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# USMLE

STEP 1
GENETICS
JAKE MAYFIELD
HERE’S THE PLAN..
•  General principles
•  Patterns of inheritance
•  Hardy-Weinberg
•  Mutations and abnormalities
•  Diseases
•  Chromosomal
•  Autosomal
•  Imprinting
•  Trinucleotide repeat expansions
•  James will cover those diseases I’m not able to cover
THE BASICS: ALLELES
•  One of two or more versions of a gene
•  Humans are diploid organisms: we have two copies of
each gene
THE BASICS: INHERITANCE
•  Mendelian genetics
•  One gene – one trait
•  Not always the case
EVALUATING INHERITANCE
Affected individuals have an affected parent?

Yes No
Dominant Recessive

## Is there male-male Are all (almost all) of

transmission? those affected male?

Yes No Yes No
Dominant dominant recessive recessive

No
Are all daughters of an affected
male also affected?
Yes

GAME SHOW: NAME THAT
INHERITANCE PATTERN!
PATTERN:
AUTOSOMAL DOMINANT
GAME SHOW: NAME THAT
INHERITANCE PATTERN!
PATTERN:
AUTOSOMAL RECESSIVE
GAME SHOW: NAME THAT
INHERITANCE PATTERN!
PATTERN:
GAME SHOW: NAME THAT
INHERITANCE PATTERN!
PATTERN:
PATTERN:
HARDY-WEINBERG
•  p2 + 2pq + q2 = 1
•  p + q = 1
•  You have a sample group in which the percentage of the
homozygous recessive genotype (aa) is 36%. Calculate:
•  The frequency of the "aa" genotype.
•  The frequency of the "a" allele.
•  The frequency of the "A" allele.
•  The frequencies of the genotypes "AA" and "Aa."
HARDY-WEINBERG
•  The frequency of the "aa" genotype.
•  36% - given in the question.
•  The frequency of the "a" allele.
•  Homozygous recessive frequency is q2, thus q2 = 0.36
•  Square root to get q = 0.6 or 60%
•  The frequency of the "A" allele.
•  Because p + q = 1, we know p + 0.6 = 1
•  Thus, p = 0.4 or 40%
•  The frequencies of the genotypes "AA" and "Aa.”
•  AA = p2 = 0.42 = 0.16 = 16%
•  Aa = pq = 0.4 * 0.6 = 24%
LET’S BREAK
HARDY-WEINBERG
•  Mutation
•  Gene flow
•  Genetic drift
•  Nonrandom mating
•  Natural selection
THE MANY FACES OF
MUTATION
•  Missense
•  Nonsense
•  Insertion
•  Deletion
•  Frame shift
•  Repeat expansion
POINT
MUTATIONS
•  Missense
•  Change in one base pair that results in a different
amino acid
•  Nonsense
•  Change in one base pair that results in a
premature stop codon
•  Silent
•  Change in one base pair that does not result in a
change in the amino acid sequence
EXAMPLES

???

???
INSERTIONS AND
DELETIONS
•  Insertions and deletions may be balanced or unbalanced
•  Unbalanced insertions result in frame shifts

