recessive (bc males give Y to sons- X is always from mom)
Phenotype only present if there are 2 affected alleles
Auto-recessive
Presents before puberty vs after puberty
Auto-recessive- before puberty (so usu only 1 generation)
Auto-dom - after puberty (Huntington’s)
Achrondroplasia
Auto-dom
Cell-signaling defect of FGF receptor 3 (fibroblast growth factor)
Causes dwarfism- head/trunk normal, but limbs are short.
A/w advanced paternal age
ADPKD
Auto-dom, adult type
Always bilateral!
Massively enlgd kidneys d/t mult lg cysts
Px w flank pain, heumatura, HTN, progressive renal failure
90% d/t mutation in APKD1 gene on chr 16
A/w polycystic liver dz, berry aneurysms(!), MV prolapse
ARPKD
Auto-rec, “infantile” form of PKD.
Same as ADPKD, just genes are just different.
What auto-dom dz’s predispose to berry aneurysms
ADPKD
Marfan’s syndrome
What auto-dom dz’s cause MV prolapse?
ADPKD
Marfan’s syndrome - causes “floppy” MV (aka prolapse)
What dz’s are d/t mutations in the APC gene?
FAP (familial adenomatous polyposis)
Gardener’s syndrome
Familial ADenonmatous Polyposis (FAP)
AD = autosomal dominant
Colon becomes covered w adenomatous polyps after puberty. (Adenomatous = benign epithelial tumor that arises from a gland).
Unless colon is resected, will progress to colon cancer.
D/t deletion on Chr 5 - APC gene
What causes MI before the age of 20?
Hypertrophic cardiomyopathy
If genetic: Familial hypercholesterolemia (aka hyperlipidemia IIA)
Hereditary hemorrhagic telangiectasia
aka Osler-Weber-Rendu syndrome
Auto-dom inherited disorder of blood vessels
Telangiectasia (dilated blood vessels near skin surface), recurrent epistaxis (nosebleeds), skin discolorations, AVMs- arterial-venous malformatons (abn connections that allow blood to go art –> vein w/o going thru capillaries)
Familial hypercholesterolemia (aka hyperlipidemia IIA)
Auto-dom Elevated LDL d/t defective or absent LDL receptor (so can't remove LDL from blood) Heterozygotes: cholesterol = 300 Homozygotes (rare): chol = 700+ Severe atherosclerotic dz early in life Tendon xanthomas (classically in achilles)
Hereditary spherocytosis
Auto-dom
Spheroid erythrocytes d/t specrin or ankyrin defect
Causes hemolytic anemia bc spleen sees them as normal and gets rid of them.
Have increased MCHC (mean cell Hb conc) since it’s a sphere it can fit more Hb inside.
Dx w osmotic fragility test
Rx splenectomy
Huntington’s dz
Auto-dom trinucleotide repeat CAG Crazy (dementia) Chorea Caudate atrophy CAG repeat Decreased GABA and ACh Deprsn Sx in pts 20-50yo Hunting 4 food - on Chr 4
Marfan’s syndrome
Auto-dom Fibrillin gene mutation CT disorder affecting skel, heart, eyes Tall w long extremities, pectus excavatum, hyperextensive joints, arachnodactyly. Cystic medial necrosis of aorta --> aortic incompetence and dissecting aortic aneurysms. Floppy mitral valve (MV prolapse) Subluxation of lenses Berry aneurysms.
Multiple Endocrine Neoplasias
Auto-dom
MEN 1, 2A, 2B
Familial tumors of endocrine glands
MEN 2A, 2B a/w Ret gene
NF1
Auto dom, aka von Recklinghausen's Cafe--au-lait spots Neural tumors Lisch nodules (pigmented iris hamartomas) Skel disorders (scoloisis) Optic pathway gliomas Pheochromocytoma Increased tumor susceptibility. On long arm of chr 17
NF2
Bilateral acoustic neuroma
Juvenile cataracts
On Chr 22 (2 for NF2, 2 for bilateral)
Tuberous sclerosis
Auto dom Mutated hamartin or tuberin gene Facial lesions (adenoma sebaceum) Hypopigmented ash leaf spots cortical and retinal hamartomas seizures MR renal cysts, renal angiolipomas cardiac rhabdomyomas (!!) astrocytomas (!!) Can have incomplete penetrance, variable presentation.
von-Hipple-Lindau dz
Auto-dom
Deletion of VHL genes (which are tumor suppressor genes) on Chr 3. This results in constitutive expression of HIF (a transcription factor) and activation of angiogenic growth factor.
