Genetic Disorders (from Pathology)

Question 1

Autosomal Dominant Diseases

Answer 1

• ADPCK
• Huntington Chorea
• Marfan Syndrome
• Familial hypocholesterolema
• Osteogenesis Imperfecta
• Achondroplasia short-limed dwaris

Question 2

Autosomal Recessive Diseases

Answer 2

• Lysosomal Storage Diseases
• Sickle Cell anemia
• Cystic fibrosis
• Tay sachs
• Glycogen storage disease
• Mucopolysaccharidoses (Hurler, Hunter syndromes)

Question 3

Autosomal Chromosome (Cytogenetic) Disorders

Answer 3

• Trisomy 21
• Trisomy 13 (Patau)
• Trisomy 18 (Edward)

Question 4

Sex Chromosome (Cytogenetic) Disorders

Answer 4

• Kleinfelter Syndrome
• Turner Syndrome
• Triple XXX
• XYY

Question 5

X-Linked Recessive Diseases

Answer 5

• Duchenne Muscular Dystrophy

Question 6

X-linked Dominant Diseases

Answer 6

• Fragile X
• Rett syndrome

Question 7

ADPCK

Answer 7

• Definition:
• Etiolathogenesis: autosomal dominant mutation in PKD1 and 2, which encode for polycystin
• Clinical: cysts in kidney, pancreas, spleen, lung, aneurysm of circle of Willis

Question 8

Huntington Chorea

Answer 8

• **Definition: **autosomal dominant disease characterized by progressive movement disorders and dementia
• **Etiopathogenesis: **unstable CAG repeats in HTT, toxic gain of function in the protein, high penetrance, shows anticipation in following generations
• **Clinical: **movement disorders, dementia

Question 9

Marfan Syndrome

Answer 9

• Definition: autosomal dominant disorder characterized by skeletal abnormalities
• Etiopathogenesis: defect in extracellular glycoprotein fibrillin-1 due to mutations of *FBN1 *or FBN2
• **Clinical: **
  
  • ​skeletal- pectus, scoliosis, joint laxity, arachnodactility, tall stature, long extremities
  • cardio- aortic dilation, cystic medionecrosis, mitral valve prolapse
  • ocular- ectopia lentis

Question 10

Sickle Cell Anemia

Answer 10

• **Definition: **autosomal recessive disorder characterized by formation of sickled RBCs
• **Etiopathogenesis: **point missense mutation in Hemoglobin A which changed glutamic acid into valine, causes new hydrophobic patch which causes aggregation of hemoglobin; sickled cells cannot move thru capillaries well, causes hypoperfusion and blood vessel occlusion
• **Clinical: **​heterozygotes: have protective factor for malaria

Question 11

Mucopolysaccharidosis IH (Hurler Syndrome)

Answer 11

• Definition: lysosomal storage disease
• Etiopathogenesis: autosomal recessive, deficiency in alpha-1-iduronidase enzymes, accumulates heparan, sulfate, dermatan sulfate, mucopolysaccharides in mononuclear phagocytes, fibroblasts, endothelial cells
• Clinical: coarse facial features, hepatosplenomegaly, corneal clouding, valve and subendothelial arterial thickening, mental retardation

Question 12

Familial Hypercholesterolemia

Answer 12

• **Definition: **autosomal dominant hyperlipidemia disorder
• Etiopathogenesis: mutation in LDL receptor, elevated serum cholesterol
• **Clinical: **early onset atherosclerosis

Question 13

Kleinfelter Syndrome

Answer 13

• **Definition: **sex chromosome hypogonadism disorder in males
• **Etiopathogenesis: **47, XXY; meotic non-disjunction
• **Clinical: **tall stature, gynaecomastia, infertility, mild learning difficulties, eunuchoid body habitus, no male secondary sex characteristics, atrophic testes, FSH and estrogen elevated, low testosterone

Question 14

Turner Syndrome

Answer 14

• **Definition: **sex chromosome hypogonadism disorder in females
• **Etiopathogenesis: **45, X, partial or complete monosomy of shot arm of X chromosome
• **Clinical: **short stature, low posterior hairline, webbing of neck, coarctation of aorta, streak ovaries, infertility, amenorrhea, peripheral lymphedema at birth

Question 15

Trisomy 21 (Down Syndrome)

Answer 15

• Definition: chromosomal disorder where chromosome 21 has an extra copy
• **Etiopathogenesis: **
  
  • ​47, XY or XX, +21** caused **by meiotic nondisjunction
  • 46, XY or XX,der(14;21)(q10;q10), +21 robertsonian translocation
  • 46, XX or XY/ 47, XX or XY, +21 mosaic caused by mitotic nondisjunction in embryogenesis
• Epidemiology: 47 XY, +21 heavily infuenced by maternal age
• **Clinical: **mental retardation, epicathic folds, flat facial profile, simian crease, congential heart defects, Alzheimer’s, acute megakaryoblastic leukemia