## •  3-base reading frame lost = massive change in amino acid

product
REPEAT EXPANSIONS
•  Expansion of repeating regions of DNA
•  Due to slippage during DNA replication
•  Results in anticipation
CHROMOSOMAL
ABNORMALITIES
CHROMOSOMAL
ABNORMALITIES: WHY?
•  Meiotic nondisjunction
•  Robertsonian translocation
ROBERTSONIAN
TRANSLOCATION
GENETIC DISEASES
•  Chromosomal abnormalities
•  Whole chromosome
•  Other abnormalities
•  Autosomal
•  Trinucleotide repeat expansions
•  Imprinting
TRISOMY 21 – DOWN
•  Characterized by:
•  Intellectual disability with later early onset Alzheimer’s
•  Flat facies with prominent epicanthal folds
•  Duodenal atresia, Hirschsprung disease
•  ASD, AV malformations, VSD
•  Detection
•  1st trimester:
•  Ultrasound: Nuchal translucency & hypoplastic nasal bone
•  Labs: Decr. serum PAPP-A︎, incr. free β-hCG︎
•  Labs: Decr. α-fetoprotein︎, incr. β-hCG, decr. estradiol, incr.
inhibin A
TRISOMY 18 – EDWARDS
•  Characterized by:
•  Intellectual disability
•  Prominent occiput, micrognathia, low set ears, short
neck
•  Rocker-bottom feet
•  Congenital heart defects
•  Detection
•  1st trimester:
•  Labs: Decr. serum PAPP-A︎, decr. free β-hCG︎
•  Decr. α-fetoprotein︎, decr. β-hCG, decr. estradiol, decr.
inhibin A
TRISOMY 13 – PATAU
•  Characterized by:
•  Intellectual disability
•  Microphthalmia, microcephaly, cleft lip and palate,
umbilical hernia, polydactyly
•  Rocker-bottom feet
•  Congenital heart and renal defects
•  Detection
•  1st trimester:
•  Ultrasound: Nuchal translucency
•  Labs: Decr. serum PAPP-A︎, decr. free β-hCG︎
XXY – KLINEFELTER
•  Or XXXY or XXYY, etc.
•  Characterized by:
•  Phenotypic male
•  Testicular atrophy, eunuchoid body shape, long
extremities, gynecomastia, female hair distribution
•  Rare mental disability, usually no or slight IQ loss
•  Reduced or eliminated fertility
•  Detection usually occurs at puberty when symptoms
appear
•  Associated with maternal or paternal meiotic
nondisjunction
XYY
•  Phenotypically normal
•  Normal fertility
•  Classically suffer from severe acne
•  Classically associated with antisocial personalities
XØ – TURNER
•  Characterized by:
•  Phenotypic female
•  Hypogonadism, streak ovaries, amenorrhea, short stature,
broad chest with widely spaced nipples
•  Coarctation of the aorta
•  Normal intelligence
•  Severely affected patients can present in infancy with
swelling of the nape of the neck
•  Cells are notable for absence of a Barr body
•  Usually infertile
CRI-DU-CHAT
SYNDROME
•  Congenital microdeletion of short arm of chromosome 5
•  Characterized by:
•  High-pitched crying/mewing
•  Intellectual disability and delayed development
•  Microcephaly
•  Hypotonia
•  Distinctive facial features: widely set eyes, low-set ears, a
small jaw, and a rounded face
•  Some are born with a heart defect (VSD)
•  Inheritance
•  Usually spontaneous – rarely from parent with balanced
translocation
WILLIAMS SYNDROME
•  Congenital microdeletion of long arm of chromosome 7
•  Characterized by:
•  “Elfin” facies
•  Intellectual disability
•  Hypercalcemia
•  Good verbal skills
•  Friendliness with strangers
•  Heart defect (SVAS)
•  Inheritance
•  Usually spontaneous
22Q11 DELETION
SYNDROMES
•  Microdeletion at chromosome 22q11
•  Presentation varies
•  Facial abnormalities
•  T-cell deficiency – thymic aplasia
•  Hypocalcemia – parathyroid aplasia
•  Increased risk of psychotic illnesses
•  DiGeorge
•  Thymic, parathyroid, and cardiac defects
•  Velocardiofacial
•  Palate, facial, and cardiac defects
•  Inheritance is usually spontaneous, but sometimes related
to translocation
DISEASE BREAK!
F.I.S.H.
•  Fluorescence in situ hybridization
•  A fluorescently labeled DNA or RNA sequence
complementary to the target sequence is prepared
•  Probe and sample are incubated
•  Probe that does not bind is washed off
•  Chromosomes are visualized
•  Metaphase chromosomes are used because this is when
they are compact and visible
Kato, T., Kosaka, K., Kimura, M., Imamura, S.-I., Yamada, O., Iwai, K., … Matsuoka, R. (2003). Thrombocytopenia in patients with 22q11.2 deletion
syndrome and its association with glycoprotein Ib-beta. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 5(2), 113–
119. doi:10.1097/01.GIM.0000056828.03164.30
GENETIC DISEASES
•  Chromosomal abnormalities
•  Autosomal
•  Dominant
•  Recessive
•  Trinucleotide repeat expansions
•  Imprinting
AUTOSOMAL DOMINANT
POLYCYSTIC KIDNEY DISEASE
•  Results in eventual destruction of both kidneys due to
multiple expanding cysts
•  Formerly known as adult polycystic kidney disease
•  Caused by a mutation in one of two genes:
•  PKD1 (85%, chromosome 16) – ESRD at ~53 years
•  PKD2 (15%, chromosome 4) – ESRD at ~69 years
•  Presenting symptoms
•  Renal insufficiency
•  Pain
•  Hematuria
•  Associated with berry aneurysms in the circle of Willis and
liver cysts
POLYPOSIS
•  Caused by a mutation in the APC
gene
•  100 polyps are necessary for dx
•  Presents in teenage years
occurs by age 30 without
prophylactic colectomy
•  Extra-intestinal manifestations
•  Hypertrophic retinal pigment
epithelium
•  Gardner and Turcot syndromes
•  Autosomal dominant
FAMILIAL
HYPERCHOLESTEROLEMIA
•  Results in elevated LDL due to absent LDL receptor
•  Heterozygotes have a 2-3x elevated plasma cholesterol
•  Homozygotes have a 5-6x elevated plasma cholesterol
•  Symptoms
•  Xanthomas
•  Early onset atherosclerosis and sequelae
MARFAN SYNDROME
•  Connective tissue disorder due to mutated FBN1 or FBN2
gene resulting in defective fibrillin-1 glycoprotein
•  Symptoms
•  Unusually tall with long, thin extremities and digits.
•  Lax hand and feet joint ligaments
•  Potential cardiovascular defects:
•  Mitral valve prolapse
•  Aortic root dilation secondary to cystic medionecrosis
•  Lens subluxation
•  70-85% of cases are inherited while the rest are sporatic
MULTIPLE ENDOCRINE
NEOPLASIAS (MEN)
•  MEN-1 (3 Ps) AKA Wermer syndrome
•  Primary hyperparathyroidism
•  Pancreatic endocrine tumors (often functional – Zollinger-
Ellison syndrome)
•  Pituitary tumors
•  MEN-2A (2 Ps)
•  Medullary thyroid carcinoma
•  Pheochromocytoma
•  Parathyroid hyperplasia
•  MEN-2B (1 P)
•  Medullary thyroid carcinoma
•  Pheochromocytoma
•  Oral/intestinal ganglioneuromatosis
NEUROFIBROMATOSIS
•  Type 1
•  Neurofibromas and gliomas of the optic nerve
•  Neurofibromas are prone to malignant transformation
•  Pigmented nodules of the iris, café au lait spots
•  Mutated NF1 gene
•  Type 2
•  Variety of resultant tumors
•  Common: bilateral eighth-nerve schwannomas
•  Juvenile cataracts
•  Multiple meningiomas, gliomas
•  Mutated NF2 gene resulting in nonfunction “Merlin” protein
VON HIPPEL-LINDAU
DISEASE
•  Affected individuals develop multiple neoplasms
•  Renal cell carcinoma
•  Pheochromocytoma
•  Hemangioblastomas
•  Cysts involving the pancreas, liver, and kidneys
•  Associated with deletion of VHL gene (chromosome 3)
HEREDITARY SPHEROCYTOSIS

