Key Concepts Flashcards
The two distinct forms of triploidy
Diandry - typically the consequence of dispermy (2 sperm fertilize the same egg) or a diploid sperm fertilizes a normal, haploid egg
Digyny - most commonly due to a diploid egg and haploid sperm, which may be the result of nondisjunction of the entire chromosome set at eithe M1 or M2 division in oogenesis
Hydatidiform mole
Abnml pregnancy that is a type of male chromosomal disorder. Typically the result of a diandric triploid that aborts in the 1st or early 2nd trimester. The chorionic villi form fluid-filled sacs, which is considered a degenerative change.
Dygynic triploids
Nonmolar and mostly abort early (~10 wks). Any surviving dygynic triploids develop as a severely growth retarded fetus w/marked head-body disproportion (large head, small body)
Triploidy reoccurence
Most triploidy occurs sporadically, but a genetic predisposition does exist. Failure of maternal M2 is a common basis for this predisposition.
Complete mole
Placental tissues - swollen chorionic villi - but no embryo. The typical karyotype is 46,XX, which is typically due to a doubling (endoreduplication) of the chromosomal complement of a single 23,X sperm (a minority are dispermic). There is not maternal chromosomal contribution - the mole’s genome is entirely paternal origin = uniparental diploidly (total UPD)
Occur more often at the beginning and end of a female’s reproductive life (teenagers, 40s)
Presents either at early ultrasonography w/a “snowstorm” pattern of the placenta (reflecting swollen villi) or vaginal bleeding. Widespread hyperplasia of trophoblasts
KIP2 staining can discern btwn complete mole (no stain) and partial mole (stain)
Tetraploidy conceptus
Caused by a number of mechanisms. The simplest being a reduplication of the diploid set in the zygote at M1.
If 92,XXXY it could be trispermy, retention of a polar body w/concomitant dispermy, or dispermy with a haploid and diploid sperm
Some tetraploidy cells in a placenta are normal (i.e. kidney cells). If the sample is >20-30% tetraploidy, this is likely a mosaic tetraploid fetus.
Confined placental mosaicism raises concerns for what?
The the fetal diploidy may have arisen due to trisomy rescue. This is true for all chromosomes, but specifically for mosaic trisomy of 7, 11, 14, or 15.
Trisomy rescue
The loss of an extra chromosome postzygotically, an event that presumably allows fetal viability. If the fetus has retained two copies of a chromosome from the same parent, however, the result is uniparental disomy
Malformations
Result from the intrinsic abnormalities in one or more genetic programs during development. Examples: neural tube defects, cleft lip/palate , extra fingers, congenital heart defects.
Oligohydraminos
Abnormally decreased amount of amniotic fluid surrounding the fetus
Deformations
Caused by extrinsic factors impinging physically on the fetus during development. Examples: craniofacial asymmetry, arthrogryposis, and talipes (clubfoot)
Disruption
May be the result of vascular insufficiency, trauma, or teratogens, which destroys normal tissue altering the formation of a structure. Examples: facials clefts and missing digits or limbs. “amniotic bands”
What is the clinical sensitivity of the 1st trimester screen for Down’s
80%, 100% for trisomies 13 & 18
true pos/true pos + false pos
What is the clinical specificity of the 1st trimester screen for Down’s?
92%, AKA true negative rate
SPC = true neg/neg
What is the clinical sensitivity of the 2nd trimester screen for Down’s
81%
What is the clinical specificity for a 2nd trimester screen for Down’s
95%
How are most neural tube defects detected
via high maternal serum AFP
Estriol (uE3)
should be low if the fetus has a NTD
New born screening in the US began when?
1960s
Most commonly receives false-pos NBS
lowest of low birthweight babies in NICU due to various medical therapies including TPN and liver immaturity
How many conditions are recommended to be on basic NBS in all states (as decided by ACMG)?
