Dr. Clark's Lectures 12 6 Flashcards
What mechanisms can cause congenital abnormalities? Are they extrinsic or intrinsic? Give an example of each
Extrinsic factors - lower recurrence risk
- Deformation: Anomaly caused by an abnormal mechanical force (can be either the presence of an abnormal force or the absence of a normal force) that alters the shape of, but does not destroy, an otherwise normal organ without halting morphogenesis.
ex: potter sequence (due to oligohydramnios causing renal agenesis), facial compression and pulmonary hyppoplasia from oligohydramnios or high arched palate in myotonic dystrophy (palate needs tongue movement to be shaped properly and doesn’t get it) - Disruption: Anomaly caused by an environmental or extrinsic factor that destroys otherwise normal tissue and interrupts normal morphogenesis.
Teratogens:
-Retinoic Acid - Accutane
MOST end in miscarriage
Absence of external auditory canal
Ear abnormality, aortic arch, brain defects, SAb
-Thalidomide
Limb defects, phocomelia
-Tobacco
Growth retardation, miscarriage
-Alcohol - Fetal Alcohol Syndrome
Fetal alcohol spectrum affects up to 1% of population in US
Poor growth, microcephaly
Mental retardation, short palpebral
fissures, smooth philtrum (pillar between upper lip), thin upper lip,
“railroad track ears”
Heart defect, Cleft lip
OR
Absence of Morphogen (needs to be there for normal development)
-Folic Acid
Neural tube defects, cleft lip, cardiac anomalies
OR
Maternal disease or infection (PKU, diabetes, rubella)
OR
vascular incidents causing insufficient blood flow
ex: amyoplasia with amniotic band: baby movement with a ruptured amniotic sac–> can wrap around baby’s limb with baby’s movement and cut off circulation or even amputate ==> baby will show distal swelling, asymmetric amputations
Instrinsic factors - higher recurrence risk
- Malformation: Anomaly caused by intrinsic factors that result in abnormal tissue or defective morphogenesis
ex: Adams oliver syndrome: autosomal dominant trait with incomplete penetrance–> cause scalp and skin defects, symmetric lesions, sctrodactyly==> caused by a gene, not amniotic banding
ex: neural tube defect (can prevent 70% by taking folic acid prior to conception)
- isolated cleft lip/palate: multifactoral–> look at lower lip for accessory salivary glands
What is folic acid? How much folic acid is the recommended supplement?
Folic acid is a water soluble B vitamin: Vitamin B9 that is a morphogen (factor required for normal morphogenesis)
Supplementation with folic acid reduces the incidence of many birth defects, including neural tube defects and diabetic embryopathy.
The CDC recommends that all women of reproductive age take a folic acid supplement of 400 micrograms, daily.
After the birth a child with spina bifida or anencephaly, a woman should take 4 milligrams daily to reduce the chance of a neural tube defect in the next pregnancy.
The average American female consumes about 140 micrograms of folic acid/day from dietary sources alone
can reduce birth defects in half if taken at the time of conception
What are 3 common teratogens and their features?
-Retinoic Acid - Accutane
MOST end in miscarriage
Absence of external auditory canal
Ear abnormality, aortic arch, brain defects, SAb
-Thalidomide
Limb defects, phocomelia
-Tobacco
Growth retardation, miscarriage
-Alcohol - Fetal Alcohol Syndrome
Fetal alcohol spectrum affects up to 1% of population in US
Poor growth, microcephaly
Mental retardation, short palpebral
fissures, smooth philtrum (pillar between upper lip), thin upper lip,
“railroad track ears”
Heart defect, Cleft lip
what is Dysplasia?
A pattern of malformations affecting the same tissue type.
ex: x-linked ectodermal dysplasia: thin hair, poor teeth, patchy sweating in females. Males have needle-like teeth and absent sweating–> need to be sprayed with water to keep cool
-achondroplasia: most common bone dysplasia: autosomal dominant–> FGFR3 of paternal origin, common in advanced paternal age–> hyper extensible, macrocephaly, hypotonia
different mutations in FGFR3 can also lead to thanatophoric dysplasia
what is association? Give an example
A pattern on anomalies that occur together more often than expected by chance alone, but not in any single pattern and not necessarily with a single cause.
ex: VATER Association
These anomalies occur together more commonly than predicted by chance alone (VATER/VACTERL):
VSD and Vertebral defects
Imperforate Anus
Tracheo-Esophageal fistula
Radial and Renal defects
2 vessel cord
Normal birth weight
No facial dysmorphism
No anomalies outside the VATER spectrum.
Other syndromes can mimic this pattern:
Esophageal atresia more common in infants conceived by ART.
