Term
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Definition
Heritable, but not based in DNA sequence.
DNA Methylation - alteration of cytosines in CpG islands, shutting down transcription of those genes.
Genomic Imprinting - Selective inactivation of gene expression in certain chromosomal regions (e.g., X inactivation in females).
Chromatin Remodeling - Protein binding and histone modification sequesters large sections of DNA. |
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Term
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Definition
| The inactive X chromatin seen in interphase nuclei. Only one X chromosome remains active in women, the other is inactivated around the 16th day of embryonic development. Some genes may remain active, and all genes reactivate in germ cells before meiotic division. |
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Term
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Definition
| Disorders with genetic components present at birth. May be inherited (e.g., hemophilia) or caused by disruptions such as infections, chemicals, drugs, or injuries during the developmental process (e.g., spina bifida). |
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Term
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Definition
| Detected by karyotyping, flow cytrometry, FISH. Polyploidy can result in infertility and abnormal features. Aneuploidy occurs in 0.5% of pregnancies and causes spontaneous abortions in 50% of cases. Usually caused by erroneous separation of chromosomes during gamete production (chromosome nondisjunction). Monosomy is generally incompatible with life, with the exception of SCAs. |
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Term
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Definition
Trisomy 21. Occurs in 1/700 live births.
Flat facial profile, mental retardation, cardiac problems, risk of acute leukemia, eventual neuropathological disorders, abnormal immune system. |
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Definition
Trisomy 18/ Occurs in 1/3000 live births.
Severe, clenched fist, survival |
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Definition
Trisomy 13. Occurs in 1/500 live births.
Cleft palate, heart damage, mental retardation, survival generally <6 months. |
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Term
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Definition
XXY. Occurs in 1/850 live births.
Male hypogonadism, long legs, gynecomastia (male breast enlargement), low testosterone level. |
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Term
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Definition
XYY. Occurs in 1/1800 live births.
Excessive height, acne, 1-2% have behavioral disorders. |
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Term
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Definition
X. Occurs in 1/2000 live births.
Bilateral neck webbing, heart disease, failure to develop secondary sex characteristics, hypothyroidism. |
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Term
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Definition
XXX, XXXX. Occur in 1/1200 newborn females.
Mental retardation increases with increasing X. |
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Term
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Definition
| Two or more genetically distinct populations from different zygotes in one individual. |
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Term
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Definition
| Two or more genetically distinct populations of cells from one zygote in an individual. Arises from mutation events affecting somatic or germ line cells. Common with SCAs such as X, XXX. Later disjunction will make additional populations. |
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Term
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Definition
| Karyotyping detects those >4 million bp, FISH detects those less. Include translocations, inversions, deletions, duplications, marker chromosomes (unkown chromosomes), and derivative chromosomes. Require the breaking and reunion of DNA, caused by chemicals, radiation, and chromosome breakage syndromes (Fanconi anemia, b1000 syndrome). Some reciprocal inversions deletions, duplications, translocations, insertions, have no phenotypic affect. 7.4% of conceptions have chromosome mutations, observed in 50% of spontaneous abortions and 5% of live births. |
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Term
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Definition
Also velocardiofacial syndrome. Del22q, occurs in 1/4000 live births.
CATCH-22 (cardiac abnormality/abnormale facies, T-cell deficit, cleft palate, hypercelcemia) |
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Term
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Definition
Del5p. 1/20000 - 1/50000 live births.
Growth deficiency, catlike cry in infancy, small head, mental retardation. |
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Term
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Definition
Wilms tumor, aniridia, genituourinary anomalies, mental retardation syndrome.
del11p. 1/15000 live births.
Aniridia (no iris), hemihypertrophy (one side of the body grows faster), other congenital anomalies. |
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Term
| Loss-of-Function Mutations |
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Definition
| A gene may be deleted so that its product is lost, or it may be missing a piece and produce a defective protein. Even if only one of the two homologous proteins is mutated, it can interfere with the normal gene product. Complex metabolic pathways are very susceptible to these mutations. If the mutation is dominant, it can mess up function of oligomers. |
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Term
| Gain-of-Function Mutation |
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Definition
| Mutations that cause overexpression of genes or create new protein functions and phenotypes. These are not common. Gene products may be produced at the wrong time or site. |
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Term
| Autosomal Dominant Transmission |
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Definition
| Disease phenotype is present even if only one chromosome is mutated (can be a gain or loss mutation). Children from one affected parent and one unaffected parent have a 50-100% chance of getting the disease. Heterozygous individuals have the phenotype. |
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Term
| Autosomal-Recessive Transmission |
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Definition
If the recessive mutaton is found on one chromosome in each of the parents, the child has a 25% chance of inheriting the disease. Only in homozygous individuals. More frequent in inbreeding of heterozygotic individuals.
