Genetic Diseases

  1. At what stage is clinical cytogenetics captured?
    • Cell genome at metaphase
    • constitutional karyotype
  2. When is a mutation likely to be disease causing?
    • Does not occur in normal population
    • Alters the protein function or expression
    • Segregates with disease in a given family and is absent in unaffected family members
  3. What are some indications for constitutional cytogenetic studies?
    • documentation of a cytogenetic syndrome
    • multiple congenital abnormalities without a known etiology
    • developmental delay and minor anomalies
    • rare diseases with unusual presentation
    • family history (including chromosomal abnormality)
    • intrauterine growth retardation or failure to thrive without a known etiology
    • history of spontaneous abortions
  4. Which chromosomal abnormality is the most common abnormality in live born individuals and the most common cause of cognitive disability?
    Trisomy 21 (maternal meiosis I nondisjunction)
  5. What's a characteristic phenotype of Trisomy 21?
    • short stature
    • microcephaly
    • small mouth, oral cavity -> tongue thrusting
    • epicanthic folds
    • cardiac anomaly
  6. Which 3 trisomies are positively correlative with advanced maternal age?
    21, 18, and 13
  7. List and describe the two common prenatal cytogenetic tests.
    • Chorionic Villus Sampling:
    • - performed at 10-12 wks
    • - cultured cells from extraembryonic chorionic mesoderm in 5-7 days
    • - rapid results early in gestation
    • - procedure risk for miscarriage: 1%
    • Amniocentesis:
    • - performed at 15-18 wks
    • - amniotic fluid contains true embryonic (fetal) cells
    • - in situ cell culture: 5-10 days
    • - procedure-related risk for miscarriage: 0.5%
  8. Describe familial inheritance of Downs
    • 3% of Trisomy 21 are familial
    • - Robertsonian translocation: centric fusion of 2 acrocentric chromosomes (multiple copies in 1 of the meiotic products and absence of 21 in the other)
    • Balanced, so no phenotype
    • Risk to have offspring with unbalanced karyotypes: 46 chromosomes, 3 copies of chrom 21 --> Downs
  9. What are some oral anomalies of Downs?
    • Palate w v-shaped high vault
    • angle of mouth pulled down (hypotonic musculature)
    • small oral cavity (protruding tongue creates speech and articulation problems)
  10. Name some dental anomalies of Downs
    • 30-50% have microdontia: affects primary and secondary dentition
    • Additional features:
    • - supernumerary teeth
    • - abnormal spacing
    • - crown variants
    • - hypoplasia and hypocalcification
    • - delayed eruption
    • Increased risk of periodontal disease
  11. Describe a chromosomal structural abnormality: deletions
    • loss of a portion of a chromosome
    • - loss of DNA segment (usually many many genes!)
    • - loss of contiguous genes
    • - monosomy for these genes
    • Terminal deletions
    • Interstitial microdeletions
  12. What are some prime examples of a microdeletion? What type of genetic testing would you employ to diagnose this?
    • (aka: 22q11)
    • DiGeorge/Velocardiofacial syndrome
    • Opitz syndrome
    • Conotruncal anomaly face syndrome
    • **USE FISH testing, as karyotypic wouldn't show the deletion
  13. What's the cause/pathway for DiGeorge, Velocardiofacial, Shprintzen Syndromes? How does this manifest?
    • Disturbance of migration of neural crest cells into pharyngeal arches and pouches
    • Thymic aplasia, hypoplasia --> T-cell immune dysfunction
    • Parathyroid hypoplasis --> hypocalcemia
    • Midline defects --> clefts, conotruncal heart defects
  14. What is the spectrum of findings of the 22q11 deletion syndrome?
    • cardiac abnormalities
    • palatal abnormalities: velopharyngeal incompetence (VPI), cleft palate, CL & CL/P, submucosal cleft, bifid uvula
