Medical Genetics Flashcards
genotype
genetic makeup
phenotype
individual’s obeservable traits
allele
variant form of gene that exists at same relative locations on homologous chromosomes
homozygous
individual inherits the same alleles for particular gene from both paretns
homozygous dominant
carries 2 copies of same dominant gene
homozygous recessive
carries 2 copies of same recessive gene
heterozygous
2 copies of different alleles of a particular gene
hemizygous
genetic variant on gene which there is only 1 copy
types of genetic diseases
single gene disorders
mitochondrial diseases
chromosomal abnormalities
multifactorial disorders
law of dominance
alleles can be dominant or recessive
rather than both alleles contributing to the phenotype the domnant one wll be expressed exclusvely
law of segregation
paired genes must segregate equally into gametes such as the offsprings have equal likelihood of inherting either factor
law of independent assortment
genes do not nfluence each other with regard to the sorting of alleles into gametes and every possible combo of alleles for every gene is equally likely to occur
recurrence risk
probability of producing a child with the genetic disease
autosomal dominant characteristics
usual recurrence risk - 50%
transmssion pattern - vertical. ds pheno seen generation to generaton
sex ratio- equal number of males and females usually
other- father to son ratio transmission of disease gene is possible
autosomal recessive characteristics
usual recurrence risk- 25%
transmission pattern disease pheno may be seen in multiple siblings, but usually not in earlier generations
sex ratio- usually equal number
other- consanguity s sometmes seen, especally for rare recessive diseases
consanguinity
relationship between blood relatives who have at least one common ancestor no more than a great great grandparent
consanguinity consequences
increased incidence of congenital malformation, AR disorder and other hearing loss and mental retardation
coefficient of relationship
proportion of shared genes, risk of disease increases as proportion increases
incomplete dominance
the phenotype of heterozygotes is somewhere in between the pheno of homozygous recessive and homozygous dominant
codominance
two alleles are simultaneously expressed and equally contribute to the phenotype
multiple alleles
there are 3 or more alternative allelic forms of a gene, only 2 of which can exist in any normal diploid ind
polygenic ingeritance
caused by the combined effect of mutations in multiple genes
linked genes
genes that are physcally close to one another on the same chromosome and likely to be ingerited together
pleiotropy
genes that exet effects on multiple aspects of physiology or anatomy
epistasis
effects of one gene are modified by one or several other genes
nonmendelian modes of inheritance
incomplete dominance codominance multiple alleles polygenic ingeritance linked genes pleiotropy epistasis
Sex linked disorders
Do not follow models laws of inheritance
X linked dom and rec
Y linked - rare
Xlinked dominant
Recurrence risk for heterozygous femal and normal male
50% sons affected
50% daughters affected
X linked dominant
Recurrence risk for affected male and normal female
0% of sons
100% daughters
X linked dominant
Transmission pattern
Vertical phenotype seen in generation after generation
X linked dominant
Sex ratio
Twice as many affected females as affected males
X linked dominate
Other info
Male to male transmission is not seen
Expression is less severe in female heterozygous than in affected males
Examples of x linked dominant
Hypophosphatemic rickets
Rett syndrome
X linked recessive
Recurrence risk for heterozygous female and normal male
50&+% sons affected
50% of daughters heterozygous carriers
Recurrence risk for affected male and normal female
0% sons affected
100% daughters heterozygous carriers
X linked recessive transmission pattern
Skipped generations may be seen, representing transmission through carrier females
X linked recessive sex ratio
Much greater prevalence of affected males
Affected homozygous females rare
X linked recessive
Other
Male to male transmission not seen
Manifesting heterozygotes may be seen in females
Z linked recessive
Examples
Hemophilia A
Duchenne muscular dystrophy
Red green color blindness
Y linked. (Holandric) disorders
Affects genes only present on Y chromosome
Effected father transmits to son.