## •  RBCs are spheroid because of mutations in ankyrin, band

3, spectrin, or band 4.2
•  Resultant red cells are less deformable and phagocytized
by splenic macrophages
•  RBC lifespan is reduced to 100-110 days from 120 days
•  Morphology
•  Small, dark-staining (hyperchromic) red cells
•  Lacking the central zone of pallor
•  Diagnosis: Abnormal results on osmotic fragility test,
morphology
•  Treatment: Splenectomy
HEREDITARY SPHEROCYTOSIS
OTHER AUTOSOMAL
DOMINANT DISEASES
•  Hereditary hemorrhagic telangiectasia
•  Tuberous sclerosis
•  Huntington disease (will discuss later)
•  Ostogenesis Imperfecta
•  Achondroplasia
GENETIC DISEASES
•  Chromosomal abnormalities
•  Autosomal
•  Dominant
•  Recessive
•  Trinucleotide repeat expansions
•  Imprinting
AUTOSOMAL RECESSIVE
POLYCYSTIC KIDNEY DISEASE
•  Results in early destruction of both kidneys and is often
fatal in childhood
•  Formerly known as childhood polycystic kidney disease
•  Caused by a mutation in PKHD1
•  Major concern if patients survive infancy: congenital
hepatic fibrosis
•  Affected individuals are often compound heterozygotes
CYSTIC FIBROSIS
•  Defect in CFTR gene on chromosome 7
•  Results in a dysfunctional ion transporter affecting fluid
secretion in exocrine glands and in the respiratory,
gastrointestinal, and reproductive systems
CYSTIC FIBROSIS Kumar, V., Abbas, A. K., & Aster, J. C. (Eds.).
(2014). Robbins and Cotran pathologic basis
of disease (Ninth edition.). Philadelphia, PA:
Elsevier/Saunders.

## Increased sweat [Cl−] (>60 mEq/L) is diagnostic of CF

CYSTIC FIBROSIS
•  Presentation
•  Persistent infection with typical cystic fibrosis pathogens:
•  Staphylococcus aureus
•  Haemophilus influenzae
•  Pseudomonas aeruginosa
•  Burkholderia cepacia
•  Chronic cough with sputum production and symptoms of
airway obstruction; digital clubbing
•  Pancreatic insufficiency (malabsorption and steatorrhea)
•  Reticulonodular pattern on chest X-ray
•  Other complications
•  Fat-soluble vitamin deficiencies
•  Nasal polyps
•  Recurrent acute pancreatitis, chronic pancreatitis
SICKLE CELL ANEMIA
•  Caused by a point mutation in the gene coding β-globin
•  Results in chronic hemolysis, microvascular occlusions,
and tissue damage
•  Complications
•  Vaso-occlusive crisis - episodes of hypoxia that cause
severe pain in the affected region
•  Splenic damage and increase risk of infection
•  Aplastic anemia precipitated by parvovirus B19
•  Vascular: stroke, retinopathy, erectile dysfunction, acute
chest
•  Treatment: hydroxyurea
•  Diagnosis: Clinical + microscopy, Hgb electrophoresis
WILSON DISEASE
•  Results in impaired copper excretion due to
mutation of the ATP7B gene
•  Decreases hepatic secretion of copper into the
bile
•  Prevents binding of copper by its carrier protein,
ceruloplasmin
•  Liver is usually the primary site of injury
•  Average presentation age is 11.4 years, but highly
variable
•  Symptoms
•  Acute or chronic liver disease
•  Movement disorders (often Parkinsonian)
•  Psychiatric symptoms
VON GIERKE'S DISEASE
•  Deficiency in glucose-6-phosphatase
•  Results in hepatomegaly and renomegaly associated with
increased glycogen stores
•  Presentation: severe fasting hypoglycemia with elevated
blood lactate
•  Failure to thrive in untreated patients

