7

refers to the genetic composition of gametes (spermatozoon or

ovum), can be passed down, colloquially used to refer to non-tumor cells

germline

refers to the genetic composition of cells other than gametes,

cannot be passed to offspring, often refer to cancer

somatic

all refer to changes passed down as germline changes in genes or sometimes as epigenetic (alterations not involving changes to the DNA sequence eg, environmental, trauma, smoking, famine)

Hereditary, inherited, heritable

condition that occurs in families more often than would be

expected by chance. These may be genetic in etiology or they may be a

sign of shared environmental or lifestyle factors

familial

the proportion of individuals with a specific genotype who

express the corresponding phenotype (observable characteristics)

penetrance

present at birth (may or may not be genetic)

congenital

transmission of information from

parent to offspring that affects gene expression

without altering the underlying DNA sequence. It allows

organisms to pass down environmental adaptations, such as

diet or stress responses, to subsequent generations through

mechanisms like DNA methylation, and non-coding RNA.

epigenetic inheritance

an epigenetic process where only one copy (either

maternal or paternal) is active while the other is silenced

imprinting

genetic variation within a population, upon which natural selection can operate

polymorphisms

The Central Dogma: genetic information flows from ____ to ____ to ____

DNA

mRNA
protein

these are the 2 major types of genetic diseases

germline and somatic

Types of genetic diseases

Germline diseases can be _____

chromosomal

• numerical - change in the number of chromosomes

• structural - change in the structure of chromosomes

Types of genetic diseases - Germline

Medelian disorders and patterns of inheritance include ____ and ____ _____

autosomal and sex linked

Types of genetic diseases - germline

mendelian disorders and patterns of inheritance are described as one molecular _____ leading to a straight forward consequence that it _____ inherited

lesion

predictably

what are the 2 types of autosomal inheritance

dominant and recessive

Types of genetic diseases - germline

single gene disorders with atypical inheritance. This includes _______ ____ and ____ ___

trinucleide repeats and imprinted regions

Somatic diseases are usually talking about _____

cancer

for complex mutagenic disorders (germline) these diseases often feature _____ polymorphisms that modify disease risk but do not fully predict _____ - it is modified by other contributing _____

multiple

phenotype

factors

examples of complex mutagenic disorders

Diabetes

Heart disease

hypertension

psychiatric disease

cleft palate

contributing factors for complex mutagenic disorders

● Multiple mutations (pathogenic variants)

● Polymorphisms (naturally occurring variations)

● Environmental exposures

● Diet

● Substance use

● Social environment

comlpex mutagenic disorders are caused by multiple _____ variations and _____ factors

genetic

environmental

why do we do genetic testing? (3)

• Diagnosis

• Prognosis

• Therapeutic decisions

what are the consequences of genetic testing

_____ loss with ____ testing

pregnancy

prenatal (fetus)

what are the consequences of genetic testing?

_____ or ______ discrimination

employment

insurance

illegal but real

what are the consequences of genetic testing?

_____ stress

social

dealing with the results

implications for family members

genetic testing has (low/high) cost

high

what are the consequences of genetic testing? (in all)

• Pregnancy loss with prenatal (fetal) testing

• Employment or insurance discrimination (illegal but real)

• Social stress

• Dealing with results

• Implications for family members

• Cost

the way that we do genetic testing is highly ____ and depends on the ____ we are interrogating

variable

lesion

appropriate selection of test depends on the molecular lesion in each clinical scenario

Changes detected by various methods

cytogenetics

numerical or large structural chromosomal changes (translocations)

Changes detected by various methods

Sequencing

small insertions/deletions, point mutations, missense, nonsense, and translocations

Tests have variable resolution

_____ have low power, while ______ has high power

cytogenetics

sequencing

Nearly all techniques of genetic testing use creative ways to take advantage of specific annealing of ____ and ____ and detection of a label or reaction product