    • facial features: long, narrow face, beaked nose
    • LD
    • Immunodeficiencies
    • Others: feeding problems, renal, hypocalcemia, hearing loss
  15. What's the deletion that most have with DiGeorge, Velocardiofacial, Shprintzen Syndrome?
    • phenotypic spectrum of genetic disease
    • most have 3 Mb deletion within 22q11.21
    • a 480 kb critical region
    • - most sporadic, but about 10% are familial
  16. Describe Microarray technology
    • comparative genomic hybridization
    • CHIP technology
    • detection of SMALL mutations (DNA sequence gains and losses)
    • Microdeletion syndrome detection
    • "private" mutations of clinical significance
    • polymorphic DNA sequence gains and losses
    • ** CMA is mix of 5 individuals of same sex --> works off ratios of patient DNA to same sex control. Loss: ratio < 0.8, Gain: ratio > 1.2.
    • - target DNA on slide (chip) is single-stranded oligomer of 60 bases.
    • - aCGH detects gains and losses ONLY (NOT balanced rearrangements)
    • - LIMITED ability to detect mosaicism
  17. List some advantages to CMA over FISH
    • - CMA detects chromosomal gains and losses, some of which may be submicroscopic. One array = 180,000 FISH studies
    • - detects abnormalities in known "hot spots" of genome
    • - genome-wide arrays may detect abnormalities in "backbone" of genome (ie: spacing)
    • - can be used to characterize chromosome abnormalities detected by karyotyping (specific size of imbalance and genes involved)
  18. List some limitations of CMA
    • - cannot detect balanced rearrangements
    • - cannot detect specific genetic/DNA mutations, single base pair changes, etc. (as in CF)
    • - may not detect low-level mosaicism
    • - detection of copy number variants (CNVs) may have unclear clinical significance
  19. What are some characteristics of Monogenic, Mendelian Disorders?
    • single gene defects
    • usually expressed in childhood
    • incidence: 0.36% in liveborn population
    • 1-3% of children have congenital malformation
    • heritable genetic disorders
  20. Describe Autosomal Dominant single gene disorder inheritance pattern
    • Phenotype expressed in every generation
    • child of affected parent has 50% risk of inheriting trait
    • mutation in ONE allele causes phenotype
  21. Name some examples of autosomal dominant genetic disorders
    • Huntington's Disease: progressive neuronal degeneration
    • Myotonic dystrophy: muscle weakness & wasting
    • familial hypercholesterolemia: vascular disease
    • osteogenesis imperfecta: fracturing
    • marfan's syndrome: abnormal elastic tissue
    • retinoblastoma: malignant tumor of eye
    • Ehlers-Danlos syndromes: abnormal collagen: skin, joint, vascular
  22. What is Huntington's Disease?
    • Adult onset neurodegenerative disorder
    • Incidence: 1/10,000 individuals of European origin
    • Mutation in Huntington gene (amplification of trinucleotide repeat (CAG))
    • Confirmation of clinical diagnosis through DNA testing for CAG repeat size
    • Can test mutation in family members prior to clinical symptoms (ethical issues)
    • * with larger repeats, age of onset is sooner!
  23. What are some examples of Autosomal Dominant Gene Mutations of the oral cavity?
    • Familial Hypodontia: mild reduction in no. of teeth
    • Mesiodens: supernumerary tooth, usually between max incisors
    • Amelogenesis Imperfecta, hypocalcified type: normal quantity of enamel, but soft
    • - prevalence: 1/14,000 live births
    • - improper differentiation of ameloblasts --> brown color
  24. Describe some features of autosomal recessive disorders.
    • Rare diseases: expression of phenotype requires inheritance of mutant allele from EACH parent
    • Phenotype observed among siblings of the proband, not parents, offspring, or other relatives
