Genetics Lecture II

PASP 661: Lab Medicine

Dr. Nicole Illuzzi DMSc, PA-C, NCMP
Instructional Objectives
•661-9: Explain the role of genes in determining a person's congenital development, including some of the gene
mutations that cause some of the common congenital problems.
•661-10: Describe how genes can impact a patient's risk for developing systemic diseases, including the highly
penetrant forms of cancer, and how we test for them.
•661-11: Discuss the role of genetic testing in preconception and prenatal care, including how tests are
classified as "standard" vs "elective."
•661-12: Explore the ethical considerations involved in genetic testing.
Postnatal Evaluation
• Newborn Screening
• Performed in the first 24-72 hours of life
• Blood sample collected by pricking
newborn’s heel
• No cost to family
• Conditions screened for vary state to “Guthrie card”
state
• 35 core conditions and additional ones vary
by state
• New York state screens for 50 diseases
including Cystic Fibrosis, HIV, PKU, Sickle
Cell Disease, & SMA
• Also, a hearing test and pulse oximetry
Metabolic Genetics
Metabolic Genetics
• Inherited metabolic disorders refer to different types of medical
conditions caused by genetic defects that interfere with the body's
metabolism
• These conditions may also be called inborn errors of metabolism
• Most are autosomal recessive
• Many of these conditions are on the newborn screen
Metabolic Genetics
• When to expect a metabolic disorder
• Can begin prenatally if severe, leading to dysmorphic features
• Children: neurologic deterioration, liver failure, hypoglycemia, cardiac
failure/myopathy, lactic acidosis, unexplained convulsions, coma, psychiatric
sx, peripheral neuropathy
• Newborns within 24 hours….
• Metabolic acidosis
• Hypoglycemia
• Hyperammonemia (neonatal catastrophe)
• Ammonia is a potent neurotoxin
Metabolic Genetics: Enzymes

Enzymes are the catalysts that mediate the efficient

conversion of a substrate to a product
 Metabolic Genetics Most of the genetic
metabolic defects involve
knocking out a particular
enzyme

This alternative pathway may lead to

accumulating byproducts or of initial
substrate that can be harmful or are
unable to be broken down further
Metabolic Genetics: Possible
Treatment
Gene Therapy
 Phenylketonuria (PKU)
Inheritance: autosomal recessive

Mutation: Gene encoding phenylalanine hydroxylase (PAH)

Mechanism: Deficiency of PAH causes inability to breakdown phenylalanine (Phe) which results in
hyperphenylalaninemia

Manifestations: Microcephaly, severe neurologic damage, intellectual disability, seizures, hyperactivity,

pale skin and eyes, a “mousy odor.” Babies will appear normal at birth but begin to show s/sx around 6
months

Treatment: Rigorous Phe-restricted diet. Diet will prevent damage but will not repair existing damage.
Testing for PKU is part of the newborn screen because it has significant morbidity and is easily treated by
dietary restrictions. Children with classic PKU who receive treatment promptly after birth can be expected
to have normal development. Phe restriction continues throughout life.
Phenylketonuria (PKU)
Pathophysiology
 Phenylketonuria Treatment

Diet free of phenylalanine limits

accumulation, so that the processing
to PPA doesn’t get overwhelmed
 Maple Syrup Urine Disease
Inheritance: autosomal recessive

Mutation: Defect in the branched-chain alpha-keto dehydrogenase complex (BCKD)

Mechanism: Cannot break down branched-chain amino acids (isoleucine, leucine, and valine) causing accumulation
of these AA and their toxic byproducts

Manifestation:
Presentation of classic MSUD:
• Babies are born asymptomatic
• 12-24 hours: maple syrup odor to cerumen
• 2-3 days: poor feeding, hypersomnolence, irritability
• 4-6 days: apnea, stereotyped movements “fencing” and “bicycling”, maple syrup odor in urine
• 7-10 days: coma, respiratory failure

Treatment: Treat with diet limiting leucine (neurotoxin), liver transplant. Nearly normal growth and development
may be achieved if treatment is begun before 10 days of life (newborn screen!).
 Lysosomal Storage Diseases
• Lysosomes are membrane bound organelles containing hydrolytic
enzymes involved in degradation of a variety of macromolecules
• Mutations in these enzymes lead to accumulation of their substrates
INSIDE the lysosome, where they remained trapped
• Accumulation and toxicity interferes with cell function, causes cell
death
• Substrate accumulation explains their progression
• In most conditions, substrate storage increases the mass of the affected
tissues and organs
Lysosomal Storage Diseases
Lysosomal Storage Diseases: Tay-Sachs
(infantile)
Inheritance: autosomal recessive; approximately 1 in 27 Ashkenazi Jewish patients is a carrier; also
prevalent in French-Canadian and Irish populations.