•  Hyperlipidemia and
hyperuricemia can result
from deranged glucose
metabolism
•  Treatment: nutritional
modification (frequent oral
glucose)
MCARDLE DISEASE
•  Deficiency in skeletal muscle glycogen phosphorylase
•  Increased glycogen in muscle leads to painful cramps
•  Often associated with myoglobinuria (red urine)
•  Serum creatine kinase is elevated and lactate levels
remain normal after exercise
KARTAGNER SYNDROME
•  AKA Primary Ciliary Dyskinesia
•  Genetically heterogeneous
•  Multiple clinical manifestations due to defective dynein
•  Pulmonary: chronic cough, recurrent pneumonia
bronchiectasis
•  Chronic otitis media, rhinitis, and nasal polyps
•  Male and female infertility
•  Increased risk for ectopic pregnancy
•  Situs inversus
•  Usually presents as respiratory distress shortly after birth
OTHER AUTOSOMAL
RECESSIVE DISEASES
•  Albinism
•  Hemochromatosis
•  Thalassemias
•  Phenylketonuria
GENETIC DISEASES
•  Chromosomal abnormalities
•  Autosomal
•  Trinucleotide repeat expansions
•  Imprinting
DUCHENNE MUSCULAR
DYSTROPHY
•  X-linked recessive frameshift truncating dystrophin
•  Dystrophin helps anchor muscle fibers
•  Poor head control in infancy may be first manifestation
•  Signs and symptoms
•  Progressive weakness, beginning in pelvic girdle muscles
•  Gowers sign is often evident by age 3
•  Pseudohypertrophy of calfs secondary to fatty infiltration
•  Intellectual impairment
•  Dilated cardiomyopathy, often as cause of death
•  Death usually occurs by 18-20 years of age
•  Western blot confirms diagnosis
LESCH-NYHAN SYNDROME
•  X-linked recessive defective purine salvage due to loss of
HGPRT
•  Leads to the buildup of 5-phosphoribosyl-pyrophosphate
(PRPP) which is normally produced by the pentose
phosphate pathway.
•  PRPP is a precursor in the production of purines.
•  HGPRT loss results in buildup of
PRPP and massive upregulation of
purine synthesis.
•  Purines are catabolized to uric
acid resulting in hyperuricemia,
gout, self-mutilation, MR, dystonia
•  Treatment?
ORNITHINE TRANSCARBAMYLASE
DEFICIENCY
•  Presentation
•  Severe hyperammonemia in affected newborns
•  Progresses to metabolic encephalopathy
•  Decreased BUN, increased orotic acid in blood and urine
BRUTON
AGAMMAGLOBULINEMIA
•  X-linked recessive mutation of the BTK gene results in
loss of Bruton tyrosine kinase (BTK) resulting in inability
of B cells to mature or differentiate
•  Signs and symptoms
•  Recurrent infections beginning in infancy
•  Low Ig levels
•  Reduced or absent CD19+ B cells
•  Normal CD4+ and CD8+ T cells
•  Notable for small or absent tonsils and lymph nodes
WISKOTT-ALDRICH
SYNDROME
•  Due to X-linked mutation in the Wiskott-Aldrich syndrome
protein (WASP) resulting in dysfunctional T cell
cytoskeletons
•  Characterized by
•  Progressive loss of T lymphocytes
•  Low IgM, normal IgG, and elevated IgA and IgE
•  Thrombocytopenia
•  Eczema
•  Recurrent infection
•  Increased risk of autoimmune disease and neoplasia
•  Treatment: Hematopoietic stem cell transplantation
HEMOPHILIA A AND B
•  Hemophilia A
•  Most common inherited life-threatening bleeding disorder
•  Deficiency in factor VIII, which essential for IX activity
•  Prolonged PTT but normal PT
•  Treatment: recombinant factor VIII therapy
•  Hemophilia B
•  Factor IX deficiency
•  Clinically indistinguishable from factor VIII deficiency
•  Prolonged PTT but normal PT
•  Treatment: recombinant factor IX therapy
GENETIC DISEASES
•  Chromosomal abnormalities
•  Autosomal
•  Trinucleotide repeat expansions
•  Imprinting
HUNTINGTON’S DISEASE
•  Signs and symptoms
•  Progressive dementia with psychiatric disturbance
•  Choreiform movements
•  Caudate atrophy, with ︎decreased GABA and Ach
•  Autosomal dominant with anticipation
•  CAG repeats located on the short arm of chromosome 4

## May or may not be

36–39 Reduced Penetrance 50%
affected

## 40+ Full Penetrance Will be affected 50%

FRAGILE X SYNDROME
•  Signs in symptoms
•  Intellectual disability (all males, 1/3 females), sometimes
autism
•  Post-pubertal macroorchidism
•  Long face with a large jaw, large everted ears
•  Mitral valve prolapse
•  Seizures
•  More than 200 CGG repeats on the X chromosomes
results in symptoms
•  Generally categorized as X-linked recessive with
anticipation
FRIEDREICH'S ATAXIA
•  Signs and symptoms
•  Primary: ataxia, areflexia, and positive Babinski
•  Nystagmus, dysarthria, loss of deep tendon reflexes
•  Degeneration of peripheral nerve fibers and the dorsal
spinal columns
•  Pes cavus and kyphoscoliosis
•  Hypertrophic cardiomyopathy – often cause of death
•  Autosomal recessive with anticipation
•  GAA repeats located on chromosome 9 – disrupts frataxin
•  Onset usually 7 - 15 years old
GENETIC DISEASES
•  Chromosomal abnormalities
•  Autosomal
•  Trinucleotide repeat expansions
•  Imprinting
GENOMIC IMPRINTING
•  Epigenetic silencing of certain regions of chromosomes
inherited from mother or father
•  Some chromosomes “remember” where they came from
•  Occurs in the ovum or sperm before fertilization
•  Thus, when genetic information received from one parent
is imprinted, only one “functional” copy remains
•  Results from deletion of band q12 in the long arm of the
chromosome 15 derived from the father
•  OR from maternal uniparental disomy
•  Characteristics
•  Mental retardation
•  Short stature, small hands and feet, and hypotonia
•  Profound hyperphagia leading to obesity
ANGELMAN SYNDROME
•  Results from deletion of band q12 in the long arm of the
chromosome 15 derived from the mother
•  OR from paternal uniparental disomy
•  Characteristics
•  Mental retardation
•  Ataxic gait
•  Seizures
•  Inappropriate laughter
USMLE STEP 1 GENETICS
3 THE BASICS: ALLELES
• One of two or more versions of a gene.
• Humans are diploid organisms: we have two copies of each gene

## 4 THE BASICS: INHERITANCE

• Genetic conditions caused by a mutation in a single gene follow predictable
patterns of inheritance within families.
• Single gene inheritance is also referred to as Mendelian inheritance as they
follow transmission patterns he observed in his research on peas.
• There are four types of Mendelian inheritance patterns – let’s try to identify them.
5 EVALUATING INHERITANCE

## 6 GAME SHOW: NAME THAT INHERITANCE PATTERN!

7 PATTERN:AUTOSOMAL DOMINANT

## Because the parents could be heterozygous, children of

two affected individuals can be unaffected in autosomal
dominant conditions.

