Lecture 20-Introduction to Clinical Genetics Flashcards
how much of the infant mortality rate can be attributed to birth defects and genetic etiologies?
1/3
How many genes do we have on each chromosome?
100s-1000s
How many newborns are born with some type of birth defect?
2-3%
Birth defects/genetic disorders are major contributors to _______
developmental disabilities
genetic disorders and consgential anomalies account for how many pediatric hospital admissions?
- 50%
What is the prevalence for specific gene disorders?
- 1/500
What is the prevalence for chromosome disorders? Chromosome disorders give rise to how many of the children with severe MR and multiple congenital anomalies (MCA)?
- 0.7%
- 10-15%
Single gene disorders are also called______. What kind of inheritance do they exhibit?
- mendelian conditions
- characteristic
The majority of single gene conditions are _____ but their combined effect is ______.
- rare
- significant
Chromosome disorders
- Inheritance pattern?
- caused by a deficiency of a chromosome segment or entire chromosome
- not inherited usually
Symptoms of chromosome disorders? (3)
- MR, physical retardation
- unique physical features
- congenital anomalies
Symptoms of sex chromosome disorders?
- mild developmental/behavioral problems
- tall or short stature
- infertility
pseudogenes
- may or may not be transcribed
- don’t lead to an end function
how big is a mutation?
- single bp OR
- large segment of chromosome
Inherited mutations
- also called _______
- mutations in a germ cell and is present throughout every cell in a persons body their entire life
- germline mutation
what is a germline de novo mutation?
- a mutation not inherited from a parent but occurs in a fertilized egg
Acquired mutations
- caused by what?
- also called _______
- mutations that occur during a person’s life in somatic cells. Usually caused by enviromental factors (UV), viruses, DNA replication mistake
- somatic mutations
Can somatic mutations be inherited?
- no
Polymorphism
allele sequence in 1% or more of the population
- considered a normal finding
- can contribute to multifactorial disorders
Rare variant
- allele sequence in <1% of the population
nonsense mutation
- stops protein from being transcribed
missense mutation
- “misspelling” of the protein
Give an ex of a loss of function mutation. What does this protein impact and what are the effects of having this gene mutated?
RB1–retinoblastoma
- tumor suppressor that regulates the cell cycle
- both copies must be mutated to have loss of function
What are the different ways that a child can develop retinoblastoma from the loss of function mutation and what are the frequency and outcomes of each(2)?
- One mutated allele inherited an the other acquires the mutation (40%).
- bilateral, early onset Rb
- both alleles of Rb acquire the mutation somatically (60%)
- unilateral, late onset in childhood
Give an ex of a gain of function mutation. What does this protein impact and what are the effects of having this gene mutated?
- FGFR3 (normally inhibits cartilage cell growth)
- keeps FGFR3 on constitutively even without FGF so cartilage cells are constantly inhibited
- achondroplasia
Dominant negative (2) - example?
- a mutation in one allele disrupts or antagonizes the function or product of the other allele
- usually related to structural proteins
- mutation in Type I collagen resulting in inability to form collagen and therefore osteogenesis imperfecta
Clinical/phenotypic heterogeneity
- mutations in the same GENE (can be in different places on the gene) give rise to different phenotypes
Types of genetic heterogeneity?
- allelic
- locus
allelic heterogeneity
- different mutations/alleles give rise to similar phenotype
locus heterogeneity
- different genes (and therefore loci) give rise to a similar phenotype
Give an example of clinical heterogeneity.
- RET gene
- MEN2B (thyroid carcinoma, neuromas of the lips and tongue, etc.) and Hirschsprung Disease (congenital aganglionic megacolon)
Give an example of allelic heterogeneity.
CFTR (cystic fibrosis transmembrane conductance regulator) mutations can block different steps within the pathway leading to the same phenotype
Give an example of locus heterogeneity.
- retinitis pigmentosa
- 339 genetic syndromes have this as a feature
- varied inheritance (AD, AR, XL)
Phenocopy
- example?
an environmentally induced condition that mimics/is very similar to a phenotype caused by a specific genotype
- 22q11 deletion/DiGeorge syndrome and retinoic acid embryopathy
teratogens (3)
- agents that cross the placental barrier
- cause structural and functional malformations, growth deficiency
- account for a SMALL percentage of congenital malformations
What are the categories of teratogens (5)
- Rx drugs (thalidomide, Fetal hydantoin syndrome)
- illicit substances (FAS)
- chemical/physical agents
- maternal metabolic/genetic factors (maternal diabetes)
- infectious agents
Pleiotropy
- example?
- multiple phenotypic effects of a single gene
- Stickler syndrome causing collagen 2A1 mutations
What’s the difference between penetrance and expressivity?
- penetrance: an individual who has the genotype for disease may or may not have signs/symptoms of the disease (on/off switch)
- expressivity: the extent to which the genetic defect is expressed but is NEVER unexpressed in those who have the genotype (dimmer switch)
How do you calculate penetrance?
- # who have disease associated with mutation/# who have mutation
Example of a gene that shows varied penetrance when mutated?
- BRCA
Example of a disorder that shows varied expressivity?
- achondroplasia: every person with mutation effected by have variable presentations
Malformation
- frequencies
- localized abnormalities in organogenesis that are intrinsic to the embryo/fetus
- can be major (3%) or minor (17%)
Dysplasia
- abnormal organization of cells, abnormal tissue development intrinsic to embryo/fetus
- all components are present but disorganized
Deformation
- example?
- extrinsic mechanical force impairs normal ongoing fetal development and can change the shape, form and position of the body
- oligohydramnios–low amniotic fluid
Disruption
- example?
- extrinsic force destroys tissues or organ that had already developed normally
- 2º limb defect from vascular event
Syndrome
- example?
- pattern of anomalies from one single etiology
- Downs
Association
- Example?
- grouping of congenital anomalies that are found together more than statistically expected with no known common etiology
- VACTERL associate
Sequence
- Example?
- congenital anomalies from one defect that causes secondary structural changes
- Robin sequence (mandibular hypoplasia resulting in tongue displacement then cleft palate
Finding areas with increased incidence of consanguinity you are more likely to find a higher rate of _______ diseases
- autosomal recessive
What are the 3 types of referrals for genetic diagnosis? What are the indications for each?
- prenatal: family history of a disease/disorder; abnormal maternal screening/ultrasound
- Pediatric: suspected physical external/internal anomalies; growth problems, developmental delays, intellectual disability
- Adult: suspicion that they may have a genetic disorder based on behavior, mental deterioration, specific medical problems; personal/family history of cancer
Successful genetic counseling is contingent upon _______
accurate diagnoses!!!
