genetic disease

  1. What is the genome?
    • total DNA content of a cell
    • makes up the entire genetic information available to the organism
    • encodes all the info for cellg rowth, division, and responsiveness to environment
    • organized in to 23 linear double stranded DNA molecules
    • somatic cells have 2 copies of each chromosome
    • 30,000 - 40,000 genes
  2. What is clinical cytogenetics?
    cell genome at metaphase constitutional karyotype
  3. What are some of the abnormalities of chromosome?
    number and structure
  4. What are the number abnormalities of chromosome?
    • aneusomy (abnormal # of chromosome)
    • monosomy
    • trisomy
  5. what are the structure abnormalities of chromosome?
    • translocations and their derivatives
    • deletions, duplications, rings
    • inversions and their recombinants
  6. Abnormalities can fall into 2 categories:
    • de novo
    • sporadic
  7. Mutations as a cause of disease - likely to be disease causing if what?
    • does not occur in the normal population
    • alters the protein function of expression
    • segregates with disease in a given family and is absent in unaffected family members
  8. what are the etiologies of genetic disease?
    • 1. chromosomal - genomic imbalances
    • 2. multifactorial - genes + environment
    • 3. single gene disorders - autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant
  9. What are the indications for constitutional cytogenetic studies (8)?
    • *cytogenetic studies are performed to diagnose and understand genetic diseases, including cancer
    • documentation of a cytogenetic syndrome
    • multiple congenital abnormalities w/o a known etiology
    • developmental delay and minor anomalies
    • rare diseases with unusual presentation
    • family history of the above
    • history of a familial chromosomal abnormality
    • intrauterine growth retardation or failure to thrive w/o a known etiology
    • history of spontaneous abortions
  10. Trisomy 21 is also known as....
    Down Syndrome
  11. What is the most common chromosomal abnormality in live born individuals?
    Trisomy 21 - Down Syndrome
  12. What is the most common cause of cognitive disability?
    Trisomy 21 - DOwn Syndrome
  13. What are the characteristic phenotype of Trisomy 21/ Down Syndrome?
    • short stature
    • microcephaly
    • small mouth, oral cavity -> tongue thrusting
    • epicanthic folds
    • cardiac anomaly
  14. What is the seen with trisomy and maternal age?
    • positive correlation with incidence of trisomies 21, 18, and 13 with advanced maternal age
    • older than 35 yrs. old
  15. Where in the cell cycle does Trisomy 21/Down Syndrome happen?
    amternal meiosis I nondisjunction
  16. Genetic counseling is offered for who?
    • for advanced maternal age
    • 35 y.o women
  17. What is the risk for autosoma trisomies and AMA for Trisomy 21, 18, 13?
    • Trisomy 21: 1/650
    • Trisomy 18: 1/8000
    • Trisomy 13: 1/20,000
  18. What is the risk for Down Syndrome child with mother being 30, 35, 40 yrs. old?
    • age 30: 1%
    • age 35: 2.8%
    • age 40: 10.4%
  19. What are the prenatal cytogenetic tests?
    • 1. chorionic villus sampling
    • 2. amniocentesis
  20. For chorionic villus sampling, when is it performed? risk for miscarriage?
    • performed at 10-12 wks gestation
    • cultured cells from extraembryonic chorionic mesoderm in 5-7 days
    • rapid results early in gestation
    • procedure -related risk for miscarriage = 1%
  21. for amniocentesis, when is it performed? risk of miscarriage? and others?
    • when - 15-18 wks gestation
    • amniotic fluid contains true embryonic fetal cells
    • in situ cell culture: 5-10 days
    • procedure-related risk for miscarriage = 0.5%
  22. what % of Trisomy 21 are familial?
