Steven Katz, MSIV
Genetics Terms
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Basic Terms (Review)
 Gene: A hereditary unit consisting of a sequence of
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DNA that occupies a specific location on a
chromosome and determines a particular
characteristic in an organism.
Trait: A distinguishing feature, a genetically
determined characteristic or condition.
Allele: Versions of a gene
Genotype: Genetic makeup, distinguished from the
physical appearance. (G for genetic and genotype)
Phenotype: The observable physical or biochemical
characteristics as determined by both genetic
makeup and environment
Genetics Terms (cont.)
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High Yield Terms:
 Classical Dominance: Dominant allele is
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expressed if present
Incomplete Penetrance: Not all individuals with
a mutant genotype display the phenotype (many
genetics dz’s but good example is NF1)
Variable Expression: Nature and severity of
phenotype changes between individuals
Co-dominance: Neither of two alleles is
dominant (e.g. blood types)
Anticipation: Severity of disease worsens or age
of onset is earlier in succeeding generations
(e.g. Huntington’s Dz)
Genetics Terms (cont.)
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High Yield Terms (cont.)
 Loss of heterozygosity: When a tumor
suppressor gene is mutated or deleted, the
complimentary allele must be lost before a
cancer develops. Not true with oncogenes!
 Dominant negative mutation: a non-functioning
protein also prevents a normal protein from
functioning appropriately (e.g Marfan’s
syndrome)
 Heteroplasmy: Both NL and mut mtDNA results
in variable expression in mitochondrial inherited
dz’s
 Uniparental disomy: offspring receives 2 copies
of a chromosome from 1 parent and none from
the other
Imprinting
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Definition: At a single locus, only one allele is
active, the other is inactive; can also occur as
a result of uniparental disomy
 Phenotype depends on origin of mutation  paternal
v. maternal
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Both syndromes due to inactivation or deletion
of genes on chromosome 15
Prader-Willi: Deletion of normally active
PATERNAL allele
 Mental retardation, obesity, hypogonadism,
hypotonia
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Angelman’s syndrome (aka “Happy Puppet
Syndrome”): Deletion of normally active
MATERNAL allele
 Mental retardation, seizures, ataxia, innapropriate
laughter
Modes of Inheritance
 Autosomal Dominant: Affects both males and
females in all generations. Presents clinically after
puberty and FH is essential for diagnosis.
 Examples: Achondroplasia, Huntington’s dz,
Neurofibromatosis types 1 & 2, and many many
more!
Modes of Inheritance
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Autosomal Recessive: only offspring of 2
carrier parents can be affected. Usually only
seen in one generation, usually due to enzyme
deficiencies.
 Commonly more severe than dominant disorders,
presents in childhood
 Examples: Albinism, Cystic Fibrosis, PKU, Wilson’s
dz, and many more!
Modes of Inheritance
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X-linked recessive: only sons of
heterozygous mothers can be affected, no
father to son transmission.
 Examples: Fragile X, Lesch-Nyhan, Hemophilia
A and B
 Females may rarely be affected due to random
inactivation of X chrom (e.g. Lyonization)
Modes of Inheritance
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X-linked dominant: Transmitted through
both parents, males and females can be
affected, but all females of affected fathers
are affected.
 Example○ Hypophosphatemic rickets: increased phosphate
wasting at proximal tubule
Modes of Inheritance
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Mitochondrial: Transmission ONLY
through the mother. All offspring of
affected mothers are affected.
 Variable expression due to heteroplasmy
Autosomal Dominant Dz’s
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Achondroplasia
 Genetics and Cell Level:
○ Defect in Fibroblast Growth Factor receptor 3
 Causes abnormal cartilage development
 Phenotypic Traits:
○ Dwarfism: short limbs, head and neck nl size
 Misc info:
○ Associated with advance paternal age
○ AD so if one parent affected then 50% of children
affected
○ Homozygotes die either before or shortly after
birth
Autosomal Dominant Dz’s
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APKD (adult polycystic kidney dz)
 Genetics and Cell Level:
○ 90% due to mut in APKD1 on chromosome 16
 Phenotypic Traits:
○ Bilateral enlargement of kidney due to multiple
cysts
 Clinical Presentation: b/l flank pain, hematuria,
HTN, progressive renal failure
○ Usually presents in adulthood (hence the name!)
