Clinical Genetics Flashcards
Single Gene Disorder
- AKA Mendelian condition. Caused by an error in a single gene/single unit of genetic information.
- 1/500 incidence
- Exhibit characteristic patterns of inheritence
- Ex) Fragile X, Achondroplasia, hereditary breast and colon cancer
Chromosome Conditions
- Caused by an excess or deficiency of a chromosome segment or an entire chromosome
- Cause mental and physical retardation, unique physical features, congenital anomalies, infertility
- In general not inherited
- 7/1000; 10-15% of children with severe mental retardation and congenital malformations; responsible for 50% of spontaneous abortions
- Ex) Down syndrome, certain types of cancer
Multifactorial Disorders
- result from te combination of genetic predisposition and environmental factors
- No specific inheritance pattern
- Ex) CL/P, asthma, schizophrenia, congenital heart defects
Mitochondrial Disorders
- Caused by mutations in mitDNA or nDNA that disrupt normal mitochondrial metabolic function
- Transmitted by the mother to all children
- Ex) MNGIE, pyruvate dehydrogenase deficiency, Alpers Syndrome, MELAS, Leigh Syndrome
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.
Inherited Mutations
- AKA germline mutations
- Present in egg and sperm cells and thus is inherited from parents gametes (not necessarily our parents)
- Present throughout an individual’s entire life and present in all cells of the body
- Can be de novo mutations
De novo mutations
Germline mutation not inherited from parents but occurs in the fertilized egg.
Acquired mutations
- AKA somatic mutations
- Occur sometime in a person’s life in cells other than the sperm and egg that form the individual
- Caused by environmental factors (i.e. UV radiation, viruses, DNA replication errors
- CANNOT be passed onto the next generation
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.
Dominant Negative Mutation
A mutation in one allele that disrupts or antagonizes the function or product of the other allele. (Mutant protein interferes with the normal protein doing its job)
Ex) Osteogenesis Imperfecta, Ehlers Danlos (mutations in collagen)
Clinical/phenotypic heterogeneity
Mutations in the SAME gene cause MULTIPLE phenotype/disease
-Ex) mutations in RET can cause MEN2B (gain of function) or Hirschsprung (loss of function)
Allelic Heterogeneity
mutations on DIFFERENT ALLELES of the SAME gene cause SIMILAR phenotypes
Ex) Cystic Fibrosis
Locus Heterogeneity
mutations on DIFFERENT GENES (different loci) cause SIMILAR phenotype
Ex) Retinitis Pigmentosa (I have this!! 399 different genetic syndromes have RP as their feature; can be inherited AD, AR, X-Linked)
Phenocopy
An environmentally induced phenotype that mimics the phenotype of a specific genotype. Can be caused by teratogens.
Ex) 22q11 deletion/DiGeorge (genetic) and retinoic acid embryopathy (Accutane - environmental)
Teratogens
An agent that crosses the placental barrier and induces structural malformations, growth deficiency, and/or functional alterations during prenatal development. What it effects depends on when it is introduced during fetal development.
Ex) prescription drugs, illicit substances, chemical & physical agents, maternal diabetes, infectious agents.
Pleiotropy
Multiple phenotypic effects of a single gene
Ex) Stickler syndrome (mutation in COL2A1)
Major Malformation
An INTRINSIC morphological abnormality that results from a birth defect and interferes with function. Requires full medical attention.
- Affects 3% of full term births
Minor Malformation
An INTRINSIC morphologic abnormality that results from a birth defect and has no serious health problems.
- Affects 17% of full term births
Dysplasia
An INTRINSIC defect involving abnormal organization of cells/abnormal tissue development. All of the components required for development are present but they can’t be organized properly.
Deformation
An EXTRINSIC mechanical force that impairs ongoing fetal development, changing the shape, form and position of the body. Ususally occurs in the fetal development stage and commonly results in musculoskeletal contortions.
Disruption
An EXTERNAL force that causes a morphological defect of a tissue that originally developed normally
Ex) Amniotic Sac can cause limb disruption
Syndrome
A recognizable pattern of anomalies that are due to a single etiology
Ex) Down Syndrome & Waardenburg Syndrome
Association
A grouping of congential anomalies found together more often than expected by chance with no common etiology
Ex) VACTERAL Association
VACTERL Association
Vertebral Defects Anal Atresia Cardiovascular Anomalies Tracheo-esophageal fistula Esophageal Atresia Renal or radial anomalies Limb Defects
Sequence
A series of congenital anomalies derived from a single defect with secondary structural changes (symptoms appear in a specific order)
Ex) Robin Sqeuence
Robin Sequence
- Mandibular Hypoplasia
- Posterior Tongue Displacement
- Cleft Palate
Autosomal Dominant Inheritance
- Affected usually have an affected parent
- Either sex affected
- Transmitted by either sex
- Offspring has a 50% chance of being affected
Autosomal Recessive Inheritance
- Affected usually born to unaffected parents
- Parents of affected are asymptomatic carriers if they do not have the condition themself
- Either sex can be affected
- Increased risk with consanguinity
- Carrier parents have a 25% chance that each child will have the disorder.