Question 16

Trisomy 18

Answer 16

• **Definition: **chromosomal disorder where chromosome 18 has an extra copy
• **Etiopathogenesis: **
  
  • 47, XX or XY, +18 meiotic nondisjunction
  • 46, XX or XY/ 47, XX or XY, +18 mitotic nondisjunction
• Clinical: mental retardation, low set ears, congential heart defects (ventricular septal defect), horseshoe kidney, rocker bottom feet

Question 17

Trisomy 13

Answer 17

• **Definition: **chromosomal disorder where chromosome 13 has an extra copy
• Etiopathogenesis:
  
  • ​47, XX or XY, +13 meiotic nondisjunction
  • translocation type (chromosomes 13 and 14)
  • mosaic type
• **Clinical: **microphthalmia, microencephaly, mental retardation, polydactly, cleft lip and palate, cardiac defects, umbilical hernia, rockerbottom feet, most children die in first year

Question 18

Wiliams Syndrome

Answer 18

• **Definition: **gene mutation disease
• **Etiopathogenesis: **microdeletion in chromosome 7
• **Clinical: **distinct facial appearence, cardiovascular abnormalities, mental retardation, distinctive congitive profile

Question 19

Tay Sachs

Answer 19

• **Definition: **autosomal recessive lysosomal storage disease
• **Etiopathogenesis: **autosomal recessive, mutations in hexosaminidase, neurons rich in galgiosides, lipid accumulation in retinal ganglion cells
• Epidemiology: found in Ashkenzazi Jews
• **Clinical: **motor and mental deterioration, death age 2-3yrs neuronal ballooning & destruction, cherry red macular choroid

Question 20

Osteogenesis Imperfecta

Answer 20

• **Definition: **autosomal dominant collagen disorder
• **Etiopathology: **type I and II caused by mutations in alpha-1 collagen
• **Clinical: **brittle bones, loose joints, type II: severe respiratory problems and early death

Question 21

Duchenne Muscular Dystrophy

Answer 21

• **Definition: **sex chromosome genetic disorder that causes muscular degeneration
• **Etiopathogenesis: **X-linked recessive mutation in dystrophin, protein that provides structural stability in muscle cell membranes
• **Clinical: **proximal muscle weakness, muscle wasting

Question 22

PCR

Answer 22

• method used for molecular genetic diagnosis that amplifies target DNA
• requires DNA template, oligonucleotide primers, thermostable polymerase, deoxynucleotides, magnesium-containing buffers
• Steps
  • DNA template heated to denature
  • cooled to hybridize and anneal primers
  • ​​mixture warmed to allow synthesis and extention of the sequences
• products analyzed via
  
  1. amplicon length analysis in gel electrophoresis (ex. triplet repeat disorders in Fragile X, Huntington’s)
  2. restriction fragment length analysis (ex. hereditary hemochromatosis)
  3. direct sequencing

Question 23

Restriction Endonucleases (Enzymes)

Answer 23

• method used for molecular genetic diagnosis that uses bacterially-derived endonucleases to cleave DNA at specific sequences
• after sequences are cut, they are run with gel electrophoresis to determine if mutations have removed restriction sequences

Question 24

Real-Time PCR

Answer 24

• method used for molecular genetic diagnosis
• DNA amplification and detection steps occur simultaneously, allowing quantificaiton of template
• fluorescent reporter binds to template DNA and emits light when it is removed by exonuclease in polymerase; emits light in direct proportion to the amount of the PCR produced
• flourescent reporter can be:
  
  • non-specific fluorescent dyes that intercalate with dsDNA
  • sequence-specific DNA probes that are labelled with fluorescent reporter which permits detection only after hybridization of the probe with its complementary sequence

Question 25

Next-Generation Sequencing

Answer 25

• method used for molecular genetic diagnosis that uses high thoughput sequencing
• parallelizes sequencing process, producing thousands/ millions of sequences at once
• sequencce can be analyzed hundreds of times, then sequences are aligned in order next to a base sequence
• mutations, large and small, can be identified
• ex. can help diagnose Marfan’s

Question 26

Comparative Genomic Hybridization Array

Answer 26

• ssDNA fragments from patient are hybridized with red fluorescent particle and reference DNA is hybridized with green fluorescent particle
• two DNA sequences are hybridized to a normal human template (compete for spots) and fluoresence is examined
  
  • equal expression: yellow
  • overexpression of sequence in patient: green
  • underexpression of sequence in patient: red
• ex. can be used to diagnose trisomy 18

Question 27

Single Nucleotide Polymorphism Array

Answer 27

• looks for sequencing containing specific polymorphisms
• can detect copy number variaiton and zygosity (genetic material missing from maternal or paternal alleles)
• ex. diagnose uniparental disomy (Angelman syndrome)

Question 28

What is Gaucher’s syndrome and why does it occur later in life?

Answer 28

lysosomal storage disease; lack of neural involvement