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ABGC Boards Exam > Cytogenetics, FISH and MCA > Flashcards

Cytogenetics, FISH and MCA Flashcards

1
Q

Down Syndrome causes

A 
-mostly meiotic errors (95%)
\+increased risk with advanced maternal age
-robertsonians (3-4%)
-mitotic errors (1-2%)
* ~1% recurrence risk
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2
Q

life expectancy in Down Syndrome

A

now about 60y, greatly increased from 9y

-can see early death in 10-20% affected individuals related to severe cardiac anomalies

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3
Q

complications associated with Down syndrome

A 
-cardiac defects (40%)
\+mostly A-V canal
-GI anomalies (~5%)
\+duodenal atresia/stenosis most common
-increased leukemia risk (15-20 fold)
-Alzheimer's disease for most affected adults
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4
Q

Down syndrome incidence

A
  • 1 in 700 live births

- 75% of SABs

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5
Q

Trisomy 18 phenotype

A
  • SGA
  • overlapping clenched fists and rocker bottom feet
  • micrognathia and severe ID
  • hyper or hypotonia
  • severe renal, GI or cardiac anomalies (95%)
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6
Q

Trisomy 18 incidence

A
  • 1 in 5000-1 in 8000 live births
  • 4:1 F:M sex ratio
  • extremely low survival, 90% affected infants die within the first year of life, 95% result in SAB
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7
Q

Trisomy 13 phenotype

A

-FTT + hypotonia
-holoprosencephaly
+micro or anopthalmia
+severe ID
+clefting
-cardiac defects
-polydactly

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8
Q

Trisomy 13 incidence

A
  • 1 in 10000-1 in 15000 live births
  • 90% die within first year of life, 95% results in SAB
  • 20% caused by robertsonian translocation
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9
Q

X inactivation

A
  • reversible in germ cell development

- 15% of X-linked genes escape this

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10
Q

Turner syndrome incidence and causes

A

-incidence 1 in 1500-1 in 5000 live births-variable by study
+1 in 30-1 in 50 female conceptuses (3%) w/94% resulting in SAB
-extremely low recurrence risk & several chromosome and mutation arrangements that cause it (50% 45, X)
+2/3 retain maternal X chromosome

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11
Q

Klinefelter incidence

A
  • 1 in 500- 1 in 600 newborns
  • no recurrence risk
  • 50% due to paternal meiosis I errors
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12
Q

48 XXYY

A

similar to Klinefelter but with more severe ID and 90% risk for dicentric chromosome w/Robertsonian

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13
Q

Klinefelter phenotype

A
  • small testes after puberty, gynecomastia, sparse facial hair, low fertility d/t fibrosis of seminiferous tubes
  • hypotonia
  • scoliosis + “Euchenoid habitus”
  • low to normal IQ, rarely ID, LD/reading disability related to language processing and verbal memory
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14
Q

Turner phenotype

A

-short stature, broad chest, webbed neck
-primary amenorrhea, gonadal dysgenesis (90%)
-cardiac anomalies (40-60%)
+coarctation of the aorta
-renal anomalies (greater than 60%)
-hand and foot edema

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15
Q

robertsonian translocations

A
  • fusion between acrocentric chromosomes (13, 14, 15, 21, and 22)
  • 90% dicentric, p arms usually not involved
  • usually get homologous chromosomes from one parent-risk for UPD higher
  • usually associated with trisomy
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16
Q

paracentric inversion

A

-no centromere involvement
-usually only in part of long arm or short arm
-usually only gives acentric or dicentric fragments
+lower risk to have unbalanced offspring

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17
Q

reciprocal translocation

A
  • mutual exchange of material between two non-homologous chromosomes
  • leads to increased risk for fetal loss and children with problems
  • occurs in 1 in 500 individuals
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18
Q

pericentric inversion

A

-centromeric involvment
-involves material on both long arm and short arm
-can result in recombination and unbalanced offspring
+can result in duplication and deletion of material

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19
Q

meiotic segregation with reciprocal translocations

A
  • not like normal homologous chromosome line-up

- all chromosomes interconnect and create a 4-way junction

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20
Q

alternate segregation

A

always results in normal outcome because two normal and two translocated chromosomes go together
-one of the most common types of segregation

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21
Q

adjacent 1 segregation

A

chromosomes on same side of horizontal axis pair

-another of the most common types of segregation, can result in normal outcomes depending on chiasma placement

