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
Omphalocele
A single anomaly with a strong association with aneuploidy trisomy 21, 18 and 13 (30%)
Intestines, liver, or other organs extend out of belly through the belly button.
Moms w/BMI > 40 are at a greater risk for a fetus with what problem
neural tube defects
Most fetuses with a NTD are what?
chromosomally normal
Echogenic bowel finding on an ultrasound presents the highest liklihood of a fetus with what?
Down’s
Premature preterm rupture of membranes (PPROM)
PPROM following a procedure has a different prognosis than when membranes rupture spontaneously in the second trimester. The majority of pregnancies (90%) with PPROM after amnio deliver at a late preterm (average 34 weeks) gestation. This is in comparison to the higher risk of loss (in some series over 80%) and very early preterm delivery (< 26 weeks) noted when PPROM occurs spontaneously. The difference may reflect the underlying causes with inflammation / infection occurring more commonly in the spontaneous rupture group.
Pulmonary hypoplasia occurs when?
After persistent oligohydramnios during the second trimester.
Ongoing oligohydramnios with spontaneous PPROM contributes to a high rate of pulmonary hypoplasia, similar to that seen in other conditions without amniotic fluid such as those with renal agenesis.
What ultrasound finding increases the chance of fetal CMV infection?
As with other viral infections, the consequences of CMV fetal infection are often marked by CNS involvement including ventriculomegaly, abnormal gyration patterns and abnormal development of CNS structures.
Isolated ventriculomegaly can occur as a normal variant but also be associated with aneuploidy, single gene disorders and genetic syndromes. The prognosis for isolated ventriculomegaly depends on whether additional CNS involvement is evident on MRI and the underlying etiology.
Smoking while pregnant
has a negative influence on newborn weight but has no connection to birth defects.
CAH mutation associated with?
salt wasting
Distinct steps of sex determination
- Establishment of chromosomal sex (i.e., XY or XX) at the time of fertilization
- Initiation of alternate pathways to differentiation of one or the other gonadal sex, as determined normally by the presence or absence of the testis-determining gene on the Y chromosome
- Continuation of sex-specific differentiation of internal and external sexual organs. Especially after puberty, development of distinctive secondary sexual characteristics to create the corresponding phenotypic sex, as a male or female
The Y chromosome is relatively gene poor. The genes that are there are restricted to what?
Gonadal and genital development
SRY
The major testis-determining gene
Lies near the PAR boundary on the Y chrome
If SRY is absent or not functioning properly, the female sex differentiation pathway ensues
The relative tolerance of human development for X chromosome abnormalities can be explained by
X-inactivation
A structurally abnormal X chromosome
Is always the inactive X
Inactivation of an X chrome depends on the presence of ___.
The X-inactivation region (XIC), location at Xq13.2
Significance of X-inactivation in medical genetics
Its chromosomal nature reduces the impact of segmental- or whole-chromosome genetic imbalance, such that many numerical and structural abnormalities of the X chromosome are relatively less deleterious than comparable abnormalities of the autosomes.
Its random nature and the resulting clonal mosaicism greatly influence the clinical phenotype of females who carry X-linked single-gene mutations on one of their X chromosomes.
Its dependence on the XIC is required for normal XX female development, because even very small fragments of the X chromosome separated from the XIC can lead to severe phenotypic anomalies as a result of their expression from both copies of genes contained on the X fragment
Sex chromosome abnormalities
The most common human genetic disorders, occurring ~1:400 live births
Can be numerical or structural, in all cells or mosaic
Clinical indications that raise the possibility of a sex chromosome abnormality
Delay in onset of puberty, primary or secondary amenorrhea, infertility, and ambiguous genitalia
Most common sex chromosome defects in liveborn infants and in fetuses
Liveborn - trisomic types (XXY, XXX, and XYY) - all are rare in spontaneous abortions
Turner syndrome - less frequent in liveborn infants, most common chromosome anomaly in spontaneous abortions
Klinefelter’s
47,XXY
~ 1:600 live births
Approx half of cases result from nondisjunction in paternal meiosis I because of a failure of normal Xp/Yp recombination in PAR
In maternal origin cases, most result from errors in maternal meiosis I; maternal age is increased in such cases.