A:T

G:C

tach advances have allowed ____ scale genetic sequence assessment for a _____ cost

large

reasonable

previously this method was used for sequencing and included a Clonal sequencing reaction in a tube (1 read, 1 direction)

dye terminator sequencing

with advancements, we now use this method of sequencing where there is Clonal sequencing reaction in each well (millions of reads)

next generation sequencing

with _____ _____ ___ you would have to do reads over and over, with ___ ____ ___ you get information much faster

dye terminator sequencing

next gen sequencing

Advantages of Next Generation Sequencing

Highly multiplexed sequencing, ____ targets at once, tens of genes to thousands of genes

many

Advantages of Next Generation Sequencing

Higher analytical sensitivity, 5 to 20 times more ______

sensitive

Advantages of Next Generation Sequencing

Markedly _____ cost per base sequenced, varies by

method, but about 2353 times _____ per million

bases sequenced at UIHC

decreased

cheaper

Advantages of Next Generation Sequencing

Requires ____ starting material

less

less cells for intitial extraction

Advantages of Next Generation Sequencing

Can multiplex different ____ ____ on the same run

patient samples

Advantages of Next Generation Sequencing

• Can detect multiplexed _____ (translocations) from RNA

fusions

Cytogenetics is a way to look at whole _____ and regions by dark and light bands

chromosomes

chromosomal abnormalities - cytogenetic analysis

This is done through a culture of ____ ____

blood lymphocytes (requires live cells)

• this is the most convenient source

  • any cell dividing in the culture may be analyzed

chromosomal abnormalities - cytogenic analysis

after cells are lysed on the glass slide, the chromosomes are _____ and viewed via ______

stained

microscopy

The most commonly diagnosed

chromosomal condition in the U.S., affecting approximately 1 in 700

babies. It occurs when an individual has an extra copy of chromosome

21

Down Syndrome (Trisomy 21)

A chronic condition that causes thick, sticky

mucus to build up in the lungs and digestive system. It is most

prevalent in white people of Northern European ancestry.

Cystic Fibrosis (CF)

A family of hereditary blood disorders that limit

hemoglobin production, causing mild to severe anemia. It is

more common in individuals of Mediterranean, Indian, and

Southeast Asian descent.

Thalassemia

The most common inherited cause of intellectual

disability. It is caused by a change in the FMR1 gene on the X

chromosome.

Fragile X syndrome

An autosomal dominant disorder that causes

the progressive breakdown of nerve cells in the brain, typically

appearing in mid-life.

Huntingtons Disease

A condition characterized by very high

levels of "bad" (LDL) cholesterol from birth, which significantly

increases the risk of early heart disease.

Familial Hyoercholestrolemia

Sickle cell disease

This is a mutatio on the HBB chromosome short arm __

11

HBB is a missense mutation where the amino acid glutamic acid is replaced by ____

valine

Sickle cell disease is Inherited in an _____ _____ manner so two mutated copies

(one from each parent) are usually required for disease

autosomal recessive

Symptoms of Sickle cell disease

Red blood cells form into a what shape

a “C” shape

Sickle cell disease symptoms

Episodes of ____ ___

severe pain

most often in your back, legs, arms and sometimes chest

Sickle cell disease symptoms (remaining)

fatigue and weakness

stroke

anemia

liver, kidney, heart

blood clots

Treatment of Sickle cell disease

______ makes blood cells less likely to sickle

Hydroxyurea

Treatment of Sickle cell disease

_____ ____ transplant

bone marrow

Treatment of Sickle cell disease

Gene therapy which edits a patient’s gene to make more normal ______

hemoglobin

Thalassemia is an Autosomal recessive disease caused by mutations in genes responsible for

_____ synthesis, resulting in reduced alpha or beta protein chains.

hemoglobin

Alpha-thalassemia involves 4 genes on chromosome __ where deletions

cause decreased production of ______

16

hemoglobin

Thalassemia is diagnosed ____ in life and ____ of symptoms may vary

early

severity

Thalassemia is characterized by mild to severe_______

anemia

Fatigue, Dizziness, Shortness of

breath, Fast heart beat, Headaches, Pale skin, Difficulty concentrating

Treatment of Thalassemia

blood transfusions, iron chelation, Folic acid supplements,

Luspatercept (drug which helps make more red blood cells), Stem cell

transplant in severe cases

Huntingtons Disease is an Autosomal dominant mutation on chromosome ___ that lead to an

abnormal protein that triggers progressive breakdown of brain nerve cells

4

brain nerve cells

symptoms of Huntingtons Disease usually starts between ages ___ and ___

30 and 50

symptoms of Huntingtons Disease - movement

Movement ie, involuntary jerking (chorea), muscle rigidity, balance

issues, and difficulty walking, speaking, or swallowing

symptoms of huntingtons disease - cognitive

ie, difficulty with planning, focus, and memory, often

leading to dementia

symptoms of Huntingtons Disease - psychiatric

ie, irritability, depression, anxiety, and personality changes

Huntingtons Disease is diagnosed with ___ ___ can detect the genetic mutation by

abnormal ____

blood test

protein

what is the cure for Huntingtons Disease

no cure or treatment to stop the disease progression

Leads to total dependency within 10 to 15 years of symptoms onset

Familial hypercholesterolemia is a Autosomal Dominant defect often on chromosome ___ (LDL Receptor) that prevents the liver from removing excess _____