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22
Q

adjacent 2 segregation

A

chromosomes on same side of vertical axis pair

-always gives abnormal outcomes

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23
Q

3:1 segregation

A

always causes abnormalities because 3 chromosomes pair together and one is alone

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24
Q

risk of unbalanced segregates

A

~11-12%, but depends upon the ascertainment of the translocation

  • if a previous child is affected, recurrence risk is about 20%
  • if multiple SABs, risk might be lower because affected babies can’t survive
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25
Q

robertsonian incidence

A
  • relatively common-1 in 1000 individuals

- rate of inheritance depends on the translocation and the parent it was inherited from

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26
Q

rob(13q14q) and rob(14q21q)

A

most common robertsonian translocations

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27
Q

risk of unbalanced segregates in robertsonian carriers

A

based on empiric, not theoretical risk

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28
Q

female carrier of rob(14q21q)

A

15-20% empiric risk for unbalanced segregants

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29
Q

male carrier of rob(14q21q)

A

2% empiric risk for unbalanced segregants

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30
Q

female carrier of rob(13q14q)

A

1% empiric risk for unbalanced segregants

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31
Q

male carrier of rob(13q14q)

A

<1% empiric risk for unbalanced segregants

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32
Q

X-inactivation mechanisms

A
  • altered chromatin structure by CpG island methylation

- X inactivation center at Xq13.2

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33
Q

XIST

A

RNA specifically produced by XIC from the initially inactivated X chromosome for initiation and continuation of X inactivation

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34
Q

de novo translocations

A

related to increased risk for ID and congenital anomalies
+20% newborns with these
+55% individuals with ID with these
+3 in 1000 individuals with ID have these

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35
Q

clinical effects of de novo translocations

A
  • position effects; genes turned off or on
  • breakage within a gene; ex: DMD
  • del/dup requiring FISH or MCA
  • UPD
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36
Q

risk of phenotypic abnormality in de novo translocation

A

6-8% of all fetuses based on empiric data

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37
Q

Fluorescent In-Situ Hybridization (FISH)

A

-metaphase cells, interphase nuclei
-prepared like karyotype, but tagged probes can hybridize to region of interest in interphase cells
+have to know what is being looked for

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38
Q

contiguous gene syndrome/segmental aneusomy/microdeletion syndromes

A

deletion of chunk of DNA, including multiple genes on a chromosome physically close to one another of unrelated function

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39
Q

detection of CGS

A
  • if 5-10Mb del-400-500 band resolution
  • if 2-5Mb del-1000 band resolution
  • if <2Mb need array or FISH
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40
Q

3Mb deletion

A

equivalent to loss of 10-100 genes

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41
Q

percutaneous umbilical blood (PUBs)

A

sampling of fetal blood from umbilical cord

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42
Q

FISH limitations

A
  • labor and time intensive to design multiple probes
  • expensive to design new probes
  • requires specified probe and knowledge of specific genome site of interest
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43
Q

traditional cytogenetic testing limitations

A

lower resolution cannot indicate the size of abnormality, nor if microdel/dups present

44
Q

traditional cytoogenetic testing benefits

A
  • detects balanced and unbalanced rearrangements

- provides origins of derivative and marker chromosomes

45
Q

FISH benefits

A
  • higher resolution

- quick results for known/suspected alterations

46
Q

protein-coding DNA

A

0.8%

47
Q

total DNA

A

-3B bp
+40-50% repetitive
-~25000 functional genes

48
Q

average gene size and density

A
  • one gene per 45kb

- 20kb average size with significant variation

49
Q

unbanded chromosome resolution

A

20Mb

50
Q

banded chromosome resolution

A

10Mb

51
Q

high resolution banding

A

3-5Mb

52
Q

FISH resolution

A

150 kb (40-250kb)

53
Q

microarray resolution

A

50-150 kb, ~30kb

54
Q

g-banding

A

-35y SoC
-detects structural and numerical anomalies
+4% detection rate for nonspecific issues like ID and MCAs
-3-10Mb resolution

55
Q

expression array

A
  • RNA based array
  • looks at series of genes and how they are expressed
  • ex: cancer profiling
56
Q

array CGH

A
  • control DNA red, test DNA green
  • two DNA types mixed in equal parts and hybridized
  • ratio of red: green analyzed electronically to detect any gains or losses of info
57
Q

BAC array

A
  • looks for small CNVs
  • can only study up to 1Mb DNA at a time
  • uses CGH
58
Q

oligo array

A

-uses current + high throughput technology
+uses CGH
+smaller probes ~60mers
-uses HGP data