  23. Another cause for Down Syndrome besides nondisjuction is what?
    Robertsonian translocation
  24. what is Robersonian translocation
    centric fusion of 2 acrocentric chromosomes
  25. If Robertsonian translocation is balanced, what happened?
    no phenotype
  26. What happens when Robertsonian translocation is not balanced?
    risk to have offspring with unbalanced karyotypes: 46 chromosomes, 3 copies of chromosome 21 -> Down Syndrome
  27. With Down Syndrome, what are the oral anomalies?
    • Palate with v-shaped high vault
    • angle of the mouth pulled down (result of hypotonic musculature)
    • small oral cavity - protruding tongue creates speech and articulation problems
  28. For Down Syndrome, what are the dental anomalies?
    • 30-50% have microdontia - affects primary and secondary dentition
    • supernumery teeth
    • abnormal spacing
    • crown variants
    • hypoplasia and hypocalcification
    • delayed eruption
    • increased risk of periodontal disease
  29. Loss of a portion of a chromosome is caused by what 3 things?
    • loss of DNA segment
    • loss of contiguous genes
    • monosomy for these genes
  30. What are the names of the syndrome cause by 22q11 deletion?
    • DiGeorge syndrome
    • Velo-cardio-facial syndrome (VCF)
    • Opitz syndrome
    • Conotruncal anaomlay face syndrome
  31. Infant with cardiac anomaly of term baby with uneventful pregnancy history, cleft lip and palate, hypocalcemia, ventricular septal defect, and absent thymus will have what deletion?
  32. What happened in and is the characteristics of DiGeorge, Velocardiofacial, Shprintzen Syndromes?
    • disturbances of migration of neural crest cells into pharyngeal arches and pouches
    • thymic aplasia, hypoplasia -> T cell immune dysfunction
    • parathyroid hypoplasia -> hypocalcemia
    • midline defects -> clefts, conotruncal heart defects
  33. What is the variability in the phenotype of DiGeorge/Velocardiofacial Syndrome?
    • cleft palate - almost always
    • cardiac disease - frequent
    • typical faces (often, subtle)
    • learning disabilities - frequent
  34. What is spectrum of findings for 22q11 Deletion Syndrome?
    • cardiac abnormalities (74%)
    • palatal anomalies (69%) - cleft palate, submucosal cleft...
    • facial features - long,narrow face, beaked nose
    • learning disabilities (70%)
    • immunodeficiency (77%)
    • other features, feeding problems, renal, hypocalcemia, hearing loss
  35. For DiGeorge, Velocardiofacial, Shprintzen Syndrome, how is their phenotype? What do they have in common? Sporadic or familial? How to test for it?
    • phenotypic spectrum
    • share same mutation - 3Mb deletion w/in 22q11
    • most sporadic, 10% familial
    • FISH testing of family members
  36. Newest technology of Microarray. Describe what it does.
    • Like thousands of FISH experiment
    • detection of small mutations - DNA sequence gains and losses
    • microdeletion syndrome detection
    • Polymorphic DNA sequence gains and losses
    • Patient DNA combine with control DNA. normal = yellow. red=loss. green = gain
    • target DNA on slide is single stranded oligomers

    • can be done with 5 different patients of same sex
    • limited ability to detect mosaicism
  37. what are the advantages of chromosomal microarray.
    • Detects chromosomal gains and losses
    • 1 array = 180,000 FISH studies
    • detects abnormalities in known "hot spots"
    • can be use to characterize chromosome abnormalities detected by karyotyping
    • genome-wide arrays may also detect abnormalities in "backbone" of genome
  38. What are the limitations of CMA?
    • cannot detect balanced rerrangments
    • cannot detect specific genetic/ DNA mutations, single base pair changes
    • detectin of copy number variants (CNVs) may have unclear clinical significance
    • may not detect low-level mosaicism
  39. What is the cause of monogenic, Mendelian disorders?
    single gene defects
  40. When is monogenic, Mendelian disorders expressed? what is the incidence? Can it be inherited?
    • usually expressed in childhood
    • incidence, about 0.36% in liveborn population
    • 1-3% of children have some congenital malformation - half involve oral/facial
    • heritable genetic disorders
  41. In automsomal dominant inheritance of single gene disorders, what characteristic do you see in family? What percentage that child will receive it? Need how many allele to cause phenotype?