Mutation: HEX A gene

Mechanism: deficiency of hexosaminidase A (HEX A) causes inability to degrade a sphingolipid,

GM2 ganglioside, and subsequent accumulation

Manifestation: Clinical impact almost solely on the brain where gangliosides are most abundant.
Infants appear normal until 3-6 months of age, then gradually undergo neurologic deterioration
including seizures, progressive weakness, increased startle response, spasticity, progressive
macrocephaly (enlarged head) and visual loss until death at age 2-4.
-Visual loss begins within the first year and leads to blindness. Associated with a “cherry-red
spot” in the retina on fundoscopic examination

Treatment: Incurable, treatment focuses on symptom management and palliative care

Lysosomal Storage Diseases: Tay-
Sachs (infantile)
Lysosomal Storage Diseases: Tay-
Sachs (infantile)
• Screening has reduced the incidence of Tay-Sachs among Ashkenazi
Jewish patients by 90%
• Carrier screening involves both serum activity of hexosaminidase A with an
artificial substrate and molecular analysis of HEX A gene
Lysosomal Storage Diseases: Gaucher Disease
Type I (non-neuronopathic)

Inheritance: Autosomal recessive, most prevalent lysosomal storage disorder; 1 in 450 Ashkenazi
Jewish patients is affected

Mutation: GBA1 gene

Mechanism: deficiency of β-glucocerebrosidase causes accumulation of its substrate, the lipid

glucocerebroside

Manifestation: Presents in childhood. Accumulation of glucocerebroside in the reticuloendothelial

system leads to gross enlargement of the liver and spleen. Bone marrow is slowly replaced by lipid
laden macrophages (Gaucher cells). Bone lesions cause pain and osteonecrosis. Anemia,
thrombocytopenia (low platelets). Chronic fatigue, easy bruising and bleeding.

Treatment: enzyme replacement therapy reduces size of liver and spleen, increases hemoglobin
levels, improves skeletal abnormalities and bone density
Lysosomal Storage Diseases: Gaucher Disease
Type I (non-neuronopathic)
Urea Cycle Disorders
• Usually autosomal recessive
• Genetic disorder that results in a deficiency of one of the six enzymes in the urea
cycle
• Urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from
the body
• Defects in enzymes of the urea cycle are the primary cause of potentially severe
and fatal hyperammonemia
• Patients present with hyperammonemic coma a few days after birth with 50%
mortality. Survivors experience severe developmental delay.
• Nitrogen builds up in the blood in the form of ammonia, a potent neurotoxin,
resulting in hyperammonemia (elevated blood ammonia levels)
• Irreversible brain damage, coma, death
Urea Cycle Disorders
Cancer Genetics
Cancer
• Neoplasia: disease process characterized by uncontrolled cellular
proliferation leading to a mass or tumor
• For a neoplasm to be cancer, it must also be malignant
• Uncontrolled growth AND capable of invading neighboring tissues that
surround the original site (primary site) and can spread (metastasize) to more
distant sites
 Cancer Genetics
Sporadic Cancer: Happens by chance;
somatic mutation occurring in non-
germline tissue; nonheritable

Familial Cancer: A clustering of cancer in

a family that may be due to genes
and/or other shared factors, such as
environment and lifestyle

