Inheritance Patterns & Pedigree Analysis

Question 1

Proband

Answer 1

The first affected person in a family for a genetic disorder.

Question 2

Consultant

Answer 2

The person seeking a genetic testing/counseling.

Question 3

Bracket with a dotted line

Answer 3

The person being adopted into a family.

Question 4

Bracket with a solid line

Answer 4

The person being adopted out of a family.

Question 5

Double Horizontal Lines

Answer 5

Consanguinity (related)

Question 6

Triangle

Answer 6

Miscarriage/Termination of pregnancy

Question 7

Red Flags of Family History

Answer 7

If cancers in the family members occur at younger age (< 50) than normal.

Question 8

Red Flags of Family History (2)

Answer 8

• Bilateral Disease
• frequent pregnancy losses
• major birth defect
• dysmorphic features plus medical conditions

Question 9

Dominant

Answer 9

Has one copy of pathogenic variant (allele); Heterozygous

Question 10

Recessive

Answer 10

Has two copies of pathogenic variant (allele); homozygous

Question 11

Compound heterozygous

Answer 11

Recessive condition in which two different pathogenic variants at the same gene/locus.

Question 12

Autosomal Dominant Recurrent Risk

Answer 12

Each affected individual has 50% chance of passing dominant allele to each child.

Question 13

Possible Characteristics of Autosomal Dominant

Answer 13

1. Multiple Generations
2. Male to Male transmission
3. Equal chance of male and female to be affected

Question 14

Examples of Autosomal Dominant

Answer 14

1. Neurofibromatosis Type 1 & Type 2
2. Huntington Disease
3. BRCA 1 & BRCA 2 gene mutations

Question 15

Neurofibromatosis Type 1

Answer 15

• 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

Question 16

Pleiotropy

Answer 16

Having multiple effects from one genetic variant

Question 17

Incomplete Penetrance

Answer 17

• Not fully expressing the trait even though carrying the pathogenic dominant allele
• Autosomal dominant condition

Ex. Breast Cancer & Ovary Cancer

Question 18

Mosaicism

Answer 18

Having more than one set of genetic information only in the germ-line (gamete cells).

Question 19

De Novo (“New”) Mutations

Answer 19

Mutations not inherited but often associated with advanced age in male gamete stem cells.

Ex. Neurofibromatosis Type 1

Question 20

Autosomal Recessive Characteristics

Answer 20

• 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

Question 21

Characteristics of Autosomal Recessive

Answer 21

1. Horizontal Transmission (usually only one affected generation)
2. Males and females equally affected
3. Consanguinity may be present

Question 22

Examples of Autosomal Recessive

Answer 22

1. Sickle Cell Disease
2. Cystic Fibrosis
3. Metabolic Disorders (PKU)

Question 23

X-Linked Inheritance

Answer 23

Different than sex-limited/sex influenced

Question 24

Characteristics of X-linked Recessive Inheritance

Carrier Mother

Answer 24

• Carrier mother has one x-chromosome recessive allele
• Daughter can be unaffected or carrier
• Son can be unaffected or affected

Question 25

Barr Body

Answer 25

Inactivated X Chromosome

Question 26

Characteristics of X-Linked Recessive

Answer 26

1. Affected mother's sons have 100% risk of inheritance 2. No male to male transmission 3. All daughters of affected male are carriers 4. All daughters of affected female are carriers

Question 27

Homoplasmy

Answer 27

All maternally inherited mitochondria have identical mtDNA.

Question 28

Heteroplasmy

Answer 28

All maternally inherited mitochondria don't have identical mtDNA.

Question 29

Mitochondrial Inheritance Disorder Feature

Answer 29

Clinical features of mitochondrial disease vary greatly due to heteroplasmy.

Question 30

Mitochondrial Disorders

Answer 30

- 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).

Question 31

Rules of Probability

Answer 31

- Sum Rule (add when "OR") | - Product Rule (multiply when "AND"/"AND THEN")

Question 32

Calculating Carrier Risk (Autosomal Recessive)

Answer 32

1. Both parents of affected individual have probability of 1. 2. 1st degree relatives of carriers have 1/2 probability of being carriers. 3. 2nd degree relatives of carriers have 1/4 probability of being carriers.

Question 33

Huntington Disease

Answer 33

- A genetic disorder in which brain cells in the basal ganglia gets deteriorated. - Age-Related Penetrance (symptoms appear in age 30-60).

Question 34

Genetic Testing in Children/Adolescents

Answer 34

Medical Benefit to the child must be the primary justification for genetic testing.

Question 35

Pharmacogenetic Testing

Answer 35

Testing to determine safety and efficacy of drugs

Question 36

Variable Expression

Answer 36

Different manifestations of the phenotype.

Question 37

Chromosomal Inheritance Disorder

Answer 37

- Disorders that involve duplication or deletion of multiple genes, or translocation of chromosome arms. - Typical pedigrees show frequent infertility or multiple pregnancy losses.

Question 38

Characteristics of X-Linked Dominant

Answer 38

- All daughters of affected male are affected. | - Affected female has 50% recurrence risk.

Question 39

Allelic Heterogeneity

Answer 39

Different mutations at the same gene (locus) leading to the same phenotype. Ex. Different mutations in BRCA 1 gene will lead breast cancer.

Question 40

Locus heterogeneity

Answer 40

Mutations at different genes (loci) leading to the same/similar phenotype.