10: Genetic Disorders Definitions Flashcards
Penetrance in single gene mutations, complex multigenic disorders, and chromosomal disorders
Single gene and chromosomal disorders: high penetrance
Complex multigenic disorders: low penetrance
Name six examples of autosomal dominant conditions
- Huntingtons
- Neurofibromatosis
- Marfan’s
- Ehler’s-Danlos
- Osteogenesis imperfecta
- Familiar hypercholesterolemia
Name three examples of autosomal recessive conditions
CF, PKU, a1-antitrypsin deficiency
Name two X-linked conditions
G6PD deficiency, fragile X syndrome
Germ cell vs somatic cell mutation
Germ cell -> inherited disease
Somatic cell -> cancer, some congenital malformations
Missense vs nonsense point mutation
Missense: changes to a different AA
Nonsense: changes to a stop codon
When can mutations in noncoding sequences be bad?
When it causes failure to form mRNA
Anticipation
As a genetic disorder is passed to the next generation, the sx become apparent at an earlier age with each generation (severity typically increases too)
What does congenital mean?
“Born with” - doesn’t imply genetic
Codominance
Both alleles contribute to a phenotype
Pleiotropism
Single mutant gene -> many end effects
Genetic heterogeneity
Mutations at several loci may produce same trait
Incomplete penetrance
Mutation is present but normal phenotype
Variable expressivity
All pts have trait, but are expressed differently
Example of variable expressivity
Neurofibromatosis: +/- cafe au lait spots, skeletal deformities, neurofibromas
What type of genetic transmission are almost all IEMs?
Autosomal recessive
Genetic transmission of Ehlers-Danlos
Some autosomal dominant, some recessive
If an autosomal recessive mutation is low frequency in a population and a child has it, what is most likely?
Consanguineous marriage
Two diseases that are sulfatidoses
Gaucher dz, Niemann-Pick dz
Condition that is a sphingolipidose
Tay-Sachs dz
Example of how we know environmental contributions play a huge role in complex multigenic disorders
Dramatic reduction in neural tube defects by taking folic acid
Why is it sometimes difficult to distinguish between single gene and multifactorial disease?
Single gene: variable expressivity and reduced penetrance
Complex multigenic: a range in severity level, which can be seen as variable expressivity and reduced penetrance
Euploid
Any exact multiple of haploid number (23)
Why are there no survivable monosomies?
Cause loss of too much genetic info -> cant even complete embryogenesis
Two incidences where Robertsonian translocation occurs
- In 1 in 1000 normal individuals
2. 3-4% of trisomy 21 cases
How does inactivation of an X chromosome happen during lyonization
One X chromosome undergoes heteropyknosis at random on about day 5.5 of embryonic life -> all cells derived from these precursors will have that X chromosome inactivated
True vs pseudohermaphrodite
True: presence of both ovarian and testicular tissue
Pseudohermaphrodite: disagreement between phenotype and gonadal sex
Heteroplasmy
Tissue and individuals harbor both wild-type and mutant mtDNA
Threshold effect
Minimum number of mutant mtDNA must be present in a cell or tissue before dysfunction gives rise to disease
Five indications to have prenatal testing done
- Advanced maternal age
- Parent known to carry a balanced chromosomal rearrangement
- Fetal anomaly on US
- Routine maternal blood screen indicating increased risk of a trisomy
- Children at known risk for many other genetic disorders
How to obtain cells for prenatal testing
Amniocentesis, chorionic villus biopsy, umbilical cord blood
New technology in prenatal testing
About 10% of free DNA in a pregnant mother’s blood is of fetal origin
Proband
Affected individual
COD for most CF patients
COPD
In 95% of trisomy 21, where is the extra chromosome from?
Maternal origin
Only way to establish a dx of 22q11.2
FISH to analyze the chromosomes