Findings: hemangioblastomas of retina/cerebellum/medulla
about half of affected pts devp multple bilateral renal cell carcinomas and other tumors (pheochromocytoma)
List the auto-recessive dz’s
Albinism ARPKD (infantile) CF Glycogen storage dz's Hemochromatosis Mucopolysacharidoses* (except Hunter's) PKU Sickle cell anemia Sphingolipidoses* (except Fabry's) Thalassemias
*lysosomal storage dz’s
List all of the lysosomal storage diseases
2 groups: 1. Sphingolipidoses: Fabry's dz Gaucher's dz (most common) Niemann-Pick dz Tay-Sachs dz Krabbe's dz Metachromatic leukodystrophy
- Mucopolysaccharidoses
Hurler’s syndrome
Hunter’s syndrome
What is the inheritance pattern of most lysosomal storage dz’s? What is the exception?
All are recessive.
Most are auto-recessive,
except:
Fabry’s dz and Hunter’s syndrome - they are X-linked recessive.
X marks the spot for the treasure Hunter.
Fabry’s dz
Spingolipid lysosomal storage dz X-linked recessive No a-galactosidase A So ceramide trihexoside accumulates Get renal failure. Periph neuropathy of hands/feet, angiokeratomas, cardiac/renal dz.
Gaucher’s dz
Most common lysosomal storage dz (sphingolipid)
Auto-recessive
No B-glucocerebrosidase,
so build up of Glucocerebroside
Get hepatosplenomegaly, bone crises, aseptic necrosis of the femur.
Also see Gaucher’s cells- macrophages that look like crumpled tsu paper.
Niemann-Pick dz
Sphingolipid lysosomal storage dz Auto-reces No sphingomyelinase So sphingomyelin accumulates Progressive neurodegeneration, cherry red spot on macula, hepatopslenomegaly, foam cells
Tay-Sachs dz
Sphingolipid lysosomal storage dz No Hexosaminidase A (saX lacks heXo) So GM2 ganglioside accumulates Progressive neurodegeneration, developmental delay, cherry-red spot on macula, lysosomes w onion-skin. (No hepatosplenomeg- vs N-P, which does)
Krabbe’s dz
Sphingolipid lysosomal storage dz auto-reces Galactocerebrosidase deficiency, So galactocerebroside accumulates Peripheral neuropathy, devtl delay, optic atrophy, globoid cells
Metachromatic leukodystrophy
Sphingolipid lysosomal storage dz Auto-recessive Deficiency of Arylsulfatase A, so Cerobroside Sulfate builds up Central and peripheral demyelination w ataxia, dementia
Hurler’s syndrome
Mucopolysaccharide lysosomal storage dz
Auto-recess
Deficiency of a-L-iduronidase,
So heparin sulfate and dermatan sulfate accumulate
Developmental delay, gargoylism, airway obstruction, corneal clouding(!)
Hunter’s syndrome
Mucopolysaccharide lysosomal storage dz X-linked recessive (treasure Hunter- X) No Iduronate sulfatase, So heparin sulfate and dermatan build up Mild Hurler's + aggression, but with no corneal clouding(!) - Hunters see clearly.
What lysosomal storage dz’s do Ashkenazi Jews have increased risk for?
Tay-Sachs
Niemann-Pick
some forms of Gaucher’s
How is ceramide made?
Several pathways:
GM2 –> GM3 –>Glucocerebroside –> Ceramide (inhibited by TS, Gaucher’s)
Ceramide trihexoside –> Glucocerebroside –> Ceramide (inhibited by Fabry’s, Gaucher’s)
Sulfatides –> Galactocerebroside –> Ceramide (inhib by metachrom leukodys, Krabbe’s)
Spingomyelin –> Ceramide (inhibt by N-P)
Lysosomal storage dz a/w renal failure?
Fabry’s
Rx is dialysis
X-linked recessive lysosomal storage dz’s
Fabry’s and Hunter’s
In X-linked recessive, there is no male-male txmsn. sons of hetero moms have 50% chance of being affected. daughters have 50% chance of being a carrier.
Most common lysosomal storage dz
Gaucher’s
Lysosomal storage dz assoc w early death (by age 3)
Tay-Sachs
Niemann-Pick
Krabbe’s
Lysosomal storage dz that is demyelinating
Metachromatic leukodystrophy
both centrally and peripherally demyelinating
Corneal clouding is seen in what diseases?
