Genetics definitions and facts

The portion of a chromosome that controls whether imprinted genes on that chromosome are expressed. If the imprinting center is missing or altered, genes that require imprinting will not function appropriately

trisomic conception followed by loss of extra chromosome during mitosis; may have milder phenotype

When a monosomic zygote is formed (only one copy of a particular chromosome – the other parent’s dropped out), and that chromosome duplicates itself.

inability to relax or release a muscle after contraction

present at birth, usually in every cell. Constitutional abnormalities may be inherited
or de novo; they can be passed on to offspring

synonymous (change in DNA base results in same AA )

non-synonymous (change in DNA base results in different AA); most common DNA mutation (correlated with ~50% of disease causing mutations)

protein-truncating (change in DNA base results in expression of stop codon and early truncation of protein synthesis)

result from the repetitive addition of certain tri-nucleotide regions (CAG often) due to DNA polymerase slippage. Results in increasing severity of disease with each generation (Fragile X, Huntington’s, myotonic dystrophy); underlies many neuro conditions

the insertion or deletion (indels) of large number of DNA bases. Often results from a high number on non-allelic homologous recombination events during meiosis with regions of similar genome sequences (confusion of regions)

Like whole genome sequencing but only protein-coding portion

the concept that the frequency of alleles in a large population will be aprox. equal from one generation to the next if the allele doesn’t affecting mating/producing offspring success and assuming that mating is random.

situations in which heterozygotes for a mutation (CF or sickle cell) have relatively higher fitness than wild-type homozygotes (in malarial areas or with diarrheal diseases)

the multiple effects that a genotype can have on multiple traits or organ systems

Screen of entire genome for all types of abnormalities, but at low resolution (3-5 Mb) - can only see if chunk 3-5 MB in size is missing which could encompass 100s of genes. Requires living cells for culture to obtain cells in metaphase. Processing of G-banded karyotype is an “artform” – variability between technologists, labs, patient specimens

Targeted test – interrogates specific regions for specific types of abnormalities; not whole genome screen. Relatively good resolution (50-100 Kb). Can be performed on cultured cells or uncultured specimens (direct smears, paraffin-embedded tissue). Provider has to direct which region to examine. Lots of variability with patients who have a similar deletion, so difficult to direct. Don’t need to have living cells to perform.

can be used on uncultured cells, direct smears, or cells embedded in paraffin. Can be used to look for any residual diseased cells remain after treatment, like with leukemia. To screen rapidly for aneuploidies on uncultured cells – results within a day. No other information gained from this technique, though.

Used to screen entire genome for copy number changes (duplications/deletions)
Can detect deletions and duplications <50 Kb in size (small)
Cannot detect balanced rearrangements (balanced translocations)
New method of choice for most constitutional postnatal disorders (not G-band)

o Typically caused by gain/loss of multiple genes (aneuploidy, deletions/dups involving multiple genes)
o Gains tolerated better than losses
o duplications often have less severe phenotypes than deletions
o Sex chromosome abnormalities cause less severe phenotypes than autosomal abnormalities – X chromosome inactivation
o Multiple gene involvement

o Numerical (abnormality of chrome #) - detectable by G-banded karyotype
o Structural – balanced or unbalanced; (Balanced = no gain or loss; usually phenotypically benign, but may predispose to unbalanced offspring)
(Unbalanced = gain and/or loss present; often associated with abnormal phenotype)
o May or may not be detectable by G-banded karyotype

o Most constitutional disorders (DD/ID, autism, MCA) – order CMA only
(Yield higher than karyotype – 15-20% vs 3%)
(Better definition of breakpoints and genes involved)
o Order karyotype for identifiable aneuploidy syndromes (Down syndrome)
(Important to distinguish translocation DS from free-lying +21)
o Note: Karyotype, FISH, CMA do not detect point mutations, repeat expansion disorders (fragile X)

o Disease/cancer affecting organs bilaterally
o Greater frequency of disease/condition in a family than statistically likely – multiple closely related family members affected
o sudden death of seemingly healthy individual
o earlier onset of a disease than would be expected (cancer, Alzheimer’s, Parkinson’s, etc.)
o >3 Miscarriages

15th-20th week of pregnancy; earlier increases the risk of miscarriage

Performed between 10-12 weeks after last period; preferred method prenatal testing before 15 weeks.

present at birth; does not necessarily imply genetic

-structural defect that deviates from normal
-Major: surgical, medical or cosmetic importance

results from intrinsically abnormal developmental process

results from mechanical forces on an otherwise normally formed tissue

destruction or interruption of normally developing tissues

During the formation of the gamete

In the embryo of the parent

0.5-1% or 1/100 - 1/200

(1/8)

At the centromere

Variations in completely unrelated gene loci cause a single genetic disorder

Different mutations within a single gene locus cause the same phenotypic expression