19

cholestrol

Familial hypercholesterolemia has significantly increased risk of early ____ ____ and ____

heart attacks and strokes

• may not be found until one of these 2 happens

Familial hypercholesterolemia

High ___ levels often identified via standard blood test during yearly physical

LDL

individuals with Familial hypercholesterolemia will have Yellowish _____ deposits (xanthomas) in: _____ particularly the achilles or knuckles, and around the ____ or a grayish ring around the cornea

cholestrol

tendons

eyes

Familial hypercholesterolemia is treated with ____and other _____-lowering medications to

bring levels down and prevent heart disease

statins

cholestrol

prognosis for familial hypercholesterolemia

with early detection and treatment is excellent but life

threatening if untreated.

Most common genetic cause of developmental delay/intellectual disability

Down Syndrome (Trisomy 21)

what is a major risk factor for down syndrome

maternal age

sporadic ____ ____ in the ovum is the most common reason for the cause of down syndrome

meiotic nondisjunction

• sister chromatids fail to separate properly, leading to gametes with an abnormal number of chromosomes

3 in the case of chromosome 21

Autosomal Dominant Mendelian Disorders

mutant product is non- functional and interferes with the function of the normal / wild-type protein

dominant negative effect

Autosomal Dominant Mendelian Disorders

mutation introduces new function of the altered protein or increases wild type

function with deleterious sequelae

gain of function

in autosomal dominant disorders, if one parent is affected ___ of their offspring is affectes

50%

_____ and ____ inheritance can be observed in autosomal dominant mendelian disorders

Maternal

paternal

for autosomal dominant and recessive, you can use a ____ ___ to determine if the individual is affected or not

punnett square

Marfan Syndrome is characterized by ______ abnormalities caused by heterozygous deleterious changes in ______ gene

mesenchymal (connective tissue)

fibrillin-1

Fibrillin-1 - loss of its function results in ______ soft tissue

abnormal

Marfan clinical manifestations

• Tall thin habitus

• Long limbs and fingers (arachnodactyly)

• Dysmorphic chest (pectus excavatum or carinatum)

• High arched palate

• Hyperflexibility

• Dental crowding

• Aortic dissection

• Mitral valve prolapse

• Severe kyphoscoliosis

Marfan syndrome is ___ inherited and ___ penetrant

75%

100%

- penetrance refers to the likelihood someone will exhibit

disease phenotype when they have the molecular lesion

in autosomal dominant recessive mendelian disorders If the trait is carried in homozygous fashion :

disease will manifest

homozygous means two abnormal copies(alleles) of a given gene.

in autosomal dominant recessive If the trait is carried in heterozygous fashion the

individual is a ____ and (does/does not) manifest disease

carrier

does not

in autosomal recessive disorders If both parents are carriers, __% chance of being carrier,

__% chance of being affected

50

25

in autosomal recessive If one parent is affected, ___% chance of being carrier

50

in autosomal recessive disorders Carrier status can be inherited from male or female parent

and May observe generational ______

skipping

Multisystem disease affecting epithelia including respiratory,

gastrointestinal, pancreas, and exocrine sweat glands

cystic fibrosis

cystic fibrosis is caused by Caused by cystic fibrosis transmembrane conductance regulator

(CFTR) gene which codes for a ____ channel

chloride

in cystic fibrosis Deficient ion transport leads to ____ secretions

viscous

Can block airways and reduce clearing of debris leading to chronic

pulmonary infections and cardiorespiratory complications

• Can block pancreatic ducts leading to obstructive chronic

pancreatitis and pancreatic insufficiency, malabsorption of fat

and protein

• Can block bile canaliculi in the liver, ultimately increased risk for

cirrhosis

viscous secretions from CF can block ____, ______ ____, and ____ ____

airways

pancreatic ducts

bile canaliculi