## 8 GAME SHOW: NAME THAT INHERITANCE PATTERN!

9 PATTERN:AUTOSOMAL RECESSIVE
Notice that 8 & 9 both don’t have the
condition, but one of their children does –
this isn’t possible in autosomal dominant.
Recessive conditions are clinically manifest
only when an individual has two copies of
the mutant allele. When just one copy of the
mutant allele is present, an individual is a
carrier of the mutation, but does not develop
the condition. Females and males are
affected equally by traits transmitted by
autosomal recessive inheritance. When two
carriers mate, each child has a 25% chance
of being homozygous wild-type (unaffected);
a 25% chance of being homozygous mutant
(affected); or a 50% chance of being
heterozygous (unaffected carrier).

## 10 GAME SHOW: NAME THAT INHERITANCE PATTERN!

• All X-linked recessive traits are fully evident in males because they only have
one copy of the X chromosome, thus they do not have a normal copy of the gene
to compensate for the mutant copy. Thus, women are rarely affected.

## 12 GAME SHOW: NAME THAT INHERITANCE PATTERN!

• (left) Because the gene is located on the X chromosome, there is no
transmission from father to son. However, all daughters of an affected male will
be affected since the father has only one X chromosome to transmit. Children of
an affected woman have a 50% chance of inheriting the X chromosome with the
mutant allele. X-linked dominant disorders are clinically manifest when only one
copy of the mutant allele is present.
• (right) Mutated dominant x-linked genes are sometimes fatal to male offspring –
see Rett syndrome.
15 HARDY-WEINBERG
•! p2 + 2pq + q2 = 1
•! p + q = 1
•! You have a sample group in which the percentage of the
homozygous recessive genotype (aa) is 36%. Calculate:
•! The frequency of the "aa" genotype.
•! The frequency of the "a" allele.
•! The frequency of the "A" allele.
•! The frequencies of the genotypes "AA" and "Aa."
16 HARDY-WEINBERG
•! The frequency of the "aa" genotype.
•! 36% - given in the question.
•! The frequency of the "a" allele.
•! Homozygous recessive frequency is q2, thus q2 = 0.36
•! Square root to get q = 0.6 or 60%
•! The frequency of the "A" allele.
•! Because p + q = 1, we know p + 0.6 = 1
•! Thus, p = 0.4 or 40%
•! The frequencies of the genotypes "AA" and "Aa.”
•! AA = p2 = 0.42 = 0.16 = 16%
•! Aa = pq = 0.4 * 0.6 = 24%
17 LET’S BREAK HARDY-WEINBERG (WHEN H-W DOESN’T APPLY)
•! Mutation
•! Gene flow
•! Genetic drift
•! Nonrandom mating
•! Natural selection
18 THE MANY FACES OF MUTATION
•! Nonsense
•! Missense
•! Insertion
•! Deletion
•! Frame shift
•! Repeat expansion
19 POINT MUTATIONS
•! Missense
•! Change in one base pair that results in a different amino acid
•! Nonsense
•! Change in one base pair that results in a premature stop codon
•! Silent
•! Change in one base pair that does not result in a change in the
amino acid sequence

20 EXAMPLES

Missense

Nonsense
21 INSERTIONS AND DELETIONS

## •! Insertions and deletions may be balanced or unbalanced

•! Unbalanced insertions result in frame shifts

## •! 3-base reading frame lost = massive change in amino acid

product
22 REPEAT EXPANSIONS

## •! Expansion of repeating regions of DNA

•! Due to slippage during DNA replication
•! Results in anticipation (see later)
23 CHROMOSOMAL ABNORMALITIES

## 24 CHROMOSOMAL ABNORMALITIES: WHY?

•! Meiotic nondisjunction
•! Robertsonian translocation
25 ROBERTSONIAN TRANSLOCATION

Note: Monosomy is
not compatible with
life (except for
monosomy X0)

•! Chromosomal abnormalities You are here
•! Whole chromosome
•! Other abnormalities
•! Autosomal
•! Trinucleotide repeat expansions
•! Imprinting

27 TRISOMY 21 – DOWN
•! Characterized by:
•! Intellectual disability with later early onset Alzheimer’s
•! Flat facies with prominent epicanthal folds
•! Duodenal atresia, Hirschsprung disease
•! ASD, AV malformations, VSD
•! Detection
•! 1st trimester:
•! Ultrasound: Nuchal translucency & hypoplastic nasal bone
•! Labs: Decr. serum PAPP-A, incr. free β-hCG
•! Labs: Decr. α-fetoprotein, incr. β-hCG, decr. estradiol, incr.
inhibin A
• Notes:
• Most common viable chromosomal disorder. 40% have
heart defects.
• Associated w/ advanced maternal age
• 95% of cases due to meiotic nondisjunction
• 4% of cases due to Robertsonian translocation
• 1% of cases due to mosaicism (no maternal association;
post-fertilization mitotic error).
28 TRISOMY 18 – EDWARDS
•! Characterized by:
•! Intellectual disability
•! Prominent occiput, micrognathia, low set ears, short neck
•! Rocker-bottom feet
•! Congenital heart defects
•! Associated w/ advanced maternal age
•! Detection
•! 1st trimester:
•! Labs: Decr. serum PAPP-A, decr. free β-hCG
•! Decr. α-fetoprotein, decr. β-hCG, decr. estradiol, decr. inhibin
A
29 TRISOMY 13 – PATAU
•! Characterized by:
•! Intellectual disability
•! Microphthalmia, microcephaly, cleft lip and palate, umbilical
hernia, polydactyly
•! Rocker-bottom feet
•! Congenital heart and renal defects
•! Detection
•! 1st trimester:
•! Ultrasound: Nuchal translucency
•! Labs: Decr. serum PAPP-A, decr. free β-hCG
30 XXY – KLINEFELTER
•! Or XXXY or XXYY, etc.
•! Characterized by:
•! Phenotypic male
•! Testicular atrophy, eunuchoid body shape, long extremities,
gynecomastia, female hair distribution
•! Rare mental disability, usually no or slight IQ loss
•! Reduced or eliminated fertility
•! Detection usually occurs at puberty when symptoms appear
•! Associated with maternal or paternal meiotic nondisjunction

