Inheritance Patterns & Pedigree Analysis Flashcards
Proband
The first affected person in a family for a genetic disorder.
Consultant
The person seeking a genetic testing/counseling.
Bracket with a dotted line
The person being adopted into a family.
Bracket with a solid line
The person being adopted out of a family.
Double Horizontal Lines
Consanguinity (related)
Triangle
Miscarriage/Termination of pregnancy
Red Flags of Family History
If cancers in the family members occur at younger age (< 50) than normal.
Red Flags of Family History (2)
- Bilateral Disease
- frequent pregnancy losses
- major birth defect
- dysmorphic features plus medical conditions
Dominant
Has one copy of pathogenic variant (allele); Heterozygous
Recessive
Has two copies of pathogenic variant (allele); homozygous
Compound heterozygous
Recessive condition in which two different pathogenic variants at the same gene/locus.
Autosomal Dominant Recurrent Risk
Each affected individual has 50% chance of passing dominant allele to each child.
Possible Characteristics of Autosomal Dominant
- Multiple Generations
- Male to Male transmission
- Equal chance of male and female to be affected
Examples of Autosomal Dominant
- Neurofibromatosis Type 1 & Type 2
- Huntington Disease
- BRCA 1 & BRCA 2 gene mutations
Neurofibromatosis Type 1
- A genetic disorder where the physical and exam can be definitive (diagnosis requires 2)
- Variable expressivity & Mosaicism possible
- Age-Related Penetrance (diagnosable by age 12)
- Pleiotropy
Pleiotropy
Having multiple effects from one genetic variant
Incomplete Penetrance
- Not fully expressing the trait even though carrying the pathogenic dominant allele
- Autosomal dominant condition
Ex. Breast Cancer & Ovary Cancer
Mosaicism
Having more than one set of genetic information only in the germ-line (gamete cells).
De Novo (“New”) Mutations
Mutations not inherited but often associated with advanced age in male gamete stem cells.
Ex. Neurofibromatosis Type 1
Autosomal Recessive Characteristics
- Affected individual’s both parents must be carriers (heterozygote) for the recessive allele.
- Recurrence risk is 25%.
- Unaffected siblings have 2/3 risk to be carrier
Characteristics of Autosomal Recessive
- Horizontal Transmission (usually only one affected generation)
- Males and females equally affected
- Consanguinity may be present
Examples of Autosomal Recessive
- Sickle Cell Disease
- Cystic Fibrosis
- Metabolic Disorders (PKU)
X-Linked Inheritance
Different than sex-limited/sex influenced
Characteristics of X-linked Recessive Inheritance
Carrier Mother
- Carrier mother has one x-chromosome recessive allele
- Daughter can be unaffected or carrier
- Son can be unaffected or affected
Barr Body
Inactivated X Chromosome
Characteristics of X-Linked Recessive
- Affected mother’s sons have 100% risk of inheritance
- No male to male transmission
- All daughters of affected male are carriers
- All daughters of affected female are carriers
Homoplasmy
All maternally inherited mitochondria have identical mtDNA.
Heteroplasmy
All maternally inherited mitochondria don’t have identical mtDNA.
Mitochondrial Inheritance Disorder Feature
Clinical features of mitochondrial disease vary greatly due to heteroplasmy.
Mitochondrial Disorders
- Affect organs/organ systems that require a lot of energy.
Ex. Nervous System; Heart; Liver; Endocrine; Digestive Tract, etc.
- Not all mitochondrial disorders have mitochondrial inheritance (most mitochondrial proteins are encoded by nuclear genes).
Rules of Probability
- Sum Rule (add when “OR”)
- Product Rule (multiply when “AND”/”AND THEN”)
Calculating Carrier Risk (Autosomal Recessive)
- Both parents of affected individual have probability of 1.
- 1st degree relatives of carriers have 1/2 probability of being carriers.
- 2nd degree relatives of carriers have 1/4 probability of being carriers.
Huntington Disease
- A genetic disorder in which brain cells in the basal ganglia gets deteriorated.
- Age-Related Penetrance (symptoms appear in age 30-60).
Genetic Testing in Children/Adolescents
Medical Benefit to the child must be the primary justification for genetic testing.
Pharmacogenetic Testing
Testing to determine safety and efficacy of drugs
Variable Expression
Different manifestations of the phenotype.
Chromosomal Inheritance Disorder
- Disorders that involve duplication or deletion of multiple genes, or translocation of chromosome arms.
- Typical pedigrees show frequent infertility or multiple pregnancy losses.
Characteristics of X-Linked Dominant
- All daughters of affected male are affected.
- Affected female has 50% recurrence risk.
Allelic Heterogeneity
Different mutations at the same gene (locus) leading to the same phenotype.
Ex. Different mutations in BRCA 1 gene will lead breast cancer.
Locus heterogeneity
Mutations at different genes (loci) leading to the same/similar phenotype.
