week 2

Steven Katz, MSIV

Genetics Terms

Basic Terms (Review)Gene: A hereditary unit consisting of a sequence of

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.) High Yield Terms:

Classical Dominance: Dominant allele is 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.) 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 Definition: At a single locus, only one allele is

active, the other is inactive; can also occur as a result of uniparental disomyPhenotype depends on origin of mutation paternal

v. maternal Both syndromes due to inactivation or deletion

of genes on chromosome 15 Prader-Willi: Deletion of normally active

PATERNAL alleleMental retardation, obesity, hypogonadism,

hypotonia 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 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 X-linked recessive: only sons of

heterozygous mothers can be affected, no father to son transmission. Examples: Fragile X, Lesch-Nyhan, Hemophilia

A and BFemales may rarely be affected due to random

inactivation of X chrom (e.g. Lyonization)

Modes of Inheritance 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 Mitochondrial: Transmission ONLY

through the mother. All offspring of affected mothers are affected. Variable expression due to heteroplasmy

Autosomal Dominant Dz’s

AchondroplasiaGenetics and Cell Level:

○ Defect in Fibroblast Growth Factor receptor 3Causes 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


APKD (adult polycystic kidney dz)Genetics and Cell Level:

○ 90% due to mut in APKD1 on chromosome 16Phenotypic 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


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


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


Huntington’s DiseaseGenetics and Cell Level:

○ Gene located on Chromosome 4, trinucleotide repeat disorder (CAG)n

○ Decreased levels of GABA and Ach in the brainClinical 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!


Marfan’s SyndromeGenetics 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


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 proto-oncogene

Misc Spontaneous mutation rate ~50%


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


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.


Tuberous SclerosisGenetics 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”


Von Hippel-Lindau diseaseGenetics 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 tumorsClinical Presentation: miscellaneous can be

discomfort from growing tumors or blindness 2/2 tumors in retina

Autosomal Recessive Dz’s

1-antitrypsin deficiencyGenetics and Cell Level:

○ Serine protease inhibitor important for elastase Clinical Presentation: COPD and cirrhosis in

early adulthoodMisc:

○ Important when presented with pt who has COPD sx’s and has only smoked for a few years

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


Cystic Fibrosis: this one is importantGenetics and Cell Level:

○ CFTR gene mutation on chrom 7 F508 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)


Cystic Fibrosis (cont.)Diagnosis:

○ increased concentration of Cl in sweat testTreatment:

○ N-acetylcysteine to loosen mucus plugsMisc:

○ If presented with . . . THINK CF!newborn with meconium ileus or failure to thriveFat soluble vitamin deficiencyPancreatic insufficiency


PKUGenetics 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!


Sickle Cell DiseaseGenetics 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 spleenHyposplenism, vaso-occlusive crises, many other

complications including priaism, stroke, etc. Misc: Parvovirus B19 can cause aplastic crisisTreatment: Hydroxyurea, Folic acid, pain control

for vaso-occlusive crises

X-Linked Recessive Dz’s 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○ 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

Hemophilia AGenetics and Cell Level:

○ Loss of Factor VIIIClinical 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

Hemophilia B aka Christmas DzGenetics and Cell Level:

○ Loss of Factor IXClinical 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 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

Muscular Dystrophies 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 muscleMisc: Look for use of Gower’s maneuver

Gower’s maneuver

Muscular Dystrophies

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’sMisc: dx is similar to Duchenne’s

Autosomal Trisomies Down Syndrome (Trisomy 21)

Most common chromosomal disorder and most common cause of congenital mental retardation

Diagnosis done by triple screen○ decr. -fetoprotein, estriol, incr. -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 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 20-241: 210 at maternal age 35-391: 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

Edward’s Syndrome (Trisomy 18) Edward’s = EighteenMost 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

Patau’s Syndrome (Trisomy 13)Incidence is 1:15000Clinical 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 syndromeGenetics 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

Variable presentation includesCleft palateAbnormal facies Thymic aplasia which leads to T-cell

deficieniesCardiac defectsHypocalcemia 2/2 parathyroid aplasia

CATCH-22

22q11 deletion syndromes

Aberrant development of 3rd and 4th branchial pouchesDiGeorge Syndrome:

○ Thymic, parathyroid (hypocalcemia), and cardiac defectsCardiac defects include Tetralogy of Fallot, VSD, and

perisistent truncus arteriosus

Velocardiofacial syndrome:○ Palate, facial, and cardiac defects

Hardy-Weinberg Genetics

If a population is in HW equilibrium and p and q are separate alleles then Disease prevalence: p2 + 2pq + q2 =1Allele prevalence: p +q = 1 2pq = heterozygote prevalenceThe prevalence of an X-linked recessive dz in

males = q and in females is q2 Hardy-Weinberg laws

1. No mutation occurring at the locus2. No selection for any of the genotypes at the

locus3. Completely random mating4. No migration

week 2

Documents

dominant allele

linked dominant

dominant disorders

cell level

offspring of affected

dominant negative mutation

females of affected

chromosome 5q21