29
In what population is glucose-6-phosphate dehydrogenase (G6PD) deficiency relatively uncommon
Least common in Hispanics
Why is mass spec used to test for PKU
It measures the concentration of Phe and the ratio Phe to tyrosine, both of which are elevated in PKU
How are fatty acid oxidation disorders detected in NBS
mass spec
What gene is most closely associated with rhizomelic chondrodysplasia punctata (RCDP)?
PEX7
What lab results are usually seen in Zellweger syndrome
Overaccumulation of VLCFAs
Overaccumulation of phytanic acids
Deficiency of plasmalogens
If suspected look for mutations in PEX genes (primarily PEX1). Can run NGS panel.
Very long chain fatty acids
22 or more carbons
Hereditary Hemochromatosis
Assoc w/heptamegaly, hepatic cirrhosis, and hepatocellular carcinoma
Clinical symptoms for HFe
Hepatomegaly, cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, hypogonadism, arthritis, and progressive skin pigmentation
Pathogenic variants I. ATP7A cause what?
Menkes disease
X-linked recessive disorder
Associated w/copper deficiencies
4 genes associated w/iron overload
HFE
HFE2B
HAMP
HJV
Gene associated with Wilson disease
ATP7B
If pili torti
Think Menkes!
Kaiser-Fleischer rings
a result of copper accumulation in eyes. Think Wilson’s disease. Can occur RARELY in Alagille syndrome.
Wilson Dosease
Autosomal recessive (13q)
Loss of function
ATP7B
Tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver
Pathogenic variants in ASPA
Canavan disease
Underlying pathogenic mechanism in cases of UPD
Abnormal chromosomal segregation
Most common variants causing HH
60-90% of patients are hom for C282Y
3-8% are compound hets for C282Y and H63D
Menkes disease
Infants appear healthy until 2-3 mo then begin to regress
hypotonia, siezures, failure to thrie, neurological changes, kinky hair (pili torti)
Pathogenic variants in ATP7A (Xq)
ATP7A mutations in Menkes disease
~80% can be detected by sequence analysis
~20% found via targeted gene del/dup analysis
If no PCR amplification, do del/dup analysis
Alagille Syndrome
Autosomal dominant (20p)
Variable expressivity w/incomplete penetrance
Haploinsufficiency is most common mechanism
Paucity of bile ducts in liver
Involvement of heart, eyes, skeleton
Mutations in JAG1 are most common cause (~89%), del20p (~7%), and less commonly are mutations in NOTCH2 (1-2%)
Canavan disease
Autosomal recessive demyelinating disease caused by deficiency of aspartoacyclase, which catalyzes the breakdown of NAA.
This disease leads to accumulation of NAA causing CNAS damage
Mutations in ASPA
Much more common in Ashkenazi Jews - two pathogenic variants account for 99% of affected Ashkenazi Jews
>50 variants account for affected non-Ashkenazi Jews
What is one drawback of using tandem mass spec for NBS?
It can identify abnormal metabolites with unknown clinical significance
Population-based heterozygote screening for genetic disorders focuses on which individuals?
Those who identify themselves as belonging to a population with a high risk of the disorder
In a population of Asian descent, approximately what percentage of cystic fibrosis transmembrane conductance regulator (CFTR) mutation carriers would you be able to detect using the current basic mutation panel for CFTR (23 mutation panel)?
50%
NBS Criteria (6)
The illness is serious & has reasonable frequency
Clinical dx is difficult & requires a test
No intervention causes irreversible damage
Test is rapid, sensitive, and specific
There is a feasible intervention available that improves outcome
The NBS program is cost effective
Test sensitivity
the fraction of affected that test positive
total pos/(total pos + false neg)
Test specificty
the fraction of unaffected who screen negative
total neg/(false pos + total neg)
Positive predictive value (PPV)
the fraction w/a pos screen who are affected
total pos/(total pos + false pos)
Unsatisfactory NBS samples
Fluid contamination
?Other contamination
Layered blood
Fragile X testing should be considered during infertility evaluations when you encounter what?