Largest category of Mendelian disorders. |
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Term
| Sex-Linked Recessive Mutations |
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Definition
| Usually X-linked, the Y chromosome has fewer genes. X-linked diseases are usually recessive, dominant ones are rare. Mostly affect men, who have no second X chromosome (hemizygous for X). Even though one of the female's X chromosomes is inactive, it can be turned back on. |
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Term
| Transmission Pattern Factors |
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Definition
Transmission can be complicated. The expression of the mutation may not be straight-forward.
Penetrance - frequency of mutation expression in individuals with gene lesions. Incomplete penetrance means the mutation will not always cause the disease phenotype. Complete penetrance is expression in all individuals with the mutation.
Variable expressivity - Range of phenotypes in individuals with the same lesions. Reflects interactions with other gene products and environmental factors. |
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Term
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Definition
Affect structural proteins, cell surface receptor proteins, regulators and enzymes.
Some (e.g., hemoglobin S) are detected by morphological studies or biochemistry. Molecular diagnostics can be used to detect gene lesions in single-gene disorders. |
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Term
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Definition
| Organelles where acid hydrolase enzymes degrade products of cellular ingestion in an acid environment. Intracellular turnover (autophagy) or phagocytosis (heterophagy) can supply these products. |
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Term
| Lysosomal Storage Diseases |
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Definition
| Caused by loss of enzyme function resulting in incompletely digested macromolecules. Can arise from defects in any protein involved in lysosome function. Causes different diseases depending on what substrate material is affected. Biochemical screening for loss of enzyme function can be followed by direct sequencing to detect mutations. |
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Term
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Definition
Mutation in the Factor V coagulation gene in exon 10, causing a hypercoagulable (thrombophilic) phenotype.
Heterozygous form is present in 4-7% of the population, homozygous form in 0.06-0.25%. Annual occurrence of deep venous thrombosis is 1/1000 people. Risk increases with contraceptive use in women. |
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Term
| Tests for Leiden V Factor |
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Definition
PCR-RFLP, SSP-PCR, qPCR, melt curve.
Prothrombin is necessary for the conversion of fibrinogen to fibrin. A mutation in the 3' end untranslated region of the gene results in an autosomal dominant increased risk of thrombosis, so labs test for F2 and F3 mutations at the same time via multiplex PCR and gel resolution of RFLP. |
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Term
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Definition
Overabsorption of iron from food, causing heart, pancreas, liver, skin disease, diabetes. Can be diagnosed by blood iron levels, transferrin saturation, or liver biopsy.
Treatable via phlebotomy.
Autosomal-recessive. |
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Term
| Molecular Basis of Hemachromatosis |
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Definition
Hemachromatosis type I gene (HFE/HLA-H) codes a membrane-bound protein in the small intestine and placenta that binds to Beta2 macroglobulin and transferrin. It directs iron absorption based on cell iron levels. If mutated, causes iron overload. C28ZY is the most common mutation, present in 10% of Caucasians with a disease frequency of 2-3/1000 people. H63D and 565C are also common.
PCR-RFLP can be used for diagnosis. |
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Term
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Definition
Autosomal recessive. Affects cells producing mucous, sweat, saliva, digestive juices, making these secretions thick and sticky, causing respiratory failure.
30,000 people have it.
Caused by mutations in cystic fibrosis transmembrane conductance regulator gene which codes for chloride channel membrane protein. The most common mutation is F508del, a 3 bp deletion that removes a phenylalanine. 1,300 other mutations.
Tests usually screen 23-44 mutations. |
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Term
| Cytochrome P-450 Reaction |
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Definition
| A-H + B-H2 + O2 --- A-OH + B + H2O |
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Term
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Definition
| Group of enzymes in the ER concentrated in the liver and small intestines. Mono-oxygenases participating in hydroxylation reactions and transferring e- to O. They act in drug, steroid, etc, metabolism, using NADH/NADPH as H donors to render lipophilic drugs more excretable. These vary from person to person, influencing drug metabolism and compounding drug interactions. |
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Term
| Cytochrome P-450 Variations |
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Definition
Over 30 reported variations.
CypIA2 and the CYP2/CYP3 families are the most important in drug metabolism, inhibiting or inducing metabolism.
Polymorphisms are unequally distributed geographically and ethnically. Testing for polymorphisms can help predict drug response. Allele-specific PCR can be used. |
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Term
| Methylenetetrahydrofolate Reductase |
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Definition
MTHFR. The gene product catalyzes 5,10-methyleneterahydrofolate to 5-methylenetetrahydrofolate which converts homocysteine to methionine. A single AA substitution can affect structure/function, leading to buildup of homocysteine in the blood and excretion in urine. Methionine is depleted. Mutations can lead to cardiovascular disease, pregnancy complications.