 Misc info:
○ Associated with polycystic liver dz, berry
aneurysms, MVP
APKD
Autosomal Dominant Dz’s
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Familial Adenomatous Polyposis
 Genetics and Cell Level:
○ Deletion on chromosome 5q21-22 (APC gene)
 Phenotypic Traits:
○ Colon covered with polyps after puberty that
progress to cancer if not resected
 Clinical Presentation: anemia, melena,
changes in bowel habits
 Misc info:
○ Will need colonoscopies early and often
FAPCC
Autosomal Dominant Dz’s
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Familial hypercholesterolemia (HLP type
2A)
 Genetics and Cell Level:
○ Defective or absent LDL receptor
○ Heterozygotes (1:500) ~ 300 mg/dl
○ Homozygotes (very rare) ~ 700+ mg/dl
 Phenotypic Traits:
○ Xanthelasma palpebrarum, tendon xanthomas
(classically on the Achilles tendon), severe
atherosclerotic dz, MI may develop early
Familial Hypercholesterolemia
Autosomal Dominant Dz’s
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Huntington’s Disease
 Genetics and Cell Level:
○ Gene located on Chromosome 4, trinucleotide
repeat disorder (CAG)n
○ Decreased levels of GABA and Ach in the brain
 Clinical Presentation: depression, progressive
dementia, choreiform movements, caudate
atrophy
○ Usually presents between the ages of 20 to 50
 Misc info:
○ Age of onset is variable but typically the more
repeats you have the earlier the onset of the
disease
○ Watch out for ethical issues!
Autosomal Dominant Dz’s
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Marfan’s Syndrome
 Genetics and Cell Level:
○ Mutation in the fibrillin gene (Chrom 15)
 Phenotypic Traits:
○ Connective tissue disorder affecting skeleton,
heart, and eyes
 Clinical Presentation: tall with long extremities,
pectus excavatum, hyperextensive joints, and
long tapering fingers and toes
 Misc info:
○ Cystic medial necrosis of the aorta leads to aortic
incompetence and dissecting aortic aneurysms
○ Floppy mitral valve
○ Subluxation of lenses
Marfan’s Syndrome
Autosomal Dominant Dz’s
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Multiple Endocrine Neoplasia (MEN)
Type 1
Type 2a
Type 2b
Eponym
Wermer’s syndrome
Sipple Syndrome
MEN 3 (old name)
Clinical
Pancreatic tumors,
Parathyroid
adenoma, Pituitary
hyperplasia
Parathyroid
hyperplasia, Medullary
thyroid carcinoma,
phechromocytoma
Medullary thyroid
carcinoma,
phechromocytoma,
marfanoid habitus,
mucosal neuromas
Gene
MEN1
RET proto-oncogene
RET protooncogene
Misc
Spontaneous
mutation rate ~50%
Autosomal Dominant Dz’s
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Neurofibromatosis 1 (NF1/von
Recklinghausen’s dz)
 Genetics and Cell Level:
○ Mutation on chromosome 17q11 (long arm of
17)
 Clinical Presentation: café-au-lait spots,
neural tumors, Lisch nodules (pigmented iris
hamartomas)
 Misc info:
○ Increased incidence of pheochromocytomas,
susceptibility to tumors, and skeletal disorders
NF1
Autosomal Dominant Dz’s
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Neurofibromatosis 2 (NF2)
 Genetics and Cell Level:
○ Mutation on chromosome 22q12
 Clinical Presentation: bilateral acoustic
neuromas on CN8, juvenile cataracts
○ Tumors may cause tinnitus, HA, hearing loss,
balance problems, vertigo, etc.
Autosomal Dominant Dz’s
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Tuberous Sclerosis
 Genetics and Cell Level:
○ Incomplete penetrance, 2/3 of new cases
arise from spontaneous mutations
 Clinical Presentation: facial lesions
(adenoma sebaceum), hypopigmented “ash
leaf spots”, cortical and retinal hamartomas,
seizures, mental retardation, renal cysts and
angiomyolipomas, cardiac rhabdomyomas,
increased incidence of astrocytomas
 Misc:
○ Needless to say presentation is VERY
variable
Tuberous Sclerosis:
“Ash Leaf Spot”
Autosomal Dominant Dz’s
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Von Hippel-Lindau disease
 Genetics and Cell Level:
○ Deletion of VHL gene (tumor suppressor) on
chromosome 3, results in expression of HIF and
activation of angiogenic growth factors
 Phenotypic Traits:
○ Hemangioblastomas of retina/cerebellum/medulla
○ About ½ of affected develop multiple b/l renal cell
carcinomas and other tumors
 Clinical Presentation: miscellaneous can be
discomfort from growing tumors or blindness 2/2
tumors in retina
Autosomal Recessive Dz’s
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a1-antitrypsin deficiency
 Genetics and Cell Level:
○ Serine protease inhibitor important for elastase
 Clinical Presentation: COPD and cirrhosis in
early adulthood
 Misc:
○ Important when presented with pt who has COPD
sx’s and has only smoked for a few years
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PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342
PiS is caused by a glutamate to valine mutation at position 264
Autosomal Recessive Dz’s
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Cystic Fibrosis: this one is important
 Genetics and Cell Level:
○ CFTR gene mutation on chrom 7 DF508
classically (loss of phenylalanine)
○ Defective Cl channel
 Clinical Presentation: secretion of abnl thick
mucus into lungs, pancreas, and liver
○ Pulm infections (P. aeruginosa and S. aureus)
○ Chronic bronchitis, bronchiectasis, pancreatic
insufficiency, male infertility (absence of vas
deferens)
Autosomal Recessive Dz’s
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Cystic Fibrosis (cont.)
