Clinical Molecular Genetics Flashcards
Mutation
Any intrinsic change in DNA
Genome mutation
Whole chromosomes are absent or present in excess (Down Syndrome)
Chromosome Mutation
Chromosome is rearranged (i.e. Translocation)
Gene Mutation
Mutation involving a single gene
Allele
Alternative variants of genetic information at a specific locus that control the same trait. Different alleles are caused by small polymorphisms and rare variants, which are non-disease causing changes.
Polymorphism
Non-disease causing change in allele sequence that is present in 1% of the population. The frequency of the less common base change must be >1% in order to be considered a polymorphism.
Rare Variant
Non-disease causing change in allele sequence that occurs in <1% in order for the change in allele sequence to be considered a rare variant.
Compound Heterozygote
Individual with 2 different mutations in the same gene.
Haploinsufficiency
One mechanism of a disease that is cause by a mutation that results in a normal functional protein but there is not enough protein for it to do its job properly.
Achondroplasia
Autosomal Dominant single gene gain of function mutation in FGFR3 receptor that leads to constant repression of cartilage formation. Majority of the individuals (~80%) do not have affected parents and their condition is the result of a new mutation on the PATERNAL chromosome. 99% of affected individuals have p.Gly380Arg transition, 1% have p.Gly380Cis transversion
Transition Mutation
Substitution of a purine for a purine/pyrimidine for a pyrimidine. Missense mutation.
Translation Mutation
Substitution of a pyrimidine for a purine or a purine for a pyrimidine. Missense mutation.
FGFR3 Mutation
Mutation causing Achondroplasia; diagnosed using restriction enzymes
- p.G 380A (99%) results in 55bp and 109bp fragments when cut with restriction enzyme SfcI
- p.G389C results in 57bp and 107bp fragments when cut with MspI restriction enzyme.
MspI
Restriction enzyme used in Achondroplasia diagnosis. Identifies minority (1%) of FGFR3 mutations. Cuts at G to C mutation producing 57bp and 107 bp fragments.
SfcI
Restriction enzyme used in Achondroplasia diagnosis. Identifies majority (99%) of FGFR3 mutations. Cuts at G to A mutation producing 55bp and 109 bp fragments.
Homozygous Mutant Achondroplasia
Lethal. In this case, the baby is AA. Homozygous mutant achondroplasia causes a restricted rib cage so the baby cannot breathe and ultimately they die.
What major factor contributes to the initial risk for Cystic Fibrosis?
Ethnicity. Carrier frequency for Cystic Fibrosis differs by ethnic group.
What are the different carrier frequencies for Cystic Fibrosis according to ethnicity?
1/25 Caucasian 1/29 Ashkenazi Jews 1/45 Hispanics 1/62 African Amer 1/150 Asians
CFTR
Gene with 27 exons located at 7q31 that encodes for a 1480 residue transmembrane protein responsible for transporting sodium across membrane in lungs. There are over 1800 mutations described (example of allelic heterogenetiy because different mutations on alleles of the same gene still produce cystic fibrosis). Most common mutations: deltaF508, pW1283X (Ashkenazi Jews), 3120+1G>A (African Amer.)
deltaF508
Mutation in CFTR gene that causes an inframe deletion of Phe at position 508. Most Cystic Fibrosis common mutation among all ethnicities. Is always accompanied (linkage disequilibrium) by poly 9T tract in intron 8 of CFTR.
p.W1282X
Nonsense mutation in CFTR gene that replaces Phe codon at position 1282 with a Stop codon causing Cystic Fibrosis. Most common mutation found in Ashkenazi Jewish pops.
What is the most common Cystic Fibrosis mutation?
deltaF508 (inframe deletion)
What is the most common Cystic Fibrosis mutation in Ashkenazi Jews?
p.W1282X (nonsense mutation)
3120+1G>A
Splicing mutation in CFTR gene that causes a loss of protein function resulting in Cyctic Fibrosis. Most common in African American populations.
What is the most common mutation in African Americans with Cystic Fibrosis?
3120+1G>A (splicing mutation)
