TERMINOLOGY LIST
INTRODUCTION TO NEUROGENETICS
Reduced penetrance = carriers of the disease gene may be unaffected
Phenocopy = patients show same clinical phenotype, but are not carrier of the same disease gene
Oligogenic disease = multiple genes are needed to manifest disease, often we see a variable phenotype
Polygenic disease = multifactorial diseases associated with both multiple genes and environmental factors. Often we see
extensive phenotypic heterogeneity
Population stratification = systematic ancestry difference between patients & controls (well-matched controls!!)
Polygenic risk score = sum of (common variant x effect size). Is generated at the population level and applied at individual level
Select variant derive effect size from population level apply on individual level
Gives the overall risk of developing a disease
Manhattan plot = shows the significance that a certain variant is distributed (threshold: p = 5x10 -8)
Burden analysis = rare variants are grouped based on biological information
Manolio plot = gives the relation between the allele frequency and the effect size
Phenotypic heterogeneity = patients have same genotype, but different phenotype
Nonsense-mediated decay = mRNA surveillance mechanism triggered when nonsense mutation results in stop codon
Principle: exon junction complexes are not displaced when a premature stop codon is introduced NMDS
Will not work when premature stop codon is
o In the last exon
o Within +/- 55 nucleotides of the final exon-junction complex
Splicing enhancers = promote the inclusion of exons
Splicing silencers= inhibit the inclusion of exons
Cryptic splicing = inclusion of exclusion of unintended exons or introns leading to aberrant mRNA transcripts
GENETIC MECHANISMS
Haploinsufficiency = 1 gene copy is not sufficient for the protein to work
Dominant-negative effect = defective allele interferes with wildtype copy, more then 50% loss of protein
Dominant gain-of-function = novel (toxic) protein function or ectopic expression of protein function. Wildtype allele is not able
to counterbalance the toxic effect of the mutation
Mutational heterogeneity = different gene mutations cause the same disease or condition
Mutational homogeneity = 1 specific mutation causes the disease or condition
Retrogene = a processed copy of another gene derived via reverse-transcription of mRNA & more or less random insertion into
the organism’s genome. Usually non-function and inactive, because lack of regulatory elements
Mosaic status = not all body cells have the same genetic make-up and a pathogenic mutation is found in some of the cells
Somatic mutation = mutation in any of the cells except for the germ cells
Heteroplasmy = variable ratios of mutant to normal mtDNA copies per cell. The larger the ratio, the more severe phenotype
TANDEM REPEAT EXPANSIONS
STRs = short tandem repeats (microsatellite) when repeat motif has a length of 1 – 9 nt
VNTRs = variable number of tandem repeats (minisatellite) when repeat motif has length of 10 – 100 nt
Premutation allele = not pathogenic, but likely to expand to a pathogenic length in the next generation. The offspring is of high
risk, but the person him-/herself will not develop disease
Permissive haplotype = not pathogenic, but has a minimally expanded repeat without interruptions (unstable) that is likely to
further expand across many generations. This results in geographical clustering of repeat disorders and linkage disequilibrium
with nearby SNPs
Anticipation = disease shows earlier onset and/or more severe phenotype with each subsequent generation due to further
expansion of a repeat (Length of repetitive DNA sequences increases across generations)
RNA foci = unusual RNA aggregates in the nucleus
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INTRODUCTION TO NEUROGENETICS
Reduced penetrance = carriers of the disease gene may be unaffected
Phenocopy = patients show same clinical phenotype, but are not carrier of the same disease gene
Oligogenic disease = multiple genes are needed to manifest disease, often we see a variable phenotype
Polygenic disease = multifactorial diseases associated with both multiple genes and environmental factors. Often we see
extensive phenotypic heterogeneity
Population stratification = systematic ancestry difference between patients & controls (well-matched controls!!)
Polygenic risk score = sum of (common variant x effect size). Is generated at the population level and applied at individual level
Select variant derive effect size from population level apply on individual level
Gives the overall risk of developing a disease
Manhattan plot = shows the significance that a certain variant is distributed (threshold: p = 5x10 -8)
Burden analysis = rare variants are grouped based on biological information
Manolio plot = gives the relation between the allele frequency and the effect size
Phenotypic heterogeneity = patients have same genotype, but different phenotype
Nonsense-mediated decay = mRNA surveillance mechanism triggered when nonsense mutation results in stop codon
Principle: exon junction complexes are not displaced when a premature stop codon is introduced NMDS
Will not work when premature stop codon is
o In the last exon
o Within +/- 55 nucleotides of the final exon-junction complex
Splicing enhancers = promote the inclusion of exons
Splicing silencers= inhibit the inclusion of exons
Cryptic splicing = inclusion of exclusion of unintended exons or introns leading to aberrant mRNA transcripts
GENETIC MECHANISMS
Haploinsufficiency = 1 gene copy is not sufficient for the protein to work
Dominant-negative effect = defective allele interferes with wildtype copy, more then 50% loss of protein
Dominant gain-of-function = novel (toxic) protein function or ectopic expression of protein function. Wildtype allele is not able
to counterbalance the toxic effect of the mutation
Mutational heterogeneity = different gene mutations cause the same disease or condition
Mutational homogeneity = 1 specific mutation causes the disease or condition
Retrogene = a processed copy of another gene derived via reverse-transcription of mRNA & more or less random insertion into
the organism’s genome. Usually non-function and inactive, because lack of regulatory elements
Mosaic status = not all body cells have the same genetic make-up and a pathogenic mutation is found in some of the cells
Somatic mutation = mutation in any of the cells except for the germ cells
Heteroplasmy = variable ratios of mutant to normal mtDNA copies per cell. The larger the ratio, the more severe phenotype
TANDEM REPEAT EXPANSIONS
STRs = short tandem repeats (microsatellite) when repeat motif has a length of 1 – 9 nt
VNTRs = variable number of tandem repeats (minisatellite) when repeat motif has length of 10 – 100 nt
Premutation allele = not pathogenic, but likely to expand to a pathogenic length in the next generation. The offspring is of high
risk, but the person him-/herself will not develop disease
Permissive haplotype = not pathogenic, but has a minimally expanded repeat without interruptions (unstable) that is likely to
further expand across many generations. This results in geographical clustering of repeat disorders and linkage disequilibrium
with nearby SNPs
Anticipation = disease shows earlier onset and/or more severe phenotype with each subsequent generation due to further
expansion of a repeat (Length of repetitive DNA sequences increases across generations)
RNA foci = unusual RNA aggregates in the nucleus
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