~15% of Klinefelter patients have mosaic karyotypes,
Phenotypic traits of Klinefelter’s
Relatively mild/variable phenotype
Can include: Lower verbal comprehension and ability several-fold increased risk for learning difficulties, especially in reading
Language difficulties may lead to shyness, unassertiveness, apparent immaturity, and an increased risk for depression.
Relatively poor psychosocial adjustment.
Genes assoc w/disorders of sex development in a 46,XY karyotype
SRY (Yp11.3) Female XY gonadal dysgenesis
DAX1 (Xp21.3) DAX1, Female XY gonadal dysgenesis
SOX9 (17q24) Female, XY gonadal dysgenesis with camptomelic dysplasia
NR5A1 (9q33) Ambiguous genitalia, XY partial gonadal dysgenesis
WNT4 (1p35) Ambiguous genitalia, cryptorchidism
AR (Xq12) Female, complete or partial androgen insensitivity syndrome
Genes assoc w/disorders of sex development in a 46,XX karyotype
SRY (Yp11.3) If SRY translocated to X - Male, XX (ovo)testicular DSD
SOX3 (Xq27.1) Male, XX testicular DSD
SOX9 (17q24) Male, XX testicular DSD
CYP21A2 (6p21.3) Ambiguous genitalia, virilization, micropenis
Gonadal dysgenesis
A progressive loss of germ cells, typically leading to underdeveloped and dysfunctional gonads, w/consequent failure to develop mature secondary sex characteristics
Complete gonadal dysgenesis (CGD)
Males: 46,XX testicular DSD
Females: 46,XY CGD
Characterized by normal-appearing external genitalia of the opposite chromosomal sex.
Can be assoc w/sex chromosomes DSD (i.e. common in Turner’s)
Partial gonadal dysgenesis
Ambiguous external genitalia
Camptomelic dysplasia
Skeletal malformation disorder assoc w/mutations in SOX9 and female XY gonadal dysgenesis
46,XX ovotesticular DSD
Individuals w/both testicular and ovarian tissue, either as an ovotestis or as a separate ovary and testis
Formerly called true hermaphroditism
What is the most common meiotic error resulting in Down syndrome?
Nondisjunction during maternal meiosis I
What term is used to describe a syndrome w/a phenotype that is caused by deletion of multiple, neighboring genes?
Contiguous gene syndrome
What is the mechanism by which recurrent deletions associated with contiguous gene syndrome occur?
Aberrant recombination occurs between low copy repeats
A microdeletion in this region is a common cause of tetralogy of Fallot w/pulmonary atresia or with absent pulmonary valve
22q11
Sex chromosome abnormality assoc w/an increased risk of breast cancer & infertility
Klinefelter syndrome
Defects in what cause female pseudohermaphroditism caused by congenital adrenal hyperplasia?
cortisol biosynthesis
Late maternal age causes errors to occur where?
Maternal meiosis I
Clinical indications that raise the possibility of sex chromosome abnormality (4)
delayed onset of puberty, primary or secondary amenorrhea, infertility, and ambiguous genitalia
At what age does is the loss of normal ovarian function considered premature ovarian failure
before 40
Congenital adrenal hyperplasia (CAH)
An inherited disorder arising from specific defects in enzymes of the adrenal cortex required for cortisol biosynthesis and resulting in virilization of 46,XX infants
Most commonly due to a deficiency of 21-hydroxylase
Salt-wasting 21-hydroxylase deficiency
75% of cases of 21-hydroxylase deficiency
due to a mineralocorticoid deficiency
Severe and can lead to neonatal death
Biochemical screen for this is included in newborn screens in many countries
Androgen insensitivity syndrome
X-linked
Testes are present, either within the abdomen or in the inguinal canal (often mistaken for hernias)
Androgen is secreted from testes but absence of androgen receptors in appropriate target cells lead to ambiguous or female genitalia
Leads to 46,XX female
Differences in CNV microarray findings in ID and ASD patients
CNVs in patients w/ID tend to be larger, encompass more genes, and are more likely of de novo origin
Fragile X
The most common cause of X-linked ID
FMR1
Zygotene
When homologous chromosomes begin to align along their entire length
Occurs during prophase of meiosis I.