    • phenotype expressed in every generation
    • 50% risk of inheriting trait of affected parent
    • mutation in 1 allele causes phenotype
  42. Hungtingon disease is an example of what type ?
    autosomal dominant gene mutations
  43. Cause of Hungtington disease?
    mutation in Huntington gene - amplification of trinucleotide repeat (CAG)
  44. Huntington disease causes what?
    adult onset neurodegenterative disorder
  45. Incidence of Huntington disease.
    1/10,000 indiv of European origin
  46. How to confirm Huntington Disease?
    through DNA testing for CAG repeat size
  47. What are several of other autosomal dominant gene mutations other than Huntington's disease?
    • Familial Hypodontia
    • Mesiodens
    • Amelogenesis imperfecta, hypocalcified type
  48. What is familial hypodontia?
    mild reduction of number of teeth
  49. What is mesiodens?
    supernumberary tooth, between max central incisors
  50. What is amelogenesis imperfecta, hypocalcified type?
    • normal quantity of enamel but soft
    • improper differentiation of emaloblasts -> brown color
    • 70% of AI is this form
    • prevalence 1/14,000 live births
  51. Describe autosomal recessive.
    • rare diseases: expression of phenotype requires 2 alleles
    • carriers have one normal allele with no phenotype
    • recurrence risk for each sibling of proband is 1 in 4
    • phenotype observed among siblings of the proband, not parents, offspring, or other relatives
  52. What are some examples of autosomal recessive disorders?
    • cystic fibrosis - abnormal ion transport protein
    • sickle cell anemia - abnormal hemoglobin
    • Phenylketonuria (PKU) - enzyme deficiency
  53. What are the characteristic of autosomal recessive disease Ellis van Creveld syndrome?
    • postaxial polydactyly
    • short stature, shortening of forearms and lower legs
    • congenital heart malformations
    • dysplastic nails and teeth
    • caused by mutations in EVC gene, chromosome 4, p16 responsible for phenotype
  54. Describe X-linked diseases.
    • mutation of genes on X chromosome
    • phenotypic expression generally in males
    • all daughters of affected males carry his X chromosome
    • sons of carrier females are at 50% risk for inheritance of mutated gene
  55. Example of X-linked disease.
    • amelogenesis imperfecta, X-lined hypoplastic type
    • in males, thin smooth enamel
    • in females, enamel with vertical furrows
  56. what is lyonization?
    random X inactivation in females
  57. What is the Lyon hypothesis?
    • Single active X chromosome in mammals
    • functionally hemizygous
    • mechanism for dosage compensation
    • random inactivation of maternal or paternal X chromosome early in female embryogenesis
    • Fidelity of X(matern) or X(patern) inactivation in clonal descendents
    • skewing of X inactiviation for tissue specificicity
  58. Genetic heterogeneity?
    mutations of more than 1 gene cause the SAME DISORDER
  59. clinical heterogeneity?
    mutations in same gene cause DIFFERENT disorders
  60. de novo (new) mutation?
    no family history
  61. variable expresssivity?
    trait is expressed differently among individuals carrying same mutatnt gene, even win a family
  62. What is the sex ration for cleft lip with or w/o cleft palate? results from what? heterogeneity?
    • sex ration - 2 Males 1 Females
    • CL/P results from failure of lip closure w/ secondary failure of palate closure
    • genetic heterogeneity - mixture of genese and environmental factors
  63. For cleft lip, what is the percentages of isolated cases, familial, and syndromic forms?
    • isolated cases - 75-80% (multifactorial)
    • familial, single gene forms (10-15%)
    • syndromic forms (1-5%)
  64. What is the most common single-gene cleft syndrome? mode of inheritance?
    • Van der Woude syndrome
    • autosomal dominant
  65. What are the dental anomalies for Van der Woude syndrome?
    • cleft lip w/ or w/o palate
    • cleft uvula
    • lower lip pits
    • hypodontia or missing lateral or central incisor
  66. What is the genetics for Van der Woude syndrome?
    • autosomal dominant
    • mutations in IRF6 in 70% of cases
    • clinical heterogeneity
  67. what is holoprosencephaly (HPE)?
