Patho - Elements of Formal Genetics

What is formal genetics?

The study of how individual sets of paired chromosomes produce certain traits within individuals and attempts to understand patterns of inheritance within families

What is genetic inheritance?

Mechanisms by which an individual’s set of paired chromosomes produces traits. Explains the patterns of inheritance for traits and diseases that appear in families

What are Mendelian traits?

Those inherited traits primarily attributed to single genes

What are some examples of Mendelian traits?

Chin clefts, dimples, earlobe configurations

What is the locus?

The location occupied by a gene on a chromosome (official term for gene location)

What is an allele?

One of several different forms of a gene at a particular locus (1 gene version from the mother and 1 gene version from the father seen in somatic cells in each chromosome)

What is a homozygous allele?

When alleles are identical (e.g. O blood type, 2-O alleles)

What is a heterozygous allele?

When alleles are different (e.g. AB blood type; A&B alleles)

What is a polymorphism?

A locus that has 2 or more alleles that occur at similar frequency in the population

What is zygosity?

Degree of similarity between the maternal and paternal alleles for a trait

What is hemizygous?

Presence of only one copy of a particular gene allele

• Almost all X-linked gene alleles are hemizygous in males because they have only one X chromosome; very few of the same genes are on the Y chromosome

What is genotype?

The genetic makeup of an organism

What is phenotype?

The observable, detectable, or outward physical appearance of the organism, conferred by the underlying genetic makeup

What are two terms used to explain when genotype and phenotype don’t match?

Penetrance and expressivity

What is penetrance?

The % of individuals with a specific genotype, who also express the expected phenotype

What is expressivity?

The variation in phenotype associated with a particular genotype. Degree of severity depends on level of gene activation.

What are two examples of conditions where there is expressivity?

Polydactyly and Neurofibromatosis Type 1

• Polydactylyl can vary in severity: small skin-tag structures to fully developed extra digits

• Neurofibromatosis Type 1: can vary with few small lesions or large disfigured regions

What is incomplete penetrance?

When you have the gene but not the disease (have incongruent genotype to phenotype — ex: BRCA1 = 55-72% penetrant breast cancer)

What is complete penetrance?

When you have the gene, you will 100% have the disease

What is a condition that is an example of complete penetrance?

Huntington’s Disease

If two different alleles are found together, then the allele that is observable is considered ____ (A) and the allele whose effects are hidden/suppressed is considered _____ (a)

dominant; recessive

What are co-dominant alleles?

Alleles that are simultaneously expressed (ex: AB bloodtype)

What is a carrier?

Someone who has one normal allele and one allele that is associated with a disease but who is phenotypically normal (no visible signs of disease). In order for a recessive allele to be expressed, a person must inherit 2 copies, only then will the recessive allele be expressed in the phenotype

• disease/traits that follow a recessive inheritance pattern, either sex-linked or autosomal recessive

What are the 4 inheritance patterns?

• Autosomal dominant

  • Chromosome 1-22

  • 1 copy of allele = disease/trait

• Autosomal recessive

  • Chromosome 1-22

  • 2 copies of allele = disease/trait

• Sex-linked dominant

  • X or Y chromosome

  • 1 copy of allele = disease/trait

• Sex-linked recessive (x-linked usually)

  • X or Y chromosome

  • 2 copies of allele = disease/trait

Describe autosomal dominant inheritance

Gene of interest is on one of chromosomes 1 through 22 and only 1 copy of that disease allele is needed for the disease/trait to manifest

• Genotype possibilities include AA or Aa - both genotypes confer the phenotype

• Ex: huntington disease

What is an example of a disease that is the result of autosomal dominant inheritance?

Huntington disease

What is Huntington disease?

A neurodegenerative disorder. Symptoms include progressive dementia and uncontrolled limb movements. Doesn’t usually manifest until later in life

In autosomal dominant diseases, conditions are expressed equally or unequally in males and females?