X-Linked Inheritance
- Affects mainly males
- Affected males are more severe than affected females (females can have skewed X-inactivation)
- No male to male transmission (because dads only pass on their Y chrom to sons)
- Affected males usually born to unaffected parents (mother is usually an asymptomatic carrier who may have affected male relatives)
Mitochondrial Inheritence
- Maternal inheritance ONLY
- All females pass the condition onto their children and children will have different levels of severity
- Expression of mitochondrial disease depends on relative proportion of normal and mutant mito DNA (heteroplasmy)
- Variable expressivity
What is the most important step in clinical genetics?
Accurate Diagnosis
Chromosome Structure
Two arms (p - short; q - long) separated by a centromere. The p arm and q arm each have their own telomere located at the end of the arm.
Human “n”
Haploid; 23 chromosomes
22 autosomal chromosomes plus 1 sex chromosome
Human “2n”
Diploid; 46
two copies of each of the 22 autosomal chromosomes = 44 plus two sex chromosomes
How many basepairs and how many genes are in the human genome?
~3 billion base pairs; 20,000 - 25,000 genes.
What percent of newborns have a birth defect?
2-3%
What percent of infant mortality rates can be related to birth defects and genetic etiologies?
33%
Fragile X
A chromosome disorder caused by a mutation of gene FMR1 on the X chromosome. Presents mainly in males; becomes more pronounced in adulthood. In children: large lowset ears, prominence of forehead. In adults: elongated faces, pointed ears, mental retardation.
Pseudogene
Differ from genes in that they may or may not be transcribed, but they never are translated and never produce a protein
What does 7q11.23 mean?
It is the location of a gene. Chromsome 7, q arm, position 11.23
Missense Mutation
A single nucleotide change (point mutation) that results in a codon that codes for a different amino acid from the original. Protein function may or may not be altered depending on the nature of the amino acid change.
Nonsense Mutation
Occur when a single nucleotide change (point mutation) results in the formation of a stop codon, rather than a codon that codes for an amino acid. Results in a premature protein chain termination.
RB1 gene
Tumor suppressor gene that regulates the cell cycle. Both copies of a cell’s RB1 must be mutated for retinoblastoma to develop because one functional gene produces enough protein produce to inhibit the development of Retinoblastoma.
FGF and FGFR3
Normally, FGF (fibroblast growth factor) binds to FGFR3 (fibroblast growth factor receptor 3, 164 BP) to inhibit the growth of cartilage. The growth of cartilage is inhibited only when FGF binds, enabling cartilage growth during development. In achondroplasia, there is a (gain of function) mutation in FGFR3 so the growth of cartilage is constantly inhibited.
Example of Dominant Negative mutation
Collagen formation - Osteogenesis Imperfecta & Ehlers Danlos
Example of Loss of Function mutation
- RB1 tumor supressor gene - Retinoblastoma
- Hirschsprung
Example of Gain of Function Mutation
FGFR3 receptor gene - Achondroplasia (autosomal dominant)
RET
Tumor supressor gene that is an example of clinical/phenotypic heterogeneity. Loss of function mutation of RET causes Hirschsprung disease. Gain of function mutation of RET causes MEN2B.
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.)
DiGeorge Syndrome
Syndrome caused by mutation in 22q11 deletion. Has phenocopy condition know as Retioic Acid Embryopathy that is an environmentally induced condition (i.e. Accutane during pregnancy).
- Symptoms: cotruncal or aortic defects, small cupped ears, low normal IQ, thymic hypo/aplasia, parathyroidhypoplasia
What do FAS, Fetal Hydantoin and Thalamide abnormalities have in common?
They are all the result of teratogen exposure.
Stickler Syndrome
Caused by a mutation in collagen 2alpha1. Example of pleiotropy in phenotypes.
Penetrance
“On/Off Switch”. Fraction of individuals with a genotype known to cause disease who have any signs of the disease.
= (# w/ phenotype)/(# w/ genotype)
Ex) Breast Cancer
Expressivity
“Dimmer” The extent to which a genetic defect is expressed.
Ex) Bardet-Beidl Syndrome
FMR1
Gene on X chromosome that is mutated (single gene mutation) in Fragile X syndrome.