24 mutations have been identified. 677CST(A222V) and I298ASC(E429A) are common. Detected with qPCR, PCR-RFLP (avoid false-positive restriction patterns). |
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Term
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Definition
| Generation of new mutations in germ line cells. These cells lead to gametes with the mutations, producing a heritable phenotype. Unexpected pedigrees result, such as multiple children with an autosomal-recessive disease coming from 2 unaffected parents. |
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Term
| Mitochondrial Gene Mutations |
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Definition
mtDNA has a 1000 bp region containing transcription and replication regulatory elements.
Mutations in mtDNA affect energy production, resulting in muscular and neurological disorders.
Southern Blots detect large mutations, PCR-RFLP for small ones. Heteroplasmy (mutated and unmutated mitochondria in the same cell) complicates analysis.
Some mitochondrial function genes are nuclear, leaving autosomal (not maternal) patterns. These can result in mitochondria showing the loss of that gene function. |
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Term
| Trinucleotide Repeat Expansion Disorders |
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Definition
| STRs of 3 bp repeating units that can be expanded or contracted during DNA replication and meiosis due to replisome slippage on DNA. These mutations may happen in coding or noncoding gene sequences. |
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Term
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Definition
Caused by triple repeat CGG expansion of up to 2000 repeats in the noncoding region 5' to the X mental retardation gene, FMR-1. Carriers have up to 200 repeats but no symptoms. Mistakes in meiotic recombination leads to amplification of CGG and mutation of the Cs, turning FMR-1 transcription off and causing visible chromosomal compacting disruption.
Symptoms - learning disorders, mental retardation, long face, large ears, macro-orchadism. Symptoms show up at puberty and get worse in subsequent generations (anticipation). |
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Term
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Definition
| Fragile X Chromosomes have a threadlike process at the end of the q arm visible in karyotypes. PCR can be used for pre-mutations in carriers but not for full mutations (which are too long). Southern Blots can detect full mutations as well as mosaicisms where pre-mutations and full mutations are present in different cell populations. PCR resolution is capillary electrophoresis wit primer binding inside the CGG region. Results in a ladder pattern. |
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Term
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Definition
Expansion of CAG repeat from 9-37 to 38-86 repeats in the Huntington structural gene (HD 4p16.3). Symptoms include impaired judgment, difficulty swallowing, abnormal movements (chorea), personality changes, depression, mood swings, intoxicated appearance. Doesn't usually onset until 30s or 40s. Children of someone with HD have a 50% chance of having it.
The expansion is in the coding region of the gene. Multiple glutamine additions cause the protein to aggregate in plaques, especially in nervous tissue. |
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Term
| Idiopathic Congenital Central Hypoventilation Syndrome |
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Definition
CCHS. A rare pediatric disorder. Children breath inadequately during sleep and may hypoventilate while awake.
Associated with Hirschsprung Disease (intestinal disorder) and symptoms of diffuse autonomic nervous system dysregulation/disfunction.
Usually present at birth with late onset at 2-4 years. |
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Term
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Definition
Several mutations are associated with CCHS, including a polyalanine expansion of PHOX2B on (4p12)13, a paired-end homeobox gene. The transcript is a transcription factor with a homeobox domain similar to other DNA-binding proteins.
An imperfect GCN expansion inserts multiple alanines into the protein. The more repeats, the worse the disease. 62-98% of patients have this gene mutation.
Detected by PCR. |
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Term
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Definition
Chromosomal disjunction can produce gametes with no or double copies of a chromosome. This means that the genetic info on that chromosome in the zygote will be from only one parent.
Deletion of part of a homologous chromosome can also remove the genetic info from one parent.
Translocations and some deletions are detected via karyotyping. FISH can detect 99% of cases. PCR, RFLP, STR also used. Methylation-sensitive restriction enzymes, melt curve analysis, Southern blots also used to diagnose. |
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Term
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Definition
Mental retardation, short stature, obesity, hypogonadism. Caused by del(15)(q11q13) on the paternal chromosome.
Can occur via:
- Deletion on chromosome 15
-Mutation on chromosome 15
-Translocation with loss of critical region
-Uniparental disomy where two maternal and no paternal chromosome 15s are inherited. |
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Term
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Definition
Ataxia, seizures, inappropriate laughter. Caused by del(15)(q11q13) on maternal chromosome.
Can occur via:
-Deletion on chromosome 15
-Mutation of chromosome 15
-Translocation with loss of critical region
-Uniparental disomy where two paternal and no maternal chromosome 15s are inherited. |
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Term
| Limits of Molecular Testing |
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Definition
-Treatments are targeted to phenotype.
-Gene mutations may not predict severity of disease in genes with variable expressivity.
- Genetic lesions may be detected without symptoms, raising questions.
-Several mutations may be present, or polymorphisms in other genes may also affect phenotype. |
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