59
Q

SNP arrays

A

-uses high throughput tech + HGP data
-polymorphic + structural probes
-detects quantitative change, not CGH
+now most use SNP backbone+oligo
-allows for UPD, IBD and areas of contiguous homozygosity detection
-only array that can detect triploidy and maternal or twin sample contamination

60
Q

identity by descent (IBD)

A

-detection of small haplotypes inherited from common ancestor
+allows for identifying difference between increase in homozygozity related to this versus consanguinity (determines degree of relation)
-greater shared homozygosity increases risk of recessive disorder

61
Q

CMA and ACMG guidelines

A
  • used for cases of MCA w/o known syndrome, apparently non-syndromic ID/DD and ASDs
  • detection requires follow-up, parental studies and clinical evaluation + counseling
62
Q

CMA detection rates

A

-detection rate of ~3.7% in individuals with ID and DD
+Hostenbach study states 19% in their population, another says 17% in selected population versus 12% in non-selected
*generally 15-20%

63
Q

risk of anomaly in consanguinity

A

2-2.5% above general population if parents are first cousins

64
Q

importance of POC

A

-15% pregnancies result in SAB in first tri
+50% are chromosomally abnormal
-some of these tissues fail to grow in culture, but reflex study by CMA can identify results successfully in 95% of cases

65
Q

challenges with POC use

A
  • low viability of cells with high culture failure
  • culture contamination
  • extended culture time
  • can get overgrowth of maternal cells and get failure of ruling out MCC or molar pregnancy
  • low resolution of g-banding
66
Q

Law of Independent Assortment

A

chromosomes and genes are inherited independently from one another

67
Q

Law of Segregation

A

gametes contain only one homologous chromosome and therefore only one gene for each trait

68
Q

maternal meiosis I

A

most non-disjunction occurs here

69
Q

interchange

A

3:1 segregation involving both translocated chromosomes

70
Q

tertiary

A

3:1 segregation involving only one translocated chromosomes

71
Q

percent of fetuses with DS that result in SAB

A

75%

72
Q

empiric risk of female 14:21 rob to have a child affected with Down Syndrome

A

5-10%

73
Q

Mosaicism testing

A

Best with karyotype, rarely picked up on oligo or SNP arrays

74
Q

Targeted arrays

A

-probes localized around known disease causing genes & platforms
+often used as part of phenotype-specific panels because sequencing misses del/dup
-limits unknown findings/VUSs

75
Q

Genome wide array

A

-probes scattered throughout genome
+helpful in determining del/dup breakpoints
-more likely to have CNVs returned with unknown significance

76
Q

targeted array

A

-probes localized to specific regions of the genome (often exons associated with disease)
+often used as part of panel tests, as sequencing can miss del/dups
-less likely to identify CNVs of unknown significance

77
Q

genome wide array

A
  • probes spread across genome
  • helps delineate specific break points
  • more likely to identify CNVs of unknown significance
78
Q

CNVs

A

-micro del/dups of ~400bp
+often benign if <500bp so most labs won’t call below this
-common in healthy individuals, though others are well-characterized in association with phenotypes
+most individuals are thought to have about 20

79
Q

SNP

A

single variable base pair in the general population

80
Q

CMA limitations

A
  • cannot detect balanced arrangements (balanced translocations, inversions)
  • may not detect low-level mosaicism
  • can detect CNVs of unknown significance
  • no info on structural nature possibly requiring further analysis
81
Q

runs of homozygosity

A
  • called LSCH or LOH
  • stretches <3Mb common
  • longer stretches identified on one chromosome may suggest UPD, across genome may suggest consanguinity based on IBD info
82
Q

coefficient of inbreeding (F)

A

avg proportion of autosomal genome that is IBD in the offspring of related parents

83
Q

percent IBD

A

estimated by sum of homozygous segments divided by total autosomal genomic length
-usually reported when about 2-5Mb

84
Q

10% IBD

A

ROH of 2-5Mb with combined effect above this cut-off are suggestive of first or second degree parental relationship
-brings up possible psychosocial concerns of rape or abuse

85
Q

interpretation confounds

A
  • variable expressivity
  • reduced penetrance
  • unknown prognosis and clinical info for rare CNVs
  • ambiguous results (CNVs of unknown significance)
  • often requires parental studies for more accurate risk assessment
86
Q