30 XYY
•! Phenotypically normal
•! Normal fertility
•! Classically suffer from severe acne & associated with antisocial personalities

32 XØ – TURNER
•! Characterized by:
•! Phenotypic female with hypogonadism, streak ovaries, amenorrhea, short
stature, broad chest with widely spaced nipples
•! Coarctation of the aorta
•! Normal intelligence
•! Severely affected patients can present in infancy with
swelling of the nape of the neck
•! Cells are notable for absence of a Barr body
•! Usually infertile

33 CRI-DU-CHAT SYNDROME
•! Congenital microdeletion of short arm of chromosome 5
•! Characterized by:
•! High-pitched crying/mewing
•! Intellectual disability and delayed development
•! Microcephaly
•! Hypotonia
•! Distinctive facial features: widely set eyes, low-set ears, a small
jaw, and a rounded face
•! Some are born with a heart defect (VSD)
•! Inheritance
•! Usually spontaneous – rarely from parent with balanced
translocation
34 WILLIAMS SYNDROME
•! Congenital microdeletion of long arm of chromosome 7
•! Characterized by:
•! “Elfin” facies
•! Intellectual disability
•! Hypercalcemia
•! Good verbal skills
•! Friendliness with strangers
•! Heart defect (SVAS)
•! Inheritance
•! Usually spontaneous
35 22Q11 DELETION SYNDROMES
•! Microdeletion at chromosome 22q11
•! Presentation varies
•! Facial abnormalities
•! T-cell deficiency – thymic aplasia
•! Hypocalcemia – parathyroid aplasia
•! Increased risk of psychotic illnesses
•! DiGeorge
•! Thymic, parathyroid, and cardiac defects
•! Velocardiofacial
•! Palate, facial, and cardiac defects
•! Inheritance is usually spontaneous, but sometimes related to
translocation
36 DISEASE BREAK! F.I.S.H.
•! Fluorescence in situ hybridization
•! A fluorescently labeled DNA or RNA sequence
complementary to the target sequence is prepared
•! Probe and sample are incubated
•! Probe that does not bind is washed off
•! Chromosomes are visualized
•! Metaphase chromosomes are used because this is when they are compact and
visible
37
A metaphase spread from a patient with 22q11.2 deletion syndrome, showing FISH mapping of the control probe to
22q13.3 (red arrow) and probe to 22q11.2 (green arrow). On the normal chromosome, a green signal (green
arrow) can be seen at 22q11.2 and a red signal (red arrow) can be seen at 22q13.3. On the deleted chromatic
chromosome, only a red signal (red arrow) can be seen at 22q13.3.

## 38 ROADMAP: GENETIC DISEASES (Slides 39 – 48)

•! Chromosomal abnormalities
•! Autosomal
•! Dominant You are here
•! Recessive
•! Trinucleotide repeat expansions
•! Imprinting
39 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
•! Results in eventual destruction of both kidneys due to
multiple expanding cysts
•! Formerly known as adult polycystic kidney disease
•! Caused by a mutation in one of two genes:
•! PKD1 (85%, chromosome 16) – ESRD at ~53 years
•! PKD2 (15%, chromosome 4) – ESRD at ~69 years
•! Presenting symptoms
•! Renal insufficiency
•! Pain
•! Hematuria
•! Associated with berry aneurysms in the circle of Willis and liver
cysts

•! Caused by a mutation in the APC gene
•! 100 polyps are necessary for dx
•! Presents in teenage years
•! Colorectal adenocarcinoma occurs by age 30 without
prophylactic colectomy
•! Extra-intestinal manifestations
•! Hypertrophic retinal pigment epithelium
•! Gardner and Turcot syndromes
•! Autosomal dominant

41 FAMILIAL HYPERCHOLESTEROLEMIA
•! Results in elevated LDL due to absent LDL receptor
•! Heterozygotes have a 2-3x elevated plasma cholesterol
•! Homozygotes have a 5-6x elevated plasma cholesterol
•! Symptoms
•! Xanthomas
•! Early onset atherosclerosis and sequelae