    • carriers have one normal allele and one mutated allele --> no phenotype
    • recurrence risk for each sib of proband is 1 in 4
  25. What are some examples of autosomal recessive disorders?
    • Cystic Fibrosis (CF): abnormal ion transport protein
    • Sickle Cell Anemia: abnormal hemoglobin
    • Phenylketonuria (PKU): enzyme deficiency (phenylalanine hydroxulase deficiency)
    • Wilson's Disease: copper metabolism
  26. What are some symptoms of the autosomal recessive disease Ellis Van Creveld Syndrome?
    • postaxial polydactyly
    • short stature, shortening of forearms and lower legs
    • congenital heart malformations in 50%
    • dysplastic nails and teeth
    • mutations in EVC gene, chromosome 4, p16 responsible for phenotype
  27. Describe inheritance patterns of X-linked diseases.
    • mutation of genes on x-chromosome
    • phenotypic expression generally in males
    • all daughters of affected males carry his x-chromosome, thus the mutated gene responsible for the condition
    • sons of carrier females are at 50% risk for inheritance of mutated gene
  28. What are some oral cavity examples of x-linked diseases?
    • Amelogenesis Imperfecta - x-linked hypoplastic type
    • in males, thin smooth enamel
    • in females, enamel w vertical furrows, or hypoplastic depressions
  29. What is "Lionizaiton" or the Lyon Hypothesis?
    • X and Y differ in size and number of genes
    • Single active X chromosome in mammals
    • functionally hemizygous
    • mechanism for dosage compensation
    • *random inactivation of the maternal or paternal x chromosome early in female embryogenesis
    • fidelity of X-mat or X-pat inactivation in clonal descendents
    • skewing of x-inactivation --> could be tissue specific
  30. Define genetic heterogeneity
    • Mutations of more than one gene cause the same disorder
    • (also defined later on in lecture as: determined by a mixture of major/minor genes + environmental factors)
  31. Define clinical heterogeneity
    mutations in same gene cause different disorders
  32. define de novo mutation
    • (new)
    • no family history
  33. define variable expressivity
    trait is expressed differently among individuals carrying the same mutant gene, even within a family
  34. CL/P results from what?
    • single gene disorder
    • failure of lip closure (6-8 wks gestation) with secondary failure of palate closure (9-11 wks)
    • 2 males: 1 female
    • one of the most common birth defects
    • *genetic heterogeneity
  35. What are the different ways to get CL/P?
    • Isolated cases (75-80%); often multifactorial
    • familial, single gene forms (10-15%)
    • syndromic forms (1-5%); includes teratogenic exposure (rubella, meds)
  36. What is the most common single-gene cleft syndrome? is it dominant or recessive? Symptoms?
    • Van der Woude Syndrome
    • Autosomal Dominant
    • associated w mutations in IRF6 (70% of cases)
    • * clinical heterogeneity (mutations also associated w Popliteal pterygium syndrome)
    • CL w/wo P, as well as clefting of uvula
    • lower lip pits (80%)
    • Hypodontia or missing lateral or central incisor
  37. What is Holoprosencephaly (HPE)?
    • developing forebrain fails to divide into 2 separate hemispheres/ventricles
    • 80% have associated craniofacial anomalies
    • 25-50%: numerical/structural chromosome anomaly
    • 18-25%: recognizable syndrome
    • Remainder: nonsyndromic HPE
  38. Describe Nonsyndromic HPE
    • inherited autosomal dominant
    • often associated w chromosomal alteration
    • extreme variability of phentoype
    • Microforms/mild expression:
    • - microcephaly
    • - single central incisor
    • - hypotelorism
    • - midfacial hypoplasia
    • - cleft lip
    • Mutations in more than 4 genes account for 40-50% of Nonsyndromic HPE
  39. What are some signs of Amelogenesis Imperfecta (AI)
    • clinical and genetic heterogeneity
    • at least 14 distinct subtypes based on clinical appearance and inheritance, with varying modes of inheritance
    • - defect of dental enamel formation
    • - teeth are small, discolored, grooved or pitted, and prone to rapid wear and breakage