Hereditary Cancer: A clustering of

cancer in a family due to inherited
germline mutations which can be passed
from parent through the gametes to the
children
Cancer Genetics
• Cancer is fundamentally a genetic disease
• When we analyze samples from cancer we find passenger mutations, which
probably occur as the cancer develops rather than directly causing the cancer,
and we find driver genes.
• Driver genes harbor mutations that are likely to be causing a cancer to develop or
progress.
• This can be a single nucleotide change or chromosomal mutation.
• Mutagens, ex. cigarette smoke, increase the rate of mutations around the
genome, if they occur around the driver genes, an oncogenic process may be
initiated
• Driver genes can be further subdivided into two categories, activated
oncogenes or tumor suppressor genes.
Activated Oncogenes
• Proto-oncogenes are normal, cellular protein coding-genes that
promote cell growth and survival including apoptosis (programmed cell
death)
• Activated oncogenes are mutant alleles of proto-oncogenes, which can
facilitate malignant transformation by stimulating uncontrolled
proliferation and allow cells to escape apoptosis
• Cancer can arise when a proto-oncogene is mutated, changing it into an
oncogene and causing the cell to divide and multiply uncontrollably.
• Some oncogenes work like an accelerator pedal in a car, pushing a cell to divide
again and again
• Promote cancer when activated or overexpressed by gain of function
Activated Oncogenes
Tumor Suppressor Genes
• Tumor suppressor genes are normal and present in all cells of our body.
When switched on, they prevent cells from growing and dividing
uncontrollably
• However, when a tumor suppressor gene is switched off, either because the
cell mistakenly deletes it or mutates it, the brake is released and the cell
may start to grow and divide uncontrollably and potentially drive the cell to
turn into a cancer cell.
• Tumor suppressor genes cause a loss of expression of proteins that are
necessary to control the development of cancers
• Promote cancer by loss of function
• More common
Tumor Suppressor Genes
Cancer Genetics
• Usually takes 2 major mutations or “2 hits” for really aberrant cell division
to occur
• Two-hit model widely accepted as explanation for many hereditary
cancers
• Example: retinoblastoma
• Heterozygous for a germline mutation in the TSG required to prevent
development of the cancer; first hit is an inherited mutation
• Undergoes a second somatic event that inactivates the other retinoblastoma
allele; second hit
• Cell loses function of both alleles, giving rise to a tumor
• Also can have two somatic events in same cell by chance which inactivate the TSG
Two-Hit Model
 Hereditary Cancer Syndromes
• Hereditary cancer syndrome represents <5% of all patients with cancer
• important to be able to identify relatives with strong hereditary predispositions, offer testing,
monitoring, and therapy
• Inheritance pattern for most cancer genes will be autosomal dominant with
incomplete penetrance
• May appear to skip generations
• Individuals inherit altered cancer susceptibility gene, not cancer
Breast Cancer
• 1 in 8 women throughout their life
• Up to 5% caused by inheritance of germline mutations such as BRCA1
and BRCA2
• Features suggestive of BRCA1 or BRCA2 mutation:
• Early age at onset
• Ovarian cancer (with family history of breast or ovarian cancer)
• Breast and ovarian cancer in the same woman
• Bilateral breast cancer
• Ashkenazi Jewish heritage (1 in 40 will carry a BRCA mutation)
• Male breast cancer
BRCA1 & BRCA2
• Tumor suppressor genes
• Follows the two-hit hypothesis; both alleles of either BRCA 1 or 2 lose
function in tumor cells
• First hit is inherited
• Second allele loses function with such high frequency that families exhibit
highly penetrant autosomal dominant inheritance
BRCA1
• BRCA1 located on chromosome arm 17q
• 85% lifetime risk for breast cancer
• 40% lifetime risk for ovarian cancer
• 50% of children of carriers will inherit the trait; appears as autosomal
dominant transmission with high penetrance
• Possibly increased risk of colon and prostate cancers
BRCA2
• BRCA2 located on chromosome arm 13q
• 85% lifetime risk of breast cancer
• 20% lifetime risk of ovarian cancer
• 50% of children of carriers will inherit the trait; appears as autosomal
dominant transmission with high penetrance
• Men with BRCA2 mutation have a 6% breast cancer risk
• Possibly increased risk of colon, prostate, pancreatic, gallbladder, bile
duct, and stomach cancers, as well as melanoma
Identifying Carriers
• Obtaining a complete, multigenerational family history
• Assess the appropriateness of genetic testing for the particular patient
• Counsel the patient
• Benefits: identify high-risk individuals, identifies non-carriers in a family with a known
mutation, allows early detection and prevention, may relieve anxiety
• Risks: does not detect all mutations, continued risk of sporadic cancer, efficacy of
interventions vary, variants of uncertain significance, psychosocial harm
• Provide and document informed consent*
• Interpret the results
• Disclose the results
• Provide post-test counseling and follow-up
Clinical Management of BRCA+
Patient
• Possible testing for other adult relatives
• Increased surveillance for breast and ovarian cancer
• Breast cancer: Self breast exam, clinical breast exam q6 months, mammography q12 months
beginning at age 25, breast MRI, breast ultrasound
• Ovarian cancer: pelvic exams, pelvic ultrasounds, serial CA125 measurements
• Chemoprevention
• Breast cancer: Tamoxifen
• Ovarian cancer: oral contraceptives
• Prophylactic surgery
• Bilateral mastectomy associated with 90% reduction in risk for breast cancer
• Bilateral salpingo-oophorectomy associated with 95% reduction in risk for ovarian cancer and
50% reduction in the risk of breast cancer if done prior to menopause
• Lifestyle changes
Multiple Endocrine Neoplasia
• MEN syndromes: a predilection for tumors involving two or more
endocrine glands
• Pituitary, thyroid, parathyroid, adrenal, pancreas
• Autosomal dominant inheritance or may occur sporadically
• Multiple different types and subtypes
• Affected individuals should have annual biochemical screening and
imaging
MEN 1
• Wermer syndrome
• MEN1 gene encodes the protein, menin
• Tumor suppressor
• Pathophysiology follows the “two-hit” hypothesis
• Inheritance of germline MEN1 mutation followed by somatic mutation
• Characterized by a triad of tumors
• Parathyroid: primary hyperparathyroidism occurs in 90% and is the most
common feature; onset age 20-25
• Pancreatic islets cell tumors
• Anterior pituitary (ex. Prolactinoma)
MEN 2
• Sipple’s syndrome
• Activation of the RET protooncogene
• Three clinical variants are recognized: MEN 2A (most common, MEN 2), MEN 2B (about
5%, MEN 3) and MTC only
• MEN 2A
• 95% will develop medullary thyroid cancer, < age 35
• Pheochromocytoma
• Parathyroid tumors
• MEN 2B
• MTC and pheochromocytoma WITH Marfanoid habitus
• Affects children; known carriers offered prophylactic thyroidectomy between ages <1 and 5 years
old
• Parathyroid tumors do not usually occur in MEN 2B
Case Study #1
• A 35 yo female patient presents to the urgent care with left flank pain
and vomiting. The urine dipstick was negative. She reports recurrent
renal stones for a few years. Her past medical history included a
prolactinoma for 12 years. She has a family history of abdominal
tumors.