 Diagnosis:
○ increased concentration of Cl in sweat test
 Treatment:
○ N-acetylcysteine to loosen mucus plugs
 Misc:
○ If presented with . . . THINK CF!
 newborn with meconium ileus or failure to thrive
 Fat soluble vitamin deficiency
 Pancreatic insufficiency
Autosomal Recessive Dz’s
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PKU
 Genetics and Cell Level:
○ Defect in phenylalanine hydroxylase which
converts Phe to Tyr
 Clinical Presentation: Mental retardation,
seizures, albinism, “musty odor” to urine and
sweat
 Misc:
○ Very treatable diet low in Phe and high in Tyr
○ Newborn screening is Mandatory!
Autosomal Recessive Dz’s
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Sickle Cell Disease
 Genetics and Cell Level:
○ Point mutation in Beta-globin chain
 Glutamic acid to Valine
 Clinical Presentation:
○ Heterozygotes usually clinically silent but added
protection to malaria
○ Homozygotes: symptoms are complications of
sickled RBC  must be vaccinated against S.
pneumo before loss of spleen
 Hyposplenism, vaso-occlusive crises, many other
complications including priaism, stroke, etc.
 Misc: Parvovirus B19 can cause aplastic crisis
 Treatment: Hydroxyurea, Folic acid, pain control
for vaso-occlusive crises
X-Linked Recessive Dz’s
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Fragile X (most common inherited form of retardation)
 Genetics and Cell Level:
○ Expansion of CGG on chrom X (FMR1 gene), full mutation is >
200 repeats
○ Associated with chromosomal breakage (hence the name)
 Clinical Presentation
○ Mental retardation ranges from mild to severe
○ Also autism, elongated face, large or protruding ears, flat feet,
macroorchidism, and low muscle tone
○ Fragile X = eXtra-large testes, jaw, and ears
 Misc: Presentation is variable but si/sx fall into six classic
categories
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Intelligence and learning
Physical
Social and emotional
Speech and language
Sensory
Disorders commonly associated or sharing features with Fragile
X
X-Linked Recessive Dz’s
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Hemophilia A
 Genetics and Cell Level:
○ Loss of Factor VIII
 Clinical Presentation: Increased PTT but
normal PT and bleeding time
○ Bleeding can occur into many sites most
common are joints, brain, muscles, and GI
tract
 Treatment is with Factor VIII
○ If dz is caused by low levels of Factor VIII and
not loss then desmopressin can be used
X-Linked Recessive Dz’s
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Hemophilia B aka Christmas Dz
 Genetics and Cell Level:
○ Loss of Factor IX
 Clinical Presentation: Increased PTT but
normal PT and bleeding time
○ Bleeding can occur into many sites most
common are joints, brain, muscles, and GI
tract
 REVIEW THE CLOTTING CASCADE
X-Linked Recessive Dz’s
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G6PD (aka Favism)
 Genetics and Cell Level:
○ Defect in glucose 6-phosphate
dehydrogenase
 Clinical Presentation:
○ Prolonged neonatal jaundice can be
complicated by kernicterus
○ Acute hemolytic anemia in the presence of
simple infection, fava beans, or rxn with
certain medicines (antibiotics, antipyretics,
and antimalarials)
 Misc: Look for Heinz bodies on peripheral
smear in active process
G6PD
Muscular Dystrophies
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Duchenne’s
 Genetics and Cell Level:
○ Frame shift mutation in dystrophin gene (DMD)
leads to deletion and accelerated muscle
breakdown.
