Amorphic Mutations
Mutations that result in a complete loss of the function encoded by the gene, termed “amorphic” (i.e. complete loss of function).
Autosome
A nuclear chromosome other than the X- and Y- chromosomes.
Back Mutation (Reversion)
A point mutation that restores the original sequence and hence the original phenotype.
Bacteriophage Immunization
Bacteriophages are viruses that infect only bacteria and are therefore non-pathogenic to humans. The simple bacteriophage ФX174 has been used as a neoantigen to immunize patients in order to evaluate their immune responses. Since normal individuals have not typically been exposed to this bacteriophage, there are no antibodies to it in IVIG preparations so immune responses can be evaluated in patients who are on IVIG. Immunizations are given IV with no adjuvant. The typical immunization protocol involves a primary immunization at baseline and a secondary immunization 6 weeks thereafter. Serum is collected prior to immunization and at 1, 2, and 4 weeks after each dose of bacteriophage. Class switching from IgM to IgG is evaluated after the secondary immunization. Other neoantigens that have been utilized to test immune responses include TNP-KLH and the rabies vaccine although these have not been as extensively studied as bacteriophage ФX174.
Bayesian Analysis
A mathematical method to further refine recurrence risk taking into account other known factors.
cDNA
Complementary DNA produced from a RNA template by the action of RNA-dependent DNA polymerase.
Centromere
A region of the chromosome to which spindle traction fibers attach during mitosis and meiosis; the position of the centromere determines whether the chromosome is considered an acrocentric, metacentric or telomeric chromosome.
Conservative Change
An amino acid change that does not affect significantly the function of the protein.
Contiguous Genes
Genes physically close on a chromosome that may deleted together in interstitial chromosomal deletion syndromes, such as the X-CGD gene CYBB that can have deletoin of the contiguous gene XK, which encodes the Kell antigen. This contiguous gene deletoin syndrome causes CGD with McLeod syndrome.
CpG Islands
Areas of multiple CG repeats in DNA.
Degenerate Codon
A codon that specifies the same amino acid as another codon.
Deletion Mapping
The use of overlapping deletions to localize the position of an unknown gene on a chromosome or linkage map.
Dominant Negative Mutations
(also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, the dominant negative form of IFNGR1 exerts an inhibitory effect on the normal allele, thereby driving interferon gamma responsiveness down to a level at which infectoins occur. In contrast, mutations that delete a single allele are recessive, that is, they have no phenotype since one perfectly nornal allele is enough to be normal as long as it is not opposed by an antagonistic allele.
Exome Sequence
A technique whereby the DNA sequence of a substantial portion of the exomic regions of an individual are ascertained without much intronic or intervening DNA sequence information
FISH
Fluorescent in situ hybridization: a technique for uniquely identifying whole chromosomes or parts of chromosomes using florescent tagged DNA.
Founder Effect
Founder effect refers to the phenomenon of loss of genetic diversity of a colony of individuals caused by their departure from a larger population and isolation. In this process mutations from the original population can be maintained and propagated in the new colony, affecting a larger number of in individuals. For example, mutations causing Familial Mediterranean Fever in Moroccan Jews are thought to be associated with a founder effect, emanating from common ancestors.
Fragile Sites
A non-staining gap of variable width that usually involves both chromatids and is always at exactly the same point on a specific chromosome derived from an individual or kindred.
Gain-of-Function Mutations
Change of the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes. Often called a neomorphic or hypermorphic mutations.
Gene Amplification
Any process by which specific DNA sequences are replicated disproportionately to their representation in the parent molecules; during development, some genes become amplified in specific tissues.
Genome Wide Association Study (GWAS)
The linkage of polymorphic variation within the human genome to specific phenotypes. These have the potential to describe otherwise unexpected regions of the genome that impact a clinical presentation.
Hypermorphic Mutations
Mutations can affect the function of the protein encoded by a gene. Hypermorphic mutations are the ones that increase the function of the resulting protein. As example in PID there are IKBA mutations related to autosomal-dominant anhidrotic ectodermal dysplasia and immunodeficiency. The mutations in STAT1 that are related to chronic mucocutaneous candidiasis are also hypermorphic or gain of function type mutations.
Hypomorphic Mutations
Mutations can result in a complete loss of the function encoded by the gene, termed “amorphic” (i.e., complete loss of function). Hypomorphic mutations are ones that affect the gene such that the resulting protein has some, but not all function. A good example of this NEMO deficiency: complete gene loss in males is fatal, so surviving males must have some residual function, just not normal function.
Imprinting
A chemical modification of a gene allele which can be used to identify maternal or paternal origin of chromosome.
