Term
| Genetic Disorders (3 broad categories) |
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Definition
1)Single genes with large effects (kinda like pleiotropy)
2)Chromosomal
3)Complex multigenic caused by multiple genes and environmental factors, each with small but accumulative effect. |
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Term
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Definition
1)some adult onset
2)5% of individuals <25 years develop a serious disease with a significant genetic component
3)~50% of SAB during first 12 weeks due to chromosome abnormality
4)0.7% of all newborn infants have a chromosome abnormality |
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Term
| Cytogenetic and Molecular Cytogenetic Testing |
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Definition
1)Chromosome abnormality is defined as changes resulting in “visible” alteration of the chromosomes (old definition)
2)Cytogenetic testing – GTG banded chromosome analysis *Trypsin*
-Advantage: can be used as a scanning tool, no need for definitive clinical information
-Disadvantage: cannot detect smaller than ~4Mb using traditional methods
3)Molecular cytogenetic testing – fluorescence in-situ hybridization (FISH)
-Advantage: can detect much smaller segments down to 0.02 Mb, can examine large number of cells easily
-Disadvantage: FISH needs specific clinical information to FISH in the right place
4)Molecular cytogenetic testing - array Comparative Genomic Hybridization (aCGH – also known as Chromosome Microarray Analysis CMA)
-Advantage: can be used as a scanning tool, does not need specific clinical information, can detect much smaller segments down to 0.02 Mb
-Disadvantage: does not detect balanced rearrangements, low level mosaicism or very small losses or gains. The genome has inherent variation that is normal (not clinically relevant) may make interpretation complex
5)Chromosome abnormality may be:
constitutional (abnormality that you are born with, all cell of body), or
acquired (abnormality as a result of malignancy, confined to tissue with tumor) |
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Term
| Karyotype (Arrangement of Chromosomes) |
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Definition
1)Normal
-Number of chromosomes
-Describe sex chromosomes
-46,XX normal female
2)Abnormal
-Describe abnormality in ascending numerical order
-47,XX,+21 Down Syndrome
-46,XY,del(5)(p15) Cry du Chat deletion syndrome |
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Term
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Definition
1)Mechanism of somatic cell division
2)One stage:
-Each chromosome behaves independently
-->no chromosome pairing
-->no recombination between sister chromatids
3)Purpose: to achieve equal and identical genetic information in each of two daughter cells |
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Term
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Definition
1)Mechanism of germ cell division
2)Two stages:
-Meiosis I halves chromosome number (reduction division)
-Meiosis II similar to mitosis but with only 23 chromosomes
3)Purpose: to achieve unique and non-identical genetic information in daughter cells – ensuring the uniqueness of human individuals |
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Term
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Definition
-Chromosomes recognize each other, align
-Pair and Recombine (cross-over or chiasma) at least one cross over per arm.
-Exception is the sex chromosomes (not autosomal) such that they align up in the pseudoautosomal region (tip of chromosome, ONLY place where sex chromosomes can cross-over). |
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Term
| The Irony of Cytogenetic Testing |
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Definition
1)Most chromosome abnormalities occur as a result of an error during meiosis
2)Most chromosome analysis is performed on cells undergoing mitosis. |
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Term
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Definition
1)Evidence of >1 major organ systems:
a)Brain or CNS
i)microcephaly
ii)developmental delay
b)Internal:
i)cardiovascular system
ii)respiratory system
iii)genito-urinary tract
iv)gastrointestinal tract
c)External:
i)major facial dysmorphy, clefting
d)Limbs:
i)contractures
ii)extra fingers, toes |
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Term
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Definition
1)Evidence of >2 minor features:
a)Facial dysmorphy
i)widely spaced eyes
ii)ear pits
iii)flattened nasal bridge
2)Hands:
i)palmar creases
ii)hypoplastic nails |
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Term
| Types of Chromosome Abnormality |
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Definition
1)Polyploidy (whole set)
2)Aneuploidy - one more or less than 46 chromosomes *we are only concerned with sex chromosomes as autosomal chromosomes do not survive.*