Most y chromosomal genes play role in male sexual differentiation, development of sex characteristics. And spermatogenesis
Mitochondrial inheritance
MtDNA inherited exclusively though maternal line
Heteroplasmy
Mutated mtDNA variant is found only in portion of ell’s mitochondria
Threshold effect
Phenotypical expression depends on proportion of cell’s normal mtENA to mutated mtDNA
Mitochondrial diseases
Kaerns-sayer syndrome
Leber hereditary optic neuropathy LHON
Mitochondrial encephalopathy, lactic acidosis and stroke like episodes (MELAS)
Myoclonic epilepsy and ragged red fiber disease MERRF
Imprinting
Epigenetic process that differential modifies genes or chromosomal segments in male/female germ line
As result either paternal or maternal allele of gene is active in somatic cells of offspring
Imprinting
Genetic mechanisms
Chromosomal microdeletions
Uniparental disomy- in which individual inherits two copies of chromosome from one parent and none from the other
Prader willi syndrome
Chromosome 15 deletion of father
From mother
Angelman syndrome
Chromosome 15 deletion of mother
From father
Anticipation
Phenomenon in which the symptoms become more severe or start at an earlier age as a disease is passed on to the next generation
Anticipation
Genetic mechanisms
Trinucleotide repeats
Number of repeats increase in each following generation
Meta centric
Shor and long arm similar size
1, 2, 3
Submetacentric chromosom
Short short arms (chromatids)
Long long arm
Chromosomes 4, 5, x
Acrocentric
Satellites for short arms, shorter long arms
Chromosome 13 14 15
Euploid
Appropriate number of chromosomes for their species
Polyploid
In human incompatible with life
Aneuploid
Error in chromosome number
Monosomy
Trisomy
Numerical chromosomal abnormalities due to
No dysfunction
Chromosome abnormality
Down syndrome
Trisomy 21
Chromosome abnormality
Klinefelter syndrome
Xxy
Chromosome abnormality
Patau syndrome
Trisomy 13
Chromosome abnormalities
Edwards syndrome
Trisomy 18
Chromosome abnormality
Turner syndrome
Monosomy x
Structural chromosomal abnormalities
Balanced
Chromosome complement is complete
No loss or gain of genetic material
Generally harmless
At risk of producing children with an unbalanced chromosomal complement
Structural abnormalities
Unbalanced
Chromosome complement contains incorrect amount of material
Serious clinical consequences
Reciprocal translocation
Break occurs in each of two chromosomes with the segments being exchanged to form two new derivative chromosomes
Robertsonian translocations
Particular type of reciprocal translocation in which the breakpoints are located at or close to the centromenres of two acrocentric chromosomes
Pericentric inversion
Inversion segment involves the centromere
Paracentric inversion
Inversion segment involves only one arm of the chromosome
Ring chromosome
Both tips of chromosome can be lost, leaving sticky ends that attach to each other, forming a ring chromosomes
Isochromosomes
Formed when a chromosome divides along an axis perpendicular to its usual axis of divisions
Produces one chromosome with only the short arms and another with only Long arms
Multifactorial/ complex disorders
Do not follow a clear inheritance pattern
Symptoms are caused by interplay between several genes and exogenous factors
Genetic testing
Analysis of chromosomes, dna, rna, or proteins to detect abnormalities that can cause a genetic disease
Single gene disorders genetic testing
Detecting variation at DNA or RNA level PCR Southern blotting Northern blotting Restriction fragment analysis High throughput DNA sequencing Microarray analysis
Mitochondrial diseases and multifactorial disorders genetic diseases
Detecting dysfunction or variations at protein level
Electrophoresis and western blotting
ELISA
Enzyme activity assays
Chromosomal abnormalities genetic diseases
Cytogenetic analyses
High resolution banding
FISH
Comparative genomic hybridization
Southern blot
Advantages / disadvantages
Laborious
Trinucleotide expansions in fragile x.
Sizing of PCR productions
Advantages/ disadvantages
Simple and cheap
ARMS-PCR
Advantages/disadvantages
Examples
Simple, cheap
CFTR mutations
Oligonucleotide ligation
Advantages/disadvantages
Example
Multiplex possible
CFTR mutations
Real time PCR
Advantages and disadvantages
Examples
Expensive equipment
FVL
Sanger sequencing
Advantages/ disadvantages
Gold standard
Known or unknown mutations
Any gene
Pyrosequencing
Advantages/disadvantages
Known or unknown mutations
Any gene
Expensive
Next generation sequencing
Advantages/disadvantages
Known or unknown mutations
Any gene
Expensive equipmtent, enormous capacity but vast amount of data to analyze
Interpretation of novel variants can be difficult
Cytogenetic assay
Fish assay
CGH assay
Fish assay
Labeled probe is hybridized to metaphase, prophase, or interphase chromosomes
Can be used to test for missing or additional chromosomal material as well as chromosome rearrangements
Use of multiple colors to detect several possible alterations simultaneously is possible
CGH assay
Differential labeled DNA from test and control sources is hybridized to probes in microarrays.
Allows the detection of chromosome duplications and deletions
Can not detect balanced rearrangements
