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 dzs 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. Huntingtons 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 Marfans syndrome) Heteroplasmy: Both NL and mut mtDNA results in variable expression in mitochondrial inherited dzs 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 disomy
Phenotype 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 allele
Mental retardation, obesity, hypogonadism,

hypotonia

Angelmans 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, Huntingtons 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, Wilsons 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 B Females 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 Dzs

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 Dzs

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 Dzs

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 Dzs

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 Dzs

Huntingtons 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 Dzs

Marfans 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

Marfans Syndrome

Autosomal Dominant Dzs

Multiple Endocrine Neoplasia (MEN)

Type 1 Type 2a Sipple Syndrome Type 2b MEN 3 (old name) Wermers syndrome

Eponym

Clinical

Pancreatic tumors, Parathyroid adenoma, Pituitary hyperplasia MEN1

Parathyroid hyperplasia, Medullary thyroid carcinoma, phechromocytoma RET proto-oncogene

Medullary thyroid carcinoma, phechromocytoma, marfanoid habitus, mucosal neuromas RET protooncogene
Spontaneous mutation rate ~50%

Gene
Misc

Autosomal Dominant Dzs

Neurofibromatosis 1 (NF1/von Recklinghausens dz)

Genetics and Cell Level: Mutation on chromosome 17q11 (long arm of 17) Clinical Presentation: caf-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 Dzs

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 Dzs

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 Dzs

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 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 Dzs

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

sxs 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

Autosomal Recessive Dzs

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 Dzs

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 Dzs

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 Dzs

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 Dzs

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 Dzs

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 Dzs

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 Dzs

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

Duchennes
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 Gowers maneuver

Gowers maneuver

Muscular Dystrophies

Beckers
Genetics and Cell Level: Defect in dystrophin gene, less severe than Duchennes defect Clinical Presentation: Progressive muscle weakness, onset later than Duchennes
Misc: dx is similar to Duchennes

Autosomal Trisomies

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

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

Edwards Syndrome (Trisomy 18)

Edwards = 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

Pataus 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

Variable presentation includes

Cleft palate
Abnormal facies Thymic aplasia which leads to T-cell

deficienies Cardiac defects Hypocalcemia 2/2 parathyroid aplasia

CATCH-22

22q11 deletion syndromes

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

If a population is in HW equilibrium and p and q are separate alleles then

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