a)trisomy – three copies of a particular chromosome
b)monosomy – one copy of a particular chromosome
3)Structural – one or more chromosome breaks that result in chromosome segment loss or gain
4)Rearrangement – one or more chromosome breaks that result in chromosome segments rearranging |
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Term
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Definition
1)Triploidy 3N = 69
a)1-3% conceptuses
b)usually partial hydatidiform mole
*can be result of 1)two sperms going in 2)egg with 2N 3)Sperm with 2N*
2)Tetraploidy (4N = 92) *cell undergoes mitosis without cytokineses--endomitosis*
-rare
-lethal
3)Complete hydatidiform mole:
-46 chromosomes, all paternal
-Mole formation ~6 weeks |
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Term
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Definition
1)Major clinical features
a)Characteristic dysmorphic facial features
b)Hypotonia
c)Multiple congenital abnormalities, e.g CHD
d)Mental retardation
2)Minor clinical features:
a)Protruding tongue
b)Pigmented irises
c)Simian crease |
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Term
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Definition
1)All autosomes and sex chromosomes can be trisomic
-(note monosomy only sex chromosomes)
2)Majority result in miscarriage (SAB)
3)Only liveborn possible:
-Trisomy 13, 18, 21
4)Only long-term survivors:
-Trisomy 21 *most common chromosomal abnormality.*
5)Major maternal age effect
-1 in 1550 live births at age 20
-1 in 25 live births at age 45
6)>90% trisomy results from maternal meiosis error. |
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Term
| Main Cause of Chromosome Abnormality |
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Definition
Meiotic Non-Disjunction (failure of chromosome to correctly separate)
*disjunction at either meiosis I or meiosis II, results in trisomy 21* |
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Term
| Another Cause of Chromosome Abnormality |
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Definition
- Mitotic Non-disjunction Chromosomal Mosaicism
1)Continuous mitotic cell division occurs in the developing embryo
2)If no error occurs, all cells in the embryo exactly the same
3)If mitotic non-disjunction error occurs:
-unequal division may result in two (or more) cells with different chromosome number (somatic cell mosaicism)
-the same change will continue in all ongoing cell divisions of that cell (although some cell lines may not survive) |
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Term
| Mosaicism for Down Syndrome |
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Definition
1)Karyotype:
47,XX,+21 / 46,XX
2)Often different percentage of each cell type in different tissues
3)Clinical presentation usually milder
4)Few genetic syndromes causes by low level mosaic trisomy (trisomy 8, trisomy 9) |
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Term
| Structural Chromosome Abnormalities |
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Definition
1)One or two breaks in the same or different arms of a chromosome
2)Segments of chromosome can be lost, gained or moved around
-Loss: deletion, ring
-Gain: duplication
3)Structural change usually leads to partial trisomy, partial monosomy, or both, for involved chromosome segments. |
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Term
| How Do Structural Errors Occur? |
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Definition
| Unequal crossover, one strand loses info., the other gains. |
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Term
| Deletion 5p: Cri du Chat Syndrome |
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Definition
1)First structural chromosome abnormality described
2)Clinical features include:
-Growth and mental retardation
-Language delays
-Moderate dysmorphic facial features, characteristic moon face
-Occasionally CHD
3)Karyotype:
-46,XY,del(5)(p15) |
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Term
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Definition
1)Normal
2)Balanced carrier
3)Partial trisomy + Partial monosomy
4)Partial monosomy + Partial trisomy |
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Term
| Robertsonian Translocation |
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Definition
1)Only involves the acrocentric chromosomes
2)13, 14, 15, 21, 22
3)Carrier of Robertsonian has 45 ‘chromosomes’ because two are fused together (also, no p arm-short arm)
4)4% of Down Syndrome patients are due to a Robertsonian translocation |
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Term
| Summary Features of Chromosomal Rearrangements |
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Definition
1)Chromosome rearrangements are usually balanced
2)Carriers of balanced rearrangements are clinically normal
3)Problems occur during gametogenesis – formation of sperm and eggs resulting in:
a)Increased miscarriage
b)Abnormal offspring with unbalanced derivative of the rearrangement.