Hurler’s (CC + MR)
Scheie’s (less severe Hurler’s- CC but no MR)
I-cell dz (CC +/- MR)
Note: Hunter’s does NOT have CC (Hunter’s need to see clearly) but does have MR like Hurler’s
a-L-iduronidase deficiency
Hurler’s (and Scheie’s)
Iduronate sulfatase deficiency
Hunter’s
Arylsulfatase A deficiency
Metachromatic leukodystrophy
a-galactosidase A deficiency
Fabry’s dz
Galactocerebrosidase deficiency
Krabbe’s dz
build up of galactocerebroside
B-glucocerebrosidase deficiency
Gaucher’s dz
build up of Glucocerebroside
Hexosaminidase deficiency
Tay-Sachs
heXos = saX
Sphingomyelinase deficiency
Niemann-Pick dz
sphingomyelin accumulates
GM2 ganglioside accumulation
Tay-Sachs
bc no HeXosaminidase A
Dermatan sulfate accumulation
Hurler’s and Hunter’s and Scheie’s
Crinkled paper cytoplasm
Macrophages of Gaucher’s dz
DDx for cherry-red spot on macula
Tay-Sachs
Niemann-Pick (+hePatosPlenomegaly)
Central retinal artery occlusion
What is I-cell dz?
Deficiency in mannose phosphorylation, so there is no Mannose-6-P to target lysosomal proteins to the lysosome
Instead, the proteins follow the default pathway and are secreted out of the cell instead of going to the lysosome.
Die by age 8
Corneal clouding, course facies, HSM, skel abn, restricted joint mvmt, +/- MR
List the possible modes of inheritance
Auto-dom Auto-rec X-dom X-rec Mito Don't freak out, that's it!
List the X-linked recessive disorders
Be Wise, Fool's GOLD Heeds Silly Hope Bruton's agammaglobulinemia Wiskott-Aldrich Fabry's G6PD def Ocular albinism (general alb is auto-rec) Lesch-Nyhan (HGPRT) Duchenne's MD (and Becker's) Hunter's Syndrome Hemophilia A and B also Fragile X!
Other mne: Fabry’s Tale: Duke the MUSCular Hunter BRUtally LYSed the Albino Gopher but wasn’t aWAre it was a Fragile Hemophilac.
T/F female carriers are rarely affected by X-linked recessive disorders.
True.
Rarely affected bc of random X-inactivation of an X chromosome of each cell.
Duchenne’s MD
X-linked recessive
Frameshift mutation - causes deletion of the dystrophin gene, so there is accelerated muscle breakdown.
Weakness starts in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf musc d/t fibrofatty replcmt of musc
Cardiac myopathy.
Gower’s sign- require upper extremities to stand.
Onset before 5.
Becker’s MD
X-linked recessive
Mutated dystrophin gene (not deleted like in Duchenne’s, just mutated so less fnl)
Less severe
Onset in early adolescence or early adulthood.
Dystrophin gene characteristics
DMD - longest known gene, so increased rate of spontaneous mutation.
Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle.
How are muscular dystrophies dx’d?
Increased CPK (bc of muscle breakdown) Fatty replcmt of muscle on biopsy.
Fragile X syndrome genetics
X-linked defect affecting methylation and expression of the FMR1 gene.
FMR1 encodes for FMRP, a cytoplasmic protein in the brain and testes.
FMRP goes to the axons and dendrites and is involved in mRNA translation.
This is a trinucleotide repeat disorder- GCG - of the FMR1 gene.
A/w chromosomal breakage.
Fragile X findings
MR (2nd most common genetic cause) Macro-orchidism (enlgd testes) Long face, large jaw, large everted ears Autism MV prolapse
Fragile X = Xtra lg testes, jaw, ears
Top 3 causes of MR
- FAS
- Down’s*
- Fragile X*
*genetic causes
Mode of inheritance of hemochromatosis
Auto-recessive
List the trinucleotide repeat dz’s, and what the repeat is
X-Girlfriend’s First Aid Helped Ace My Test
the second word is the middle(!) letter of each of the repeats
Fragile X = CGG
Fredric’s ataxia = GAA
Huntington’s = CAG
Myotonic dystrophy = CTG
May show genetic anticipation (worse severity or decrsd age of onset) in successive generations
Germline expansion in females
Genetics of Down’s Syndrome
Trisomy 21 (1 in 700 live births) 95% of cases are d/t meiotic non-disjn of homologous chromosomes (maternal ages affects this a lot) 4% of cases d/t Robertsonian translocation 1% d/t Down mosaicism (not materinal association)
Most common chromosomal disorder
Most common genetic cause of congential MR
Meiotic Nondisjunction
This is where some of the cells end up with the wrong thing at the end of meiosis.