Synapsis
The process of meiotic pairing - bringing corresponding DNA sequences into alignment along the length of the entire chromosome pair.
Occurs during prophase of meiosis I after zygotene
Bivalents
Paired chromosome homologues held together by the synaptonemal complex
Occurs during prophase of meiosis I after synapsis
Synaptonemal complex
Ribbon-like proteinaceous structure that joins bivalents in M1.
Pachytene
The time when meiotic crossing over takes place (during prophase I), after which the synaptonemal complex breaks down.
Anaphase in Meiosis I
The two members of each bivalent move apart, not the sister chromatids (as in mitosis anaphase). The homologous centromeres are drawn to opposite poles of the cell (disjunction) , yielding two new cells that are haploid in chromosome number.
Disjunction
When homologous centromeres (with their attached sister chromatids) are drawn to opposite poles of the cell
Occurs during anaphase of MI.
Non-disjunction
Chromosome mis-segregation
Occurs in M1 and is a frequent cause of pregnancy loss and of chromosome abnormalities like +21
Meiosis II
Similar to ordinary mitosis, except chromatids of each of the 23 chromosomes separate, and one chromatid of each chromosome passes to each daughter cell.
B/c of crossing over during M1, the chromosomes of the resulting gametes are not identical.
Interphase
Period btwn successive mitoses
The state in which most of the life cycle of the cell is spent
Important difference btwn a cell entering mitosis and one that has just completed mitosis
A cell in G2 has a fully replicated genome (4n DNA complement) and each chromosome consists of a pair of sister chromatids.
In contrast, after mitosis, the chromes of each daughter cell have only one copy of the genome. This copy will not be duplicated until a daughter cell reaches S phase of the next cell cycle.
The mammalian somatic cell cycle is approximately 24 hours in length. Which of the following phases of the cell cycle requires the most time?
G1
What is the main cause of numerical chromosome abnormalities in humans?
meiotic nondisjunction
Disregarding crossing over, which increases the amount of genetic variability, estimate the probability that all your chromosomes have come to you from your father’s mother and your mother’s mother. Would you be male or female?
(1/2)^23 × (1/2)^23; you would be female.
In our species, at the end of meiosis I, how many chromosomes are there per cell? How many chromatids?
23;46
At the end of meiosis II, how many chromosomes are there per cell? How many chromatids?
23;23
In meiosis, when is the diploid chromosome number restored? When is the two-chromatid structure of atypical metaphase chrome restored
At fertilization; at S phase of the next cell cycle
The extent of the haplotype block surrounding a disease mutation depends on which two of the following factors?
Recombination frequency in the region & number of generations since the disease mutation arose
In humans, DNA is associated with several classes of proteins and packaged into complexes known as:
Chromatin
An impt and distinct feature of meiosis is
Recombination
Failure of homologous chromosomes to segregate to opposite poles during meiosis is called
Nondisjunction
In human males, when is meiosis initiated and completed?
At puberty, it is continuous
In human females, when is meiosis initiated and completed?
Prenatally, at fertilization
The following items are related to each other in a hierarchical fashion: chromosome, base pair, nucleosome, kilobase pair, intron, gene, exon, chromatin, codon, nucleotide, promoter. What are these relationships?
The sequence of the haploid human genome consists of nearly 3 billion nucleotides, organized into 24 types of human chromosome. Chromosomes contain chromatin, consisting of nucleosomes. Chromosomes contain G bands that contain several thousand kilobase pairs of DNA (or several million base pairs) and hundreds of genes, each containing (usually) both introns and exons. The exons are a series of codons, each of which is three base pairs in length. Each gene contains a promoter at its 5′ end that directs transcription of the gene under appropriate conditions.
Contrast the mechanisms and consequences of RNA splicing and somatic rearrangement.
RNA splicing generates a mature RNA from the primary RNA transcript by combining segments of exonic RNA and eliminating RNA from introns. RNA splicing is a critical step in normal gene expression in all tissues of the body and operates at the level of RNA. Thus the genomic DNA is unchanged. In contrast, in somatic rearrangement, segments of genomic DNA are rearranged to eliminate certain sequences and generate mature genes during lymphocyte precursor cell development as part of the normal process of generating immunoglobulin and T-cell receptor diversity. Somatic rearrangement is a highly specialized process, specific only to these genes and specific cell types.