○ Dystrophin anchors muscle fibers, primarily
skeletal and cardiac muscles
 Clinical Presentation: Dx by increased CPK and
muscle biopsy, onset before age 5
○ Weakness begins in pelvic girdle and progresses
superiorly
○ Pseudohypertrophy of calf muscles 2/2 fibrofatty
replacement of muscle
 Misc: Look for use of Gower’s maneuver
Gower’s maneuver
Muscular Dystrophies
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Becker’s
 Genetics and Cell Level:
○ Defect in dystrophin gene, less severe than
Duchenne’s defect
 Clinical Presentation:
○ Progressive muscle weakness, onset later
than Duchenne’s
 Misc: dx is similar to Duchenne’s
Autosomal Trisomies
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Down Syndrome (Trisomy 21)
 Most common chromosomal disorder and most
common cause of congenital mental retardation
 Diagnosis done by triple screen
○ decr. a-fetoprotein, estriol, incr. b-hCG
○ Quad screen is above plus inhibin A (incr is +)
○ U/S shows increased nuchal translucency
 Clinical Presentation:
○ Mental retardation, flat facies, prominent
epicanthal folds, simian crease, duodenal atresia,
congenital heart dz (septum primum type ASD),
hypotonia
 Misc: increased risk of ALL and Alzheimer's dz
Autosomal Trisomies
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Down Syndrome (Trisomy 21) (cont.)
 95% of cases due to meiotic nondisjunction
of homologous chromosomes
○ Associated with advanced maternal age
 1:1500 at maternal age 20-24
 1: 210 at maternal age 35-39
 1: 25 at maternal age >45
 4% of cases due to Robertsonian
translocation
○ Long arm of chrom 21 is attached to another
chromosome and is kept diploid during
gametogenesis
 1% of cases due to Down mosaicism
Down Syndrome
Autosomal Trisomies
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Edward’s Syndrome (Trisomy 18)
 Edward’s = Eighteen
 Most common trisomy in live birth after
Down syndrome (1:8000)
 Clinical Presentation:
○ Severe mental retardation, rocker-bottom feet,
micrognathia, low-set ears, clenched hands,
prominent occiput, congenital heart dz
 Misc: Death usually within one year of age
Autosomal Trisomies
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Patau’s Syndrome (Trisomy 13)
 Incidence is 1:15000
 Clinical Presentation:
○ Severe mental retardation, rocker-bottom feet,
microphthalmia, microcephaly, cleft lip/Palate,
holoProsencephaly, Polydactyly, congenital
heart dz (anyone see a theme??)
 Misc: Death usually within 1 year of birth
Nondisjunction
Cri-du-Chat syndrome
 Genetics and Cell Level:
○ Congenital microdeletion of short arm of
chromosome 5 (46 XX or XY, 5p-)
 Clinical Presentation:
○ Microcephaly, moderate to severe mental
retardation, epicanthal folds, cardiac
abnormalities
 Misc: Cri-du-chat is French for cry of the cat.
The disease is named this way as the
children affected make a high pitched
mewing/crying sound.
Williams syndrome
 Genetics and Cell Level:
○ Congenital microdeletion of long arm of
chromosome 7 (46 XX or XY, 7q-) which
includes the elastin gene
 Clinical Presentation:
○ Distinctive “elfin” facies, mental
retardation, well-developed verbal skills,
cheerful disposition, extreme friendliness
with strangers, cardiovascular problems
22q11 deletion syndromes
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Variable presentation includes
 Cleft palate
 Abnormal facies
 Thymic aplasia which leads to T-cell
deficienies
 Cardiac defects
 Hypocalcemia 2/2 parathyroid aplasia
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CATCH-22
22q11 deletion syndromes
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Aberrant development of 3rd and 4th
branchial pouches
 DiGeorge Syndrome:
○ Thymic, parathyroid (hypocalcemia), and
cardiac defects
 Cardiac defects include Tetralogy of Fallot, VSD, and
perisistent truncus arteriosus
 Velocardiofacial syndrome:
○ Palate, facial, and cardiac defects
Hardy-Weinberg Genetics
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If a population is in HW equilibrium and p
and q are separate alleles then
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Disease prevalence: p2 + 2pq + q2 =1
Allele prevalence: p +q = 1
2pq = heterozygote prevalence
The prevalence of an X-linked recessive dz in
males = q and in females is q2
Hardy-Weinberg laws
1. No mutation occurring at the locus
2. No selection for any of the genotypes at the
locus
3. Completely random mating
4. No migration