MEN 1 or MEN 2?
Case Study #2
• A 30 year old man presents to the ENT for frequent difficulty
swallowing. He has recently begun medication for hypertension. He
reports a strong family history of thyroid cancer.

MEN 1 or MEN 2?
Lynch Syndrome
• Hereditary non-polyposis colorectal cancer
• Autosomal dominant inheritance
• Disease is the phenotype by there are multiple genotypes
• MLH1, MSH2, MSH6, PMS2, EPCAM….
• One or more cases of colorectal cancer diagnosed before age 50,
colorectal cancer involving at least two generations, 3 or more
relatives with colon cancer (one much be a first degree relative of the
other two)
• Individuals with multiple primary cancers
Lynch Syndrome
• Increased risk of:
• endometrial cancer (30-60% lifetime risk)
• ovarian cancer
• brain cancer
• sebaceous skin tumors
• cancer in the GI tract (stomach, liver, pancreas, gallbladder ducts, small
intestine)
• Members of such families should undergo annual colonoscopy
beginning at age 25, pelvic ultrasounds and endometrial biopsies for
women beginning at age 30
 Familial Adenomatous Polyposis
(FAP)
• Inherited condition characterized by early
development of hundreds to thousands of
colonic adenomatous polyps and
adenocarcinoma
• 0.5% of all colorectal cancers
• 90% mutation in APC gene; autosomal
dominant
• 8% mutation in MUTYH gene: autosomal
recessive
• Prophylactic colectomy recommended to
prevent inevitable colon cancer, usually before
age 20
Bioethics
• Respect for autonomy: personal rule of the self
• Right to know
• Right not to know
• Informed consent