Equally

Describe autosomal recessive inheritance

Gene of interest is on one of chromosomes 1 through 22 and 2 copies of that disease allele are needed for the disease/trait to manifest

• Genotype possibilities include aa

• Ex: Cystic Fibrosis or Sickle Cell

What is an example of a disease that is the result of autosomal recessive inheritance?

Cystic Fibrosis

What is Cystic Fibrosis?

Progressive disorder of excessive mucus production. Causes severe damage to lungs, GI tract, and other organs. Characterized by thick, sticky mucus

In autosomal recessive diseases, conditions are expressed equally or unequally in males and females?

Equally

True or false: in an autosomal recessive pedigree chart, there can be many generations of silent carriers

True

What is consanguinity?

Intermarrying of blood relatives. This can increase the rate of occurrence of autosomal recessive conditions

What is sex-linked inheritance?

Involves genes located on sex chromosomes. Leads to distinct inheritance patterns dependent on sex of parent and offspring

Number of alleles required for recessive disease/trait depends on biologic sex

• For males - 1 allele

• For females - 2 alleles

Most sex-linked traits are located where?

The X chromosome (Y chromosomes contain only a few dozen genes)

Sex-linked inheritance is more commonly expressed in males or females due to hemizygosity?

Males (females have an additional X chromosome that can mask disease)

• Any allele present on a male’s X chromosome — whether dominant or recessive — will be directly expressed because there is no second X chromosome to mask it

Who can affected males of sex-linked inheritance transmit the gene to? Sons or daughters?

Daughters

For sex-linked inheritance, sons of female carriers have what % risk of being affected?

50%

What are two examples of sex-linked inheritance diseases?

Hemophilia A and Duchenne Muscular Dystrophy

What is Duchenne Muscular Dystrophy (DMD)?

An X-linked recessive inheritance disease that is characterized by progressive muscular degeneration. It results from deletion of the DMD gene causing dystrophin not to work properly. Consequently, muscle cells do not survive. It occurs in 1 of 3500 males

What are the 3 scenarios regarding X-linked recessive inheritance?

• Unaffected father and heterozygous unaffected (carrier) mother

  • most common scenario

  • female offspring has 50% chance being carrier

  • male offspring has 50% chance being affected

• Affected father and homozygous unaffected (carrier) mother

  • Any female will be a carrier

  • Males won’e be a carrier or be affected since they are only getting the Y from father

• Affected father and heterozygous unaffected (carrier) mother

  • Female has 50% chance being affected and 50% chance being carrier

  • Male offspring have 50% chance being affected and 50% chance not being affected

What are sex-limited trait/diseases?

A trait/disease that can occur in only ONE of the sexes

Ex: inherited uterine/testicular defects

What are sex-influenced traits/diseases?

A trait/disease that occurs significantly MORE OFTEN in one sex than in the other

Ex: hormone receptor + HR + breast cancer

• Since females produce more progesterone than males, risk for developing hormone-receptor positive breast cancer in females is greater than in males, making this a sex-influenced disease

What is incidence rate?

The number of new cases of a disease reported over a specific time period (typically 1 year) divided by the number of individuals in the population

• good way to describe viral outbreak

What is prevalence rate?

Proportion of the population affected by a disease at a specific point in time (ex: how many were living with hypertension in 2018?)

• used when describing disease burden of chronic diseases; prevalence rate will always be higher than incidence bc many will typically live with disease for several years

What is relative risk?

Incidence rate of a disease among individuals exposed to a risk factor divided by the incidence rate of a disease among individuals not exposed to a risk factor

What are polygenic traits?

When effects of multiple genes cause the variation in traits. Multiple genes are giving input and creating different variations and traits.

Ex: height, hair color, intelligence

What is an example of a polygenic trait?

Height

What are multifactorial traits?

When genetic and environmental factors cause the variations in traits

Ex: diabetes, high blood pressure, cardiovascular disease

What is an example of a multifactorial trait?

Diabetes

What is a concordant trait?

When both members of a twin pair share a trait. Concordance should be 100% in monozygotic twins

What is a discordant trait?

When twins do not share a trait