Premature ovarian failure
Chorionic villus sampling (CVS) occasionally produces cytogenetic results that are somewhat ambiguous such as mosaicism. The finding of a mosaic trisomy 15 in a CVS leads to a secondary amniocentesis, which demonstrated a normal diploid karyotype. What is the best next step?
Consider uniparental disomy molecular cytogenetic studies for chromosome 15
One etiology of mosaicism is considered to be an initially trisomic conception which undergoes trisomic rescue, this would put the pregnancy at risk for retention of two chromosomes from the same parent, uniparental disomy testing would be indicated.
When noted as an isolated finding on second trimester ultrasound, findings such as choroid plexus cyst, echogenic bowel, echogenic cardiac focus, or short femur are most likely occur in what type of fetus, genetically speaking?
A normal fetus
Each of these findings in isolation can occur in as many as 1-5% of pregnancies; in the majority of instances the karyotype is normal.
Among male causes of infertility, what is commonly associated with a man with oligospermia?
balanced translocation
Azoospermia is associated with what?
Sex chromosome aneuploidy and Sertoli cell only syndrome
What adverse outcome is associated w/CVS?
An increase in hemangiomas. This increased risk in hemangiomas appears to be concentrated in transcervical CVS and is not gestational age dependent (in contrast to the limb reduction abnormalities which were concentrated in the < 10 week CVS cases).
Among male causes of infertility, what would be the most likely cause in the man with obstructive azoospermia?
Delta F508 mutation
Two days following an amnio, mom is diagnosed with premature rupture of membranes. What is most likely happening?
Reaccumulation of amniotic fluid
Premature rupture of membranes following amniocentesis occurs in approximately 1% of cases. Reaccumulation of the amniotic fluid occurs in > 90% of patients though on average takes 3 weeks. The outcomes are generally favorable which is in contrast to spontaneous rupture of membranes in the second trimester which is associated with fetal demise, miscarriage and chorioamnionitis.
In order to reach 80% detection of trisomy 21 in women under the age of 35 with nuchal translucency and first trimester serum markers, approximately how many women will have positive screening results?
> 10%
Non-obstructive azoospermia is associated with?
chromosome aneuploidy
DAZ deletion is a cause of
azoospermia
As part of an infertility evaluation, Mrs. Smith at age 35 years is diagnosed with premature ovarian failure based on an elevated follicle stimulating hormone. She is otherwise healthy with an unremarkable clinical history. What should be considered in the differential dx?
Premutation carrier of Fragile X
Congenital bilateral absence of the vas deferens (CBAVD) is present in almost all males with classic cystic fibrosis. Among men with CBAVD alone, what is the likelihood that they will have at least one mutation of the CFTR region (including mutations in 5T)?
85%
Mr. Jones and his wife are a Northern European couple who have experienced two years of infertility. Mr. Jones visits his urologist and is diagnosed with bilateral congenital absence of the vas deferens (CBAVD). He is otherwise well with an unremarkable clinical history. Analysis of his cystic fibrosis transmembrane receptor gene (CFTR) most likely reveals what?
Heterozygosity for a classic CFTR mutation
Among children born following assisted reproduction, the risk of a major congenital malformation is approximately how much greater than the general population risk?
30%
Early amniocentesis (9.0-12.9 weeks) is associated with the highest risk of fetal loss when compared to any other diagnostic modalities. Why?
Proportionately a greater volume of amniotic fluid removed
Assisted reproductive technologies are associated with an increased risk of congenital malformations. What type of genetic conditions are most common?
Imprinting disorders
The difference of cf fetal nucleic acids from intact fetal cells.
CF fetal nucleic acids rapidly clear from the maternal circulation within hours of delivery, whereas, intact fetal cells which may be harbored for decades in the mother.
The persistence of fetal cells in the maternal circulation was one factor which hindered progression of noninvasive prenatal testing which has been overcome by the rapid clearance of the cell free nucleic acids