• Beneficence: obligation to act for the patient’s benefit

• Nonmaleficence: requires clinician not to intentionally cause harm

• Justice: fair, equitable and appropriate treatment

Which of the following is a sign or symptom of Maple Syrup Urine
Disease? Select all that apply.
a. sweet smelling cerumen
b. Poor feeding
c. Respiratory failure
d. Stereotyped movements
Mary and Patrick are both carriers of a mutation in the GBA1 gene
which causes Gaucher Disease. The chance that their first child will be
affected with Gaucher Disease is:
a. 50%
b. 100%
c. 75%
d. 25%
Genetic Disorders
• Wilson’s Disease What to Include (approximately 10-15 minutes):
• Duchenne Muscular Dystrophy
• Achondroplasia • Gene
• Inheritance patterns
• Neurofibromatosis • Affected populations
• Marfan Syndrome • Testing
• Huntington’s Disease • Phenotypic presentation
• Hemochromatosis • Pathophysiology
• Treatment
• Alpha 1 Antitrypsin Deficiency
• Interesting facts/history
• Hypercholesterolemia • Case studies
• Alpha and Beta Thalassemia • Images
• Prader-Willi • Sources in AMA format
• Angelman
Please email to me as a powerpoint presentation @
• Cri-du Chat nilluzzi@pace.edu by 5pm Monday 9/25/2023 
• Sickle Cell Anemia
Congenital
Hypothyroidism
 General Information, Interesting Facts and
History

● Occurs in 2000-4000 live births.1

● Most common endocrine problem during neonatal
period.1
● Universal newborn screening was introduced in 1974
and is now required by law in all states ²
● One of the most common preventable causes of
intellectual disability
 Gene, Inheritance Pattern, and Affected
Populations

● Mutation: Thyrotropin receptor (TSHR) or the PAX8 gene.

● Inheritance Pattern: Autosomal Recessive.

● Affected Populations: For unknown reasons, affects more than twice

as many women as men.
Testing
● Three major screening strategies:
○ Initial blood T4 assay, with follow-up thyrotropin
assay if blood T4 is low*
○ Initial blood TSH assay*
○ Simultaneous T4 & TSH assays
● Part of normal newborn screening / heel prick
● Confirmatory values: low levels of T4 & high
levels of TSH
○ If TSH is marginally elevated on initial testing,
usually monitor carefully and repeat testing
Normal Pathophysiology

● If there’s no mutation in the PAX8 or the TSHR gene, the thyroid gland
functions normally 3
● Thyroid gland produces thyroid hormone (T4 and T3) 3
● The main function of T3 and T4 is to increase cellular metabolic activity
such as carbohydrate and fat metabolism, increasing GI motility, nervous
system structural development and proper bone growth. 4
Pathophysiology of Congenital
Hypothyroidism

● PAX8 or TSHR gene → proper growth and development of the thyroid

gland 4
● If there’s a mutation in the gene → disrupts normal growth
development of the thyroid gland 4
● In 80-85% of cases, the thyroid gland is absent, substantially reduced in
size, or abnormally located. These cases are classified as thyroid
degenesis. Other cases show a normal sized or goiter thyroid gland, but
production of thyroid hormone is decreased or absent, causing the
hypothyroidism. 4
Phenotypic Presentation

● Most newborns are asymptomatic (>95%)5

○ Some maternal T4 crosses the placenta
● If symptomatic, usually in infants born in regions lacking newborn
screening programs4
● Clinical manifestations include:4
○ Jaundice
○ Somnolence ○ Hypotonia (floppy muscle tone
○ Difficulty feeding ○ Cool, pale skin
○ Constipation ○ Large stomach with protruding
○ Swelling around the eyes navel
○ Poor or slow growth ○ Intellectual disability
 Treatment5
● If treatment begins in the first two weeks after birth, infants usually
develop normally
● Treatment includes giving thyroid hormone medication
- Pill form = Levothyroxine (L-T4)
- For children, this medication is crushed and given once daily in water,
formula, or breast milk
● Many children require treatment for life
● Periodic thyroid function tests are performed to determine dose as
children grow
● Giving medication everyday and regular consultation with pediatric
endocrinologist ensures normal growth and brain development
 Case Study
1 month old female born in a region lacking newborn screening programs presents
with lethargy, somnolence and difficulty feeding. On physical exam,
patient is hypotonic and jaundice with a large abdomen and
protruding navel. Blood test shows low T4 and high TSH. Patient is
started immediately on levothyroxine. She is also referred to pediatric
endocrinology to ensure normal growth and brain development