42 MARFAN SYNDROME
•! Connective tissue disorder due to mutated FBN1 or FBN2 gene
resulting in defective fibrillin-1 glycoprotein
•! Symptoms
•! Unusually tall with long, thin extremities and digits.
•! Lax hand and feet joint ligaments
•! Potential cardiovascular defects:
•! Mitral valve prolapse
•! Aortic root dilation secondary to cystic medionecrosis
•! Lens subluxation
•! 70-85% of cases are inherited while the rest are sporatic
43 MULTIPLE ENDOCRINE NEOPLASIAS (MEN)
•! MEN-1 (3 Ps) AKA Wermer syndrome
•! Primary hyperparathyroidism
•! Pancreatic endocrine tumors (often functional – Zollinger- Ellison
syndrome)
•! Pituitary tumors
•! MEN-2A (2 Ps)
•! Medullary thyroid carcinoma
•! Pheochromocytoma
•! Parathyroid hyperplasia
•! MEN-2B (1 P)
•! Medullary thyroid carcinoma
•! Pheochromocytoma
•! Oral/intestinal ganglioneuromatosis
44 NEUROFIBROMATOSIS
•! Type 1
•! Neurofibromas and gliomas of the optic nerve
•! Neurofibromas are prone to malignant transformation
•! Pigmented nodules of the iris, café au lait spots
•! Mutated NF1 gene
•! Type 2
•! Variety of resultant tumors
•! Common: bilateral eighth-nerve schwannomas
•! Juvenile cataracts
•! Multiple meningiomas, gliomas
•! Mutated NF2 gene resulting in nonfunction “Merlin” protein
45 VON HIPPEL-LINDAU DISEASE
•! Affected individuals develop multiple neoplasms
•! Renal cell carcinoma
•! Pheochromocytoma
•! Hemangioblastomas
•! Cysts involving the pancreas, liver, and kidneys
•! Associated with deletion of VHL gene (chromosome 3)

46 HEREDITARY SPHEROCYTOSIS
•! RBCs are spheroid because of mutations in ankyrin, band 3,
spectrin, or band 4.2
•! Resultant red cells are less deformable and phagocytized by
splenic macrophages
•! RBC lifespan is reduced to 100-110 days from 120 days
•! Morphology
•! Small, dark-staining (hyperchromic) red cells
•! Lacking the central zone of pallor
•! Diagnosis: Abnormal results on osmotic fragility test,
morphology
•! Treatment: Splenectomy
47
Compound heterozygosity with defects in two of the listed structural proteins results in much more severe disease.
Spherocytes will rupture in liquid solutions less concentrated than the inside of the red blood cell
Something about the environment of the spleen results in destruction of spherocytes. Splenectomy improves sx.

## 48 OTHER AUTOSOMAL DOMINANT DISEASES (Covered in Part 2)

•! Hereditary hemorrhagic telangiectasia
•! Tuberous sclerosis
•! Huntington disease (will discuss later)
•! Ostogenesis Imperfecta
•! Achondroplasia
49 ROADMAP: GENETIC DISEASES (Slides 50 – 59)
•! Chromosomal abnormalities
•! Autosomal
•! Dominant
•! Recessive You are here
•! Trinucleotide repeat expansions
•! Imprinting
50 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE
•! Results in early destruction of both kidneys and is often fatal in
childhood
•! Formerly known as childhood polycystic kidney disease
•! Caused by a mutation in PKHD1
•! Major concern if patients survive infancy: congenital hepatic
fibrosis
•! Affected individuals are often compound heterozygotes
51 CYSTIC FIBROSIS
•! Defect in CFTR gene on chromosome 7
•! Results in a dysfunctional ion transporter affecting fluid
secretion in exocrine glands and in the respiratory,
gastrointestinal, and reproductive systems

52 CYSTIC FIBROSIS
Kumar, V., Abbas,
A. K., & Aster, J.
C. (Eds.). (2014).
Robbins and
Cotran pathologic
basis of disease
(Ninth edition.).
Elsevier/Saunders.

53 CYSTIC FIBROSIS
•! Presentation
•! Persistent infection with typical cystic fibrosis pathogens:
•! Staphylococcus aureus
•! Haemophilus influenzae
•! Pseudomonas aeruginosa
•! Burkholderia cepacia
•! Chronic cough with sputum production and symptoms of airway
obstruction; digital clubbing
•! Pancreatic insufficiency (malabsorption and steatorrhea)
•! Reticulonodular pattern on chest X-ray
•! Other complications
•! Fat-soluble vitamin deficiencies
•! Nasal polyps
•! Recurrent acute pancreatitis, chronic pancreatitis
54 SICKLE CELL ANEMIA
•! Caused by a point mutation in the gene coding β-globin
•! Results in chronic hemolysis, microvascular occlusions, and tissue
damage
•! Complications
•! Vaso-occlusive crisis - episodes of hypoxia that cause
severe pain in the affected region
•! Splenic damage and increase risk of infection
•! Aplastic anemia precipitated by parvovirus B19
•! Vascular: stroke, retinopathy, erectile dysfunction, acute chest
•! Treatment: hydroxyurea
•! Diagnosis: Clinical + microscopy, Hgb electrophoresis
55 WILSON DISEASE
•! Results in impaired copper excretion due to mutation of the
ATP7B gene
•! Decreases hepatic secretion of copper into the bile
•! Prevents binding of copper by its carrier protein,
ceruloplasmin
•! Liver is usually the primary site of injury
•! Average presentation age is 11.4 years, but highly variable
•! Symptoms
•! Acute or chronic liver disease
•! Movement disorders (often Parkinsonian)
•! Psychiatric symptoms
54 VON GIERKE'S DISEASE
•! Deficiency in glucose-6-phosphatase
•! Results in hepatomegaly and renomegaly associated with
increased glycogen stores
•! Presentation: severe fasting hypoglycemia with elevated blood
lactate
•! Failure to thrive in untreated patients
54 MCARDLE DISEASE
•! Deficiency in skeletal muscle glycogen phosphorylase
•! Increased glycogen in muscle leads to painful cramps
•! Often associated with myoglobinuria (red urine)
•! Serum creatine kinase is elevated and lactate levels remain normal after
exercise