Incomplete Penetrance
The gene for a condition is present, but not obviously expressed in all individuals in a family with the gene.
Isochromosome
A metacentric chromosome produced during mitosis or meiosis when the centromere splits transversely instead of longitudinally; the arms of such chromosome are equal in length and genetically identical, however, the loci are positioned in reverse sequence in the two arms.
Linkage
The greater association in inheritance of two or more nonallelic genes than is to be expected from independent assortment; genes are linked because they reside on the same chromosome.
Analysis of pedigree the tracking of a gene through a family by following the inheritance of a (closely associated) gene or trait and a DNA marker.
Lod Score
Logarithm of the odd score; a measure of the likelihood of two loci being within a measurable distance of each other.
Loss-of-Function Mutations
Are the result of gene product having less or no function. When the allele has a complete loss of function (null allele) it is often called an amorphic mutation. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency). Marfan syndrome is an example of a disease in which haploinsufficiency of fibrillin 1 leads to impaired TGFbeta metabolism.
Missense Mutation
A change in the base sequence of a gene that alters but does not eliminate a protein. Missense mutations lead to replacement of the normal amino acid with a different one. These can be important or not, depending on the location, the amino acid, and the gene function.
Nephelometer
A nephelometer is an instrument for measuring suspended particulates in a liquid or gas colloid. It does so by employing a light beam (source beam) and a light detector set to one side (usually 90°) of the source beam. Particle density is then a function of the light reflected into the detector from the particles. It is commonly used in the clinical laboratory to measure immunoglobulin levels.
Nonsense Mutation
A mutation in which a codon is changed to a stop codon, resulting in a truncated protein product.
Pleiotropy
The phenomenon of variable phenotypes for a number of distinct and seemingly unrelated phenotypic effects.
Proband
Individual in a family who brought the family to medical attention.
Radiation Sensitivity Testing
Testing that is used to identify patients who have genetic defects that cause problems with DNA repair (see “DNA Repair Defects” above). In this test, the patient’s cells are exposed to ionizing radiation which causes double-stranded DNA breaks. Normal cells will repair the DNA damage and the cells will survive and continue to grow. Cells from patients with genetic defects in proteins required for repairing this type of DNA damage (such as ATM, NBS1, MRE11, etc.) are unable to repair the breaks and do not survive.
Single Nucleotide Polymorphism (SNP)
A normally occurring nucleotide variation at a single position that is present in >1% of the population. This may or may not have impact upon phenotype, but can be linked to other heritable characteristics or variations.
Somatic Cell Hybrid
Hybrid cell line derived from two different species; contains a complete chromosomal complement of one species and a partial chromosomal complement of the other; human/hamster hybrids grow and divide, losing human chromosomes with each generation until they finally stabilize, the hybrid cell line established is then utilized to detect the presence of genes on the remaining human chromosome.
Somatic Mutation
A mutation occurring in any cell that is not destined to become a germ cell; if the mutant cell continues to divide, the individual will come to contain a patch of tissue of genotype different from the cells of the rest of the body.
Spectratype (immunoscope)
A method used as a surrogate for functional TCR diversity using PCR to determine the range of TCR length diversity used in the generation of specific V-beta families.
Translocation
A chromosome aberration which results in a change in position of a chromosomal segment within the genome, but does not change the total number of genes present.
TREC (T-cell Receptor Excision Circle)
Episomal DNA circles generated by the DNA recombination process used by T lymphocytes to produce antigen-specific alpha/beta T cell receptors. Measurement of TRECs in peripheral blood T cells is used to study thymic output and is typically done by real-time quantitative-PCR assay for the specific detection and quantification of TCR episomal DNA circles. This is now the basis for newborn screening, using TREC number as a surrogate marker for lymphocyte production.
Variable Number Tandem Repeats (VNTR)
Any gene whose alleles contain different numbers of tandemly repeated oligonucleotide sequences.
Whole Genome Sequence
A technique where the entire sequence of input DNA is defined irrespective of its potential relevance. This term is often used interchangeably (but incorrectly) with whole exome sequencing. Be careful to distinguish between them, since WES looks only at exons.
X-inactivation
The repression of one of the two X-chromosomes in the somatic cells of females as a method of dosage compensation; at an early embryonic stage in the normal female, one of the two X-chromosomes undergoes inactivation, apparently at random, from this point on all descendent cells will have the same X-chromosome inactivated as the cell from which they arose, thus a female is a mosaic composed of two types of cells, one which expresses only the paternal X-chromosome, and another which expresses only the maternal X-chromosome.