Infant of diabetic mother
Fanconi Anemia
Valproic acid embryopathy
what s sequence? give an example
A pattern of anomalies in which a primary defect leads to one or more secondary defects; a cascade effect.
ex: Holoprosencephaly Sequence
Failure of cleavage of cranial hemispheres: lobar, semilobar, alobar
Maternal diabetes strongly associated with HPE
Chromosome anomalies 41%:
Trisomy 13, 18p-
Of those with a normal karyotype:
Microdeletions 8.5%
Mutations 14%: SHH, ZIC2, SIX3, TGIF
Examine parents for microforms: (don’t always fully express) hypotelorism, anosmia, single incisor, microcephaly
the face predicts the brain—> lack of cupids bow, lack of midline frenulum, only one nostril==> deletion of SHH gene
Common characteristics of Turner Syndrome
45, X
missing a chromosome. Associated with young maternal age. No significant recurrence risk. High lethality in utero - common in spontaneous abortuses.
Coarctation of the aorta, horseshoe kidney, edema, webbed neck, short stature, lack of secondary sexual characteristics, infertile.
Common Characteristics of Prader-Willi syndrome
deletion of paternal 15q11 Hypotonia Poor feeding in infancy “Almond shaped “ eyes Narrow bitemporal diameter Hypopigmentation compared to relatives Hypogenitalism in males Decreased pain sensation Obesity and lack of satiety in childhood No vomiting (the lack of satiety and no vomiting can lead to stomach rupture) Mild to moderate intellectual disability Growth hormone can make a difference in their tone/body
Angelman syndrome is a result of the same deletion on the maternal gene.
FISH
FLuoresence in situ hybridization
FISH will pick up a deletion but will not pick up uniparental disomy because it isn’t a deletion
probe DNA and then label it with fluorescent dye–> denature and hybridize
look at fluorescent image to look for any trisomy/monosomy
Array Comparative Genomic Hybridization
Patient’s single stranded DNA (green) and DNA from a reference human (red) compete for hybridization to a target array
Detects copy number variation (CNV)
Deletion in the patient = excess red in the target region on the array
Duplication in the patient = excess green in the target region on the array
*do not need to know what you’re looking at
Advantages over conventional cytogenetics
Finer resolution of breakpoints, defines genes involved and higher detection rates
Cytogenetics can detect 5Mb deletions and duplications but not smaller.
Disadvantages over conventional cytogenetics
Higher Cost
Does not detect balanced rearrangements (inversions, translocations)
Need to confirm results with FISH
Many CNVs are of unknown clinical significance
Some are benign polymorphisms, may need to test parents
aCGH has a high yield in detecting mental retardation
-about 9-18% of congenital developmentally delayed individuals have a chromosomal etiology that can be detected with aCGH
-will NOT detect:
deletions too small to be detected with probes in the array
balanced chromosome rearrangements (reciprocal translocations and inversions)
low level mosaicism
mitochondrial DNA deletions
gene mutations
SNP microarray
get tracts of SNPs
normally AA first row, then AB, then BB on bottom
A=the most common allele
B=less common allele
Absence of heterozygosity (AOH) or Loss of heterozygosity (LOH)
Regions of Homozygosity (ROH) can be caused by:
Consanguinity, incest
Common haplotype block shared by parents who are of same ethnicity
(haplotype: distinctive chromosome segment associated with a region or ethnicity)
Uniparental isodisomy (both copies of a chromosome are identical and are inherited from the same parent). Note: Heterodisomy will not be detected.
ROH can identify likely loci for an autosomal recessive trait
Look at the areas of ROH that affected siblings in consanguineous families have in common for “autozygosity” gene mapping
Founder Effect
A high frequency of a specific gene mutation in a population founded by a small ancestral group
Missense mutation, nonsense mutation, frameshift mutation, splice-site mutation
missense: changes to a codon for another AA –> can be harmful or neutral
nonsense: change from an AA codon to a stop codon–> producing a shortened protein
frameshift: insertion or deletion of base pairs changing subsequent AA codons –> normally results in a stop codon and shortened protein
splice-site mutations: a change that results in altered RNA sequence
endonucleases create DNA fragments of different lengths–> size of gene fragments may vary when a mutation changes the length of a fragment or cleavage site
Southern Blot
Restriction endonucleases create DNA fragments of different lengths, called Restriction Fragment Length Polymorphisms (RFLP)
RFLPs migrate in an electrophoretic gel according to their size, shape and polarity, creating a pattern of normal and abnormal sized fragments.
Southern blots can also determine the number of gene copies in a genome.
Southern blot – DNA electrophoresis
northern blot – RNA electrophoresis
western blot – protein electrophoresis
can only pick up mutations if the length of DNA changes–> the restriction site has to be changed by the mutation
Linkage analysis
looks for pattern of DNA markers near the gene of interest that segregate with the disease.
*requires analysis of multiple family members
use southern blot to find bands that are always associated with disease–> link a physical trait to a disease state: linkage via RFLP and southern blot