58 KARTAGNER SYNDROME
•! AKA Primary Ciliary Dyskinesia
•! Genetically heterogeneous
•! Multiple clinical manifestations due to defective dynein
•! Pulmonary: chronic cough, recurrent pneumonia
bronchiectasis
•! Chronic otitis media, rhinitis, and nasal polyps
•! Male and female infertility
•! Increased risk for ectopic pregnancy
•! Situs inversus
•! Usually presents as respiratory distress shortly after birth
59 OTHER AUTOSOMAL RECESSIVE DISEASES (Covered in Part 2)
•! Albinism
•! Hemochromatosis
•! Thalassemias
•! Phenylketonuria
60 ROADMAP: GENETIC DISEASES (Slides 61 – 68)
•! Chromosomal abnormalities
•! Autosomal
•! Dominant
•! Recessive
•! Trinucleotide repeat expansions
•! Imprinting
61 DUCHENNE MUSCULAR DYSTROPHY
•! X-linked recessive frameshift truncating dystrophin
•! Dystrophin helps anchor muscle fibers
•! Poor head control in infancy may be first manifestation
•! Signs and symptoms
•! Progressive weakness, beginning in pelvic girdle muscles
•! Gowers sign is often evident by age 3
•! Pseudohypertrophy of calfs secondary to fatty infiltration
Jake Mayfield !

•! Intellectual impairment
•! Dilated cardiomyopathy, often as cause of death
•! Death usually occurs by 18-20 years of age
•! Western blot confirms diagnosis
62 LESCH-NYHAN SYNDROME
•! X-linked recessive defective purine salvage due to loss of
HGPRT
•! Leads to the buildup of 5-phosphoribosyl-pyrophosphate
(PRPP) which is normally produced by the pentose phosphate
pathway.
•! PRPP is a precursor in the production of purines.
62 ORNITHINE TRANSCARBAMYLASE DEFICIENCY
•! Presentation
•! Severe hyperammonemia in affected newborns
•! Progresses to metabolic encephalopathy
•! Decreased BUN, increased orotic acid in blood and urine
•! Treatment
•! Hemodialysis (if indicated for ammonia)
•! Protein restriction
•! Pharmacological treatment

64 BRUTON AGAMMAGLOBULINEMIA
•! X-linked recessive mutation of the BTK gene results in loss of Bruton
tyrosine kinase (BTK) resulting in inability of B cells to mature or
differentiate
•! Signs and symptoms
•! Recurrent infections beginning in infancy
•! Low Ig levels
•! Reduced or absent CD19+ B cells
•! Normal CD4+ and CD8+ T cells
•! Notable for small or absent tonsils and lymph nodes
65 WISKOTT-ALDRICH SYNDROME
•! Due to X-linked mutation in the Wiskott-Aldrich syndrome protein
(WASP) resulting in dysfunctional T cell cytoskeletons
•! Characterized by
•! Progressive loss of T lymphocytes
Jake Mayfield !
•! Low IgM, normal IgG, and elevated IgA and IgE
•! Thrombocytopenia
•! Eczema
•! Recurrent infection
•! Increased risk of autoimmune disease and neoplasia
•! Treatment: Hematopoietic stem cell transplantation

66

67
Jake Mayfield !
68 HEMOPHILIA A AND B
•! Hemophilia A
•! Most common inherited life-threatening bleeding disorder
•! Deficiency in factor VIII, which essential for IX activity
•! Prolonged PTT but normal PT
•! Treatment: recombinant factor VIII therapy
•! Hemophilia B
•! Factor IX deficiency
•! Clinically indistinguishable from factor VIII deficiency
•! Prolonged PTT but normal PT
•! Treatment: recombinant factor IX therapy

## 69 ROADMAP: GENETIC DISEASES (Slides 70 – 72)

•! Chromosomal abnormalities
•! Autosomal
•! Dominant
•! Recessive
•! Trinucleotide repeat expansions You are here
•! Imprinting

70 HUNTINGTON’S DISEASE
•! Signs and symptoms
•! Progressive dementia with psychiatric disturbance
•! Choreiform movements
•! Caudate atrophy, with decreased GABA and Ach
•! Autosomal dominant with anticipation
•! CAG repeats located on the short arm of chromosome 4

71 FRAGILE X SYNDROME
•! Signs and symptoms
•! Intellectual disability (all males, 1/3 females), sometimes
autism
•! Post-pubertal macroorchidism
•! Long face with a large jaw, large everted ears
•! Mitral valve prolapse
•! Seizures
•! More than 200 CGG repeats on the X chromosomes results in
symptoms
Jake Mayfield !
•! Generally categorized as X-linked recessive with anticipation
72 FRIEDREICH'S ATAXIA
•! Signs and symptoms
•! Primary: ataxia, areflexia, and positive Babinski
•! Nystagmus, dysarthria, loss of deep tendon reflexes
•! Degeneration of peripheral nerve fibers and the dorsal spinal
columns
•! Pes cavus and kyphoscoliosis
•! Hypertrophic cardiomyopathy – often cause of death
•! Autosomal recessive with anticipation
•! GAA repeats located on chromosome 9 – disrupts frataxin which
•! Onset usually 7 - 15 years old

## 73 ROADMAP: GENETIC DISEASES (Slides 74 – 76)

•! Chromosomal abnormalities
•! Autosomal
•! Dominant
•! Recessive
•! Trinucleotide repeat expansions
•! Imprinting You are here

74 GENOMIC IMPRINTING
•! Epigenetic silencing of certain regions of chromosomes
inherited from mother or father
•! Some chromosomes “remember” where they came from
•! Occurs in the ovum or sperm before fertilization
•! Thus, when genetic information received from one parent is
imprinted, only one “functional” copy remains

•! Results from deletion of band q12 in the long arm of the
chromosome 15 derived from the father
•! OR from maternal uniparental disomy
•! Characteristics
•! Mental retardation
•! Short stature, small hands and feet, and hypotonia
•! Profound hyperphagia leading to obesity