  40. What are the four main types of AI?
    • Hypoplastic
    • Hypomaturation
    • Hypocalcified
    • Hypomaturation/Hypoplasia/Taurodontism
  41. Describe Osteogenesis Imperfecta (OI)
    • group of genetic disorders due to improper formation of type I collagen
    • Range in severity from lethal (in utero, type II) to extremely mild (type I)
    • Clinical features:
    • - multiple fractures
    • - short stature
    • - hearing loss
    • - blue sclera
    • - dentinogenesis imperfecta
  42. What are some clinical features of Dentinogenesis Imperfecta (DI)?
    • Characteristic tooth crown color:
    • - blue-gray or yellow-brown and translucent
    • - caused by defective, abnormally- colored dentin shining through overlying enamel - "opalescent dentin"
    • - underlying defective dentin not able to adequately support the unaffected enamel
    • - often flakes off
  43. Name 2 types of DI.
    • Type I: associated w Osteogenesis Imperfecta -> caused by defects in the 2 genes encoding type I collagen
    • Type II: most common type. No increased frequency of bone fractures --> caused by mutation in DSPP gene, inherited in autosomal dominant pattern
  44. When DI is found by itself, it is considered to be "x". When it travels in combination with multiple medical findings, it is considered to be "y"
    • x: isolated
    • y: syndromic
  45. What is ectodermal dysplasia?
    • Primary defect in the development of 2+ tissues derived from ectodermal layer (ie hair, skin, nails and teeth)
    • >190 clinically distinct syndromes associated w ectodermal dysplasia
  46. Describe Ectodermal Dysplasia 1
    • Christ-Siemens-Touraine syndrome
    • usually inherited as x-linked recessive
    • caused by mutation in Ectodysplasin A gene (ED1)
    • Characteristic facial abnormalities:
    • - prominent forehead
    • - sunken nasal bridge "saddle nose"
    • - unusually thick lips
    • - large chin
    • eye abnormalities, decreased tearing
    • normal intelligence
    • partial or complete absence of eccrine sweat glands --> leads to lack of or diminished sweating, heat intolerance, fever
    • soft, thin, dry skin
    • skin peeling/scaling (newborn) and eczema
    • spoon-shaped nails
    • fine, brittle and scant hair (hypothrichosis)
    • absent or scanty eyelashes and eyebrows
  47. oral manifestations of ED1
    • Malformation of certain teeth
    • - conical or pegged teeth
    • - hypodontia or complete anodontia
    • - delayed eruption of permanent teeth
    • Jaw radiographs indicated for infants with fever of unknown origin and family history of EDS
    • - perform orthopantography at an early age if hypodontia or dental abnormalities are present
  48. What is Cowden Syndrome? What are some clinical features?
    • Multiple hamartoma syndrome
    • - autosomal dominant
    • - age-related penetrance (90-95% by 20 yrs of age)
    • - Increased risk factor for cancer (breast, thyroid, endometrial)
    • Clinical features:
    • - gingival and palatal lesions (benign fibromas); cobblestone appearance
    • - thickening or furrowing of the tongue (fissured)
    • - multiple skin tags
    • - subcutaneous lipomas
  49. What is FAP? Inheritance pattern? Clinical features?
    • Familial Adenomatous Polyposis
    • - autosomal dominant inheritance
    • accounts for 1% of ALL colorectal cancer
    • caused by mutations in APC tumor repressor gene
    • 30% of patients have de novo germline mutations
    • Clinical features:
    • - 100-1,000s of adenomas by early adulthood
    • - untreated polyposis leads to 100% risk of colorectatl cancer
    • - risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain)
  50. What is Gardner's Syndrome?
    • A variant of FAP
    • Extraintestinal lesions:
    • - desmoid tumors
    • - osteomas
    • - supernumerary teeth
    • - soft tissue skin tumors
Card Set
Genetic Diseases
Genetic Diseases I & II - Path