Prenatal - CVS amniocentesis

Postnatal - Peripheral blood (MOST COMMON)

47, XXY

6 y.o. - behavioral issues and learning disabilities

15 y.o. - gynecomnastia

30 y.o. - male w/ hx. of infertility/azoospermia 

Both deletions of the 22q11.2

Di George - 3rd and 5th pharyngeal pouch defects (thymic and parathyroid hypoplasia and cardiac defects)

VCFS: cleft palate, cardiac anomalies, malar hypoplasia, prominent nose, retrognathia, ear anomalies, learning disabilities 

Autosomal recessive

Cathopsin C mutation

Hyperkeratosis, gingivitis, periodontitis 

Autosomal dominant

No gene known

Bilateral (4 quadrant) multilocular expansions; radioluscent (less dense than normal bone) lesions; 1st seen from 2-5 years; tooth displacement and eruption failure 

Autosomal dominant

Cbfa1/Runx2

Aplasia (or hypoplasia) of the clavicl; hundreds of unerupted teeth (clinical hypodontia) because of lack of secondary cementum; delayed suture closure (open fontanels); narrow, high arched palate, sometimes cleft; deciduous teeth have normal eruption but prolonged retention

Autosomal dominant

FGFR2 (fibroblast growth factor 2) gene

Premature closure of sutures; mandibular prognathism and underdeveloped maxilla and midface; bulging eyes (ocular proptosis); normal intelligence

Autosomal dominant

FGFR2 (Fibroblast growth factor)

Craniofacial synostosis; syndactly; midfacial hypoplasia; teeth crowding; palate appears cleft but its just overgrown gingiva; mental retardation 

Autosomal dominant

TCOF1

Underdeveloped mandible, facial clefting, hypoplastic zygoma, depressed cheeks, downward palpebral slant; tooth crowding 

Gorlin (aka multiple nevoid basal cell carcinoma)

AD - high penetrance

Mutation in patched on chrmosome 9

Multiple basal cell carcinomas (even in unexposed skin) and multiple odontogenic keratocytes 

Neurofibromatosis (aka von Recklinghausen disease of the skin):

AD or spontaneous

NF1 (neurofibromatosis) gene on c'some 17

Characterized by neurofibromas - benign tumor of nervous tissue 

Describe Multiple Endocrine neoplasia, type IIB:

AD

Mutation of ret-proto-oncogene on c'some 10

Multiple mucosal neuromas, pheochromocytoma (secretion of catecholamines), medullary carcinoma of the thyroid 

AD

No known gene

Pigmentations see on peri and intraoral skin; also form intestinal polyps of which 2-3% will become malignant 

AD, X-linked, AR

Multiple presentations - hypoplastic, hypomaturation, hypocalcified 

AD, AR, sporadic

Type 1 collagen gene mutation

No pulp chambers present or shell teeth with large pulp chambers 

AR

No gene

Dec in alkaline phosphatase (necessary for tooth development); premature exfoliation because of no cementum 

X linked dominant trait

Exfoliated teeth becasue of inflammatory response and large pulp chambers and pinpoint pulp exposures resulting in nonvital teeth 

Tobacco, alcohol, areca nut

Radiation, HPV or EBV, iron and Vitamin A deficiency

Oncogenes and tumor suppressors deficient; familial and genetic predisposition 

• Carcinogen is metabolized and taken up by oral mucosa
• Metabolites are electrophilic and bind DNA to change genotype and cell features
• Cell proliferation

What are chances? - high risk, can't be more specific

How can we predict? - 20% will progress

How can we effectively monitor? - don't know 

Normal oncogene is like the green light to keep cell cycle going; abnormal oncogene is a constant green light and cycle never stops

Normal tumor suppressor is like a red light but abnormal will not stop a mutation when it should 

• No predictive histo pattern
• No test to prove likely progression
• Must reevaluate frequently and remove if recurs

• Don't demonstrate simple mendelian inheritance pattern
• Demonstrate familial aggregation (family hx)
• Gene and environmental interractions are significant

CL(P) 1:550

CP 1:1000 

Sporadic (isolated) ~ 75%

Familial ~ 25% 

4% if one child is affected

9% if two children are affected

17% if one child and parent are affected 

Alcohol

Dilantin (seizure med)

Retinoic acid (acne med)

Smoking

Agricultural chemicals 

Penetrance = 100%

Autosomal dominant IRF6

Lip pits, depressions (blind sinuses) that descend through orbicularis muscle to a dept of 1-3 cm and communicate with salivary ducts; hypodontia; variable clefting 

Nucleotide change leading to amino acid change

Change leads to stop codon

Addition that leads to a frameshift 

Purines A and G

Pyrimidines C and T

Transition = Pyr --> pur or Pur --> Pyr

A --> G or C --> T 

Transversion = Pyr --> Pyr or Pur --> Pur

G --> T or A --> C 

C - G

C is frequently methylated or spontaneous deamidation of C to T (transition)

8.5 times more likely to change than any other dinucleotide pair 

Silent - "wobble"

Nonsense - AA to stop

Missense

    Conservative - changes aa to same or similar aa

    Non-conservative - changes aa by function or charge 

Promoter/enhancer element

Splice sites and introns 

Null allele - no gene product

Dominant negative - antagonizes normal product

Neomorph - novel activity of product 

Haploinsufficiency

Dominant negative

Gain of function 

• Co-dominant expression
• New mutations
• Homozygous for an AD trait - may be more sever phenotype
• Variable expression
• Penetrance
• Sex limited
• Variation in age of onset

Alleles that are both expressed when they occur in the heterozygous state

ABO blood group antigens 

Males and females equally as likely to inherit;

Seen in sibs but not other relatives

Risk of recurrence in sibs is 25%

2/3 of unaffected sibs will be carriers

Consanguinity increases risk 

Genes on X (X-linked)

Genes on autosome (autosomal dominant 

Autosomal recessive

Female homozygote for XL??? 

• Affects mainly males
• Affected males are usually born to unaffected parents
• Females can be affected if born to an affected father and carrier mother
• Females can be affected if they have very skewed lyonization
• No male to male transmission
• Males born to carrier mother have 50% risk of inheriting altered gene

• Linear blisters in newborn girls
• Crops followed by scarring
• Small teeth
• Eye abnormalities
• Patchy hair loss
• Only girls affected (most boys die inutero)

• Familial
• Mulitfactorial - significant env. effect
• Segregation analysis suggests AD transmission although it is likely a complex inheritance pattern
• Heterogeneous

• Random mating
• No inbreeding
• No migration
• No mutation
• Large population
• No selection

• Disease is deleterious
• Disease is treatable
• Has a reliable test
• Early treatment makes a difference
• Cost effective

before: guthrie test with blood samples on a bacteria lawn

now: Mass spec 

Old belief in Classic Medical genetics causing a medical disease through a single gene or c'some; usually early onset (pediatric); believed that these types make up 20% of diseases

Currently: 80% of genetic variation is in the form of genetic susceptibility and delayed onset adult disorders = common gene variations gene + environment 

Codeine to morpine (the active metabolite) by CYP2D6;

7-10% of caucasians have a genetic variant that produces limited CYP2D6 activity and slow metabolism of CYP2D6 substrates and 7% are ultrametabolizers