    • developing forebrain fails to divide into 2 separate hemispheres/ventricles
    • with about 80% have associated craniofacial anomalies
    • genetic heterogeneity = 25-50% numberical/structural chromosome anomaly
    • 18-25% recognizable syndrome
  68. How is nonsyndromic HPE inherited? expressions?
    • inherited in autosomal dominant manner
    • extreme variability of phenotype
    • mild expression - microcephaly, singl central incissor, hyptelorismm midfacial hypoplasia, cleft lip
  69. Nonsyndromic HPE mutations where?
    in more than 4 genes account for 40-50% of HPE
  70. AI heterogeniety?
    clinical and genetic heterogeniety
  71. AI causes what?
    • defect of dental enamel formation
    • teeth are small, discolored, grooved or pitted, and prone to rapid wear and breakage
  72. What are the 4 main types of AI?
    • hypoplastic
    • hypomaturation
    • hypocalcified
    • hypomaturation/hypoplasia/taurodontism
  73. What is osteogenesis imperfecta (OI)?
    • group of genetic disorders due to improper formation of type I collagen
    • range from lethal(Type II) to mild (type I)
  74. wut is the clinical features of OI?
    • multiple fractures
    • short stature
    • hearing loss
    • blue sclera
    • dentinogenesis imperfecta
  75. what is the caracteristic tooth crown color for dentinogenesis imperfecta (DI)?
    • blue gray or yellow brown and translucent
    • caused by defective, abnormally colored dentin shining thru the overlying enamel
    • underlying defective dentin not able to adequately support the unaffected enamel
    • often flakes off
  76. There are 2 types of Dentinogenesis imperfecta. what is it?
    • Type I - associated with osteogenesis imperfecta
    • Type II - most common. no increased frequencey of bone fractures
  77. Inheritance for OI/DI.
    autosomal dominant
  78. What is ectodermal dysplasia?
    • primary defect in development of 2 or more tissues derived from ectodermal layer (hair, skin, nails, teeth)
    • more than 2190 hundred clinically distinc syndromes - ectodermal dysplasia type I (ED1) most common
  79. What is Christ-Siemens-Touraine syndrome? Inherited as? caused by?
    • Ectodermal dysplasia I
    • inherited as X-linked recessive
    • caused by mutation in ectodysplasin A gene
  80. Characteristic of ED1 Christ-Siemens-Touraine syndrome?
    • prominent forehead
    • sunken nasal bridge
    • unusually thick lips
    • large chin
    • eye abnormalities, decreased tearing
  81. ED1 in skin.
    • partial of complete absense of certain sweat glands
    • soft thin and dry skin
    • skin peeling/scaling and eczema
  82. ED1 with nails.
    spoon shaped nails
  83. ED1 with hair.
    • fine, brittle and scant hair (hypothrichosis)
    • absent or scanty eyelashes and eyebrows
  84. ED1 in teeth.
    • malformation of certain teeth: conical or pegged teeth, hypodontia or complete anodontia, delayed eruption of permanent teeth
    • jaw radiographs indicated for infants w/ fever of unknown origin and family history of EDs
  85. hamartoma?
    benign focal malformation that resembles neoplasm in the tissue of origing
  86. What is Cowden syndrome?
    • multiple hamartoma syndrome
    • clinical features:
    • gingival and palatal lesions; cobbestone appearance
    • thickening or furrowing of tongue
    • facial tricheilemmonas
    • multiple skin tags
    • subcutaneous lipomas
  87. How is Cowden syndrome inherited? age related penetrance? Increased risk for what kind of cancer? Gene mutation?
    • autosomal dominant
    • age related penetrance
    • PTEN gene mutation
    • increase risk for cancer - breast, thyroid, endometrial
  88. How is familial adenomatous polyposis inherited? mutation in what? % of de novo germline mutations?
    • autosomal dominant
    • mutations in APC tumor suppressor gene
    • 30% de novo germline mutations
  89. Clinical features of FAP?
    • hundred to thousands of adenomas by early adulthood
    • untreated polyposis -> 100% risk of colorectal cancer
    • risk of extracolonic tumors
  90. A variant of FAP is what syndrome?
    Gardner's syndrome
  91. Gardner's syndrome has what kind of lesions?
    • extraintestinal:
    • desmoid tumors
    • osteomas
    • supernumery teeth
    • soft tissue skin tumors
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