WES detection rates

A 
25-51% (quote ~30% clinically)
-dependent upon 
\+indication of patient and phenotyping
\+ethnic background of patient
\+availability of family members for testing that can aid in interpretation
87
Q

ACMG WES recommendations

A
  • non-specific phenotype in patient or family history that suggests undiagnosed genetic etiology with overlap in symptoms that are not consistent with a single condition (ex: pt with epilepsy and MCAs)
  • presenting phenotype has a high degree of genetic heterogeneity
  • prior specific testing has not provided an answer for the phenotype
  • fetus with suspected syndrome not identified by targeted approaches
88
Q

Coverage

A

Number of reads at a particular site in genome

89
Q

Variant pipeline sorting

A
  • allele frequency
  • conservation
  • inheritance pattern
  • phenotype of patient
  • in silico predictors
90
Q

Human Genome Mutation Database

A
  • collection of clinically meaningful variants implicated in human inherited disease
  • contains approximately 4000 genes
91
Q

Informatics pipeline

A

-common variants filtered out
-uncommon variants (~400-500) studied in association with relationship to SGDs
+phenotypic info helps specify candidates
-study filtered variants into those that are or are not thought to be deleterious
-deleterious variants confirmed via Sanger in individual and tested family members to confirm a diagnosis

92
Q

Secondary/incidental findings

A

-deleterious, clinically actionable mutations identified that do not relate to the phenotype of the patient
+typically opt in/opt out
+VUSs not reported
-includes hereditary cancer, hereditary cardiac and connective tissue disorders

93
Q

Interpretation challenges

A

-reduced penetrance and variable expressivity
-multifactorial disease
-non-detectable epigenetic factors
-phenocopies
+ex teratogens mimicking syndrome
-UPD
-XL mutations in females
+related to skewed X inactivation?

94
Q

benefits of WES

A

-more cost effective than individual panels and single gene tests
+best approach for non-specific phenotypes and high heterogeneity conditions
-identifies atypical presentations of known syndromes
-novel gene discovery
+this is important, as most monogenic disorders are not thought to have been discovered yet

95
Q

limitations of WES

A

-limited detection of large rearrangements and CNVs, mtDNA mutations, trinucleotide repeat expansions
-only 85-92% exons targeted
+plus all targeted exons aren’t well covered (~90%)-if requested labs can provide specific targeting
-cannot detect regulatory and intronic regions
-many labs will not report adult-onset Alzheimer’s and dementia genes

96
Q

WES risks

A
  • discovery of undisclosed non-paternity, family secrets and relationships
  • incidental findings
  • greater numbers of VUSs and possibly ambiguous results
  • may provide unwanted insight into health of other family members or have implications for their health
  • discovery of a novel gene can limit counseling regarding long term outcomes
  • possible risks for future disability and life insurance coverage
97
Q

MUTYH secondary finding

A

only homozygotes reported, despite slight increased risk for heterozygotes

98
Q

chromosome 18p deletions

A
  • ID, DD, SD, behavioral problems
  • brachydactly
  • hypodontia, frequent cavities, cleft palate
  • antihelix abnormalities with protruding ears
  • characteristic facies: ocular hypotelorism, “carp” mouth, brachycephaly, sometimes cyclopia
  • GU anomalies
  • neck webbing
  • hypotonia and growth restriction
99
Q

triploidy

A
  • low hCG is a sign, often causes FT loss
  • sporadic with minimal RR
  • 69, XXY>69XXX»>69XYY
100
Q

maternal triploidy

A
  • small placenta

- severe asymmetric IUGR with large head

101
Q

paternal triploidy

A
  • large cystic placenta
  • IUGR
  • normal to microcephalic
102
Q

Sotos syndrome

A
  • 5q del of NSD1
  • more common in Japanese pop
  • overgrowth, macrocephaly
  • hypotonia, ID, DD, LD
  • dysmorphic features-flushed cheeks, long face, high forehead, pointed chin
  • poor balance
103
Q

complete hydatidaform mole

A

-usually diploid, 46,XX pregnancy completely of paternal decent
+23, X sperm fertilizes an egg lacking a nucleus
-trophoblastic hyperplasia with grossly disorganized or absent fetal tissue

104
Q

partial hydatidiform mole

A
  • usually diandric triploid
  • fetus will be present early on, then will demise
  • hydropic villi
105
Q

ovarian teratoma

A
  • usually 46, XX completely of maternal origin

- growth that can contain multiple tissues including hair and teeth

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