If it happens in Meiosis I:
In Anaphase I, both copies (maternal and paternal) of the chromosome go into the same daughter cell (so the other daughter cell that should have gotten a copy is blank). Then, after Anaphase II, one chromatid of each chromosome of the extra full cell goes into a daughter cell. So, instead of having 4 daughter cells that are N, there are 2 daughter cells that are N+1 and 2 daughter cells that are blank (N-1)
If it happens in Meiosis II:
Anaphase I is totally fine, the maternal chromosome goes to one daughter cell and the paternal goes to another. But, in Anaphase II, one of those splits as it should, but the other puts two of its sister chromatids in one cell. So instead of having 4 cells each with N, you get 2 with N (this is correct), 1 blank (N-1) and one w extra (N+1)
See the pic p88
Pregnancy quad screen results for Down Syndrome
Increased B-hCG (!)
Decreased AFP
Decreased Estriol
Increased Inhibin A
Down Syndrome (findings)
MR Flat facies, prominant epicanthal folds Simean crease, gap bt first 2 toes Duodenal atresia Congenital heart dz bc of endocardial cushion defect- most commonly septum primum-type ASD.
On US: increased nuchal rigidity
A/w increased risk of ALL, AML, Alzheimer’s at <35yo
Edwards’ Syndrome
Trisomy 18 Severe MR Rocker-bottom feet Micrognathia (Small jaw) Low set ears Clenched hands Prominent occiput Congenital heart dz Usu die w/in 1 year 2nd most common trisomy resulting in live birth (but only 1/8000)
Pregnancy quad screen for Edwards’
Decreased B-hCG
Decreased AFP
Decreased estriol
Normal Inhibin A
Patau’s syndrome
Trisomy 13 Severe MR Rocker-bottom feet (like Edwards) Micropthalmia Microcephaly Cleft lip/palate HoloProsenencephaly (single eye) Polydactyly Congenital heart dz Usu die w/in 1 year 1:15,000
Preg quad screen for Patau’s
Everything is normal: APF, B-hCG, estriol, inhibin A
Robertsonian Translocation
Non-reciprocal.
Chr 13, 14, 15, 21, 22 (bc they’re acrocentric)
Long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost.
Balanced translocations usu don’t cause an abn phenotype
Unbalanced translocations result in miscarriage, stillbirth, chromosomal imbalance (trisomy- Down’s, Patau)
T/F A non-Robertsonian translocation is reciprocal
True.
Robertsonian is NON-reciprocal
Chromosomal inversion
Chr rearrangement in which a segment of a chr is reversed end to end. May result in decreased fertility.
Pericentric - involves centromere, proceeds thru meiosis
Paracentric- does not involve centromere, does not proceed thru meiosis
Cri-du-chat syndrome
Congential microdeletion of short arm of Chr 5. (46XX or XY, 5p-) Microcephaly, MR High-pitched crying/mewing! Epicanthal folds Cardiac abn
Williams syndrome
Congenital microdeletion of Chr 7
The deleted region includes the elastin gene
Elfin facies
MR
Hypercalcemia (bc increased sensitivity to Vit D)
Extreme friendliness and well-devpd verbal skills
CV problems
Think of WILL ferrel in Elf
DiGeorge syndrome
Thymic, parathyroid, cardiac defects
90% d/t 22q11 deletion
What do the 3rd and 4th brachial pouches develop into?
3rd pouch –> thymus, inf parathyroids
4th pouch –> superior parathyroids
Velocardiofacial syndrome
Palate, facial, cardiac defects
d/t 22q11 deletion
22q11 deletion
CATCH-22 Aberrant devt of 3rd and 4th brachial pouches. variable presentation, incl: Cleft palate Abn facies Thymic aplasia (so T cell deficiency) Cardiac defects Hypocalcemia (bc of parathyroid aplasia)
Incl DiGeorge, Velocardiofacial syndrome
Genetic dz w Multiple fractures, confused w child abuse
Osteogenesis Imperfecta
Genetic dz w hemangioblastomas of the retina, cerebellum, medulla
VHL
Genetic dz w recurrent pulm infections, steatorrhea
CF