Note: offspring may also have entirely normal chromosomes or inherit the same balanced chromosome rearrangement carried by the parent
4)Average risk for carrier to have an offspring with an imbalance:
-Translocation 10-15%
5)Features of imbalance:
-Offspring clinically (phenotypically) abnormal
-Usually not able to reproduce (biologically ‘unfit’) so minimum ongoing risk for further generations
-If ‘new’ in individual (not from carrier parent), no increased risk for sibs
-If inherited from ‘carrier’ parent, other family members at risk |
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Term
| Microdeletion and Microduplication |
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Definition
1)Submicroscopic deletions (or duplications) not seen by routine analysis of chromosomes
2)~100 regions identified as lost or gained, some classified as syndromes
3)Requires additional molecular cytogenetic testing strategies, FISH or aCGH
4)Examples include:
-Angelman Syndrome (15q)
-Prader-Willi (15q)
-Di George (22q) |
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Term
| Features of Di George Syndrome |
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Definition
-CHD
-Mildly dysmorphic facial features
-Cleft palate
-Short stature
-Speech delay
-Mild mental retardation
1)Primary defect:
-4th branchial arch
derivatives of 3rd and 4th pharyngeal pouches
-~5th week of embryogenesis
2)Results in defective development of:
-thymus
-parathyroids
-great vessels |
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Term
| Fluorescence In-Situ Hybridization (FISH) |
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Definition
1)Piece of specific DNA used as a “probe” and labeled with fluorescent stain
2)Patient’s chromosomal DNA and probe DNA denatured to single stranded
3)Probe hybridizes to region of overnight, slide washed and visualized using fluorescent microscope
4)Requires specific clinical referral to select the correct ‘FISH’ probe:
-Specific genes and loci
-Centromeres, telomeres
-Gene rearrangements (cancer) |
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Term
| array Comparative Genomic Hybridization (aCGH) |
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Definition
1)DNA clones from across the entire genome arranged as a grid on a glass slide
2)Processed slide is scanned to measure fluorochrome intensity at each site
3)Algorithm software translates fluorochrome signals into interpretable displays
4)Losses and gains due to patient’s chromosome imbalance demonstrated by color change (on the readout, loss = left, duplication = right). |
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Term
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Definition
1)> 70% microdeletion chromosome 22q11.2
2)Can be diagnosed by both FISH and aCGH
3)Di George syndrome can occur both sporadically and in families
4)Although rare, some structural abnormalities can be inherited. It is often observed that the clinical issues are worse from one generation to the next
-Grandmother: history of CHD – probably coincidental finding
-Proband: history of CHD, learning problems, immaturity found to have microdeletion
-Daughter: history of CHD, microcephaly, hypotonia, FTT, repeated opportunist infections, found to have microdeletion (did not survive) |
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Term
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Definition
1)Errors occurring during meiosis may result in chromosome abnormality, either numerical or structural. Because meiotic cell division is a pre-zygotic event, a chromosome abnormality will be present in all cells.
2)Numerical abnormality results in a change in ploidy described as aneuploidy = one more chromosome (trisomy) or one less chromosome (monosomy).
3)Although all chromosomes can be trisomic, only trisomy 13, 18 and 21 are capable of being born alive, however trisomy is always associated with major clinical problems and only trisomy 21 has long term survival.
4)Errors occurring during mitosis may result in chromosome abnormality. Because mitotic cell division is a post-zygotic event, a chromosome abnormality will usually only be present in a proportion of cells (mosaic).
5)Structural abnormalities are caused by chromosome breaks that lead to loss or gain of parts of chromosomes and are usually clinically significant.
6)Chromosomes can break and rearrange with other chromosomes or within themselves. Overall there is usually no gain or loss chromosome material when rearranged so the ‘carrier’ is rarely clinically affected. Nonetheless a carrier has an increased likelihood of miscarriage and the birth of chromosomally abnormal children.
7)Microdeletion syndromes are a group of clinically specific genetic disorders usually only diagnosable by molecular cytogenetic methodology.
8)Molecular cytogenetic FISH is a technique that uses colored labeled DNA probes to detect submicroscopic chromosome abnormality. Unlike cytogenetic analysis, it is not a screening test and requires a specific physician recognition of clinically significant features.
9)Molecular cytogenetic array comparative genomic hybridization (aCGH) is a technique that measures the competitive hybridization of color labeled patient DNA and different colord normal control DNA. Software algorithms analyze the color signals for interpretation of loss or gain of chromosome material at a particular clone on a grid. aCGH, like cytogenetics, is a screening test. |
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