Translation involves which type of RNA?
mRNA, rRNA, tRNA
What types of sequences are located in the 5’ region of the human genes
Promoters and enhancers
What type of sequence is located in the 3’ region of human genes?
Polyadenylation sequences
Gene families can arise by which mechanism?
Gene duplication
Pseudogenes
DNA sequences that resemble known genes but are nonfunctional
What are the final products of a gene?
DNA and RNA
Which of the following steps must a primary RNA transcript undergo before it becomes a fully processed, mature mRNA?
Capping, polyadenylation, and splicing
Translation is always initiated at a codon for which amino acid?
Methionine
Which of the following describes the system of codons in our DNA?
It is degenerate
This modification of cytosine phosphate guanine (CpG) islands is associated with transcriptional repression:
Methylation
In humans, what is a mechanism by which a single gene can produce multiple gene products?
RNA splicing
What is needed in determining to assess whether a nondisjunction event occurred at meiosis I or meiosis II?
Whether the abnormal gamete contributed two copies of the same chromosome or one of each homolog
To be stable, a rearranged chromosome must have what?
A centromere and two telomeres
From largest to smallest, put these techniques in order in terms of the size of the genetic abnormality each could detect.
- Comparative genome hybridization
- G-banding
- Allele specific oligonucleotide hybridization
- Fluorescent in situ hybridization (FISH)
2, 4, 1, 3
Haploinsufficiency
Inability of one copy of a gene to perform the function of the normal two copies of the gene
Which of the following is the most common meiotic error resulting in Down syndrome?
Nondisjunction during maternal meiosis I
Which of the following terms is used to describe a syndrome with a phenotype that is caused by deletion of multiple, neighboring genes?
Contiguous gene syndrome
What is the mechanism by which recurrent deletions associated with contiguous gene syndromes occur?
Aberrant recombination occurs between low copy repeats
A microdeletion in which chromosomal region is a common cause of tetralogy of Fallot with pulmonary atresia or with absent pulmonary valve?
22q11
Klinefelter syndrome is assoc w/what?
increased risk of breast cancer and infertility
Defects in what cause female pseudohermaphroditism caused by congenital adrenal hyperplasia?
Cortisol biosynthesis
What is the leading indication for prenatal testing in the United States?
AMA
What is assoc w/an increased level of maternal serum alpha fetoprotein?
neural tube defect
When during pregnancy is CVS generally performed?
10-12 wks
Nutritional supplementation of pregnant women with what reduces the risk of neural tube defects in the fetus?
Folic acid
The results of a second trimester screen for your patient are the following:
Low levels of unconjugated estriol
Low levels of maternal serum α-fetoprotein
High levels of free β-human chorionic gonadotropin
With what fetal disorder are these results consistent?
+21
For the majority of metabolic disorders, what is the recurrence risk in a family that has had an affected child?
25%
What is the advantage of prenatal biochemical testing for metabolic disorders compared to genetic testing?
It detects an effect caused by any mutant allele for the gene of interest
Why not lower the cutoff on maternal serum α-fetoprotein screens so that near complete ascertainment of neural tube defects via the screen would be had?
There would be too many false positives.
Genomic Disorders
~50-100 syndromes involving contiguous gene rearrangement
Many of these disorders localize to segmental duplications
What leads to deletion or duplication products that occur in genomic disorders?
Unequal crossing over between misaligned sister chromatids or homologous chromosomes containing highly homologous copies of seg dups
Segmental duplications
Low-copy repeated sequences in the genome, often occur around centromeric and telomeric breakpoints
Are vulnerable to unequal recombination events
Often associated w/genomic disorders
Idiopathic chromosome abnormalities
Characterized by sporadic, variable breakpoints, I.e. deletion syndromes (Cri du chat)
Most occur de novo and have highly variable breakpoints in the particular chromosomal region that reflect a range of different mechanisms
Ex. Cri du chat can occur via terminal del, interstitial del, or recombination btwn copies of repetitive elements
The hallmark of imprinted genes
Only one allele, either maternal or paternal, is expressed in relevant tissue
Alleles
Alternative versions of the DNA sequence at a locus
