Genetics of Dental Health and Diseases

Orofacial Genetics for Dentists

• Genetics plays a role in the etiology of various dental and oral conditions.
• Recent studies indicate a genetic component in caries, periodontal disease, dental anomalies (e.g., cleft lip and palate), malocclusion, and oral cancer.
• Molecular genetics likely will be used to diagnose and treat these conditions.

Biomarkers for Oral Cancer

• S100A7 is a predictive marker for premalignant oral lesions (e.g., leukoplakia, lichen planus).
• S100A7 is also implicated in epithelial, breast, and thyroid cancer, as well as Alzheimer's disease.

Genetics and Caries

• Twin studies suggest a partial genetic control (20%-85%) of caries.
• Caries experience can vary due to population or race-level genetic or environmental differences.
• Early childhood caries strongly influenced by maternal health, such as obesity and diabetes.

Genes Involved in Caries

• Gene: Matrix metalloproteinase 20 (MMP20)
  • Role: Early stages of tooth development
  • Disease: Caries, dental fluorosis
• Gene: Ameloblastin (AMBN)
  • Role: Enamel matrix
  • Disease: Amelogenesis imperfecta, caries, hypomineralization
• Gene: Amelogenin (AMELX)
  • Role: Tooth mineralization
  • Disease: Amelogenesis imperfecta, caries, hypomineralization
• Gene: Enamelin (ENAM)
  • Role: Enamel matrix
  • Disease: Amelogenesis imperfecta, hypomineralization, caries
• Gene: Kallikrein 4 (KLK4)
  • Role: Enamel matrix strengthening
  • Disease: Hypomaturation, amelogenesis imperfecta, caries
• Gene: Aquaporin 5 (AQP5)
  • Role: Saliva production
  • Disease: Caries
• Gene: Carbonic Anhydrase VI (CA6)
  • Role: Saliva pH regulation
  • Disease: Caries
• Gene: Mucin 5 (MUC5B)
  • Role: Inhibits biofilm formation
  • Disease: Caries susceptibility

Genetics and Periodontal Disease

• Monogenic congenital syndromes, such as Papillon-Lefèvre and Chediak-Higashi syndromes, can cause aggressive periodontitis.
• Periodontal disease is a two-step process, needing genetic susceptibility plus a bacterial challenge to develop.
• Genetics plays a role in periodontal structure and host response to subgingival microbiota
• Vitamin D receptor (VDR), Interleukin-10 (IL-10), and immunoglobulin platelet receptor gene (Fc-yRIIA) are potential candidate genes in periodontal disease according to a 2017 systematic review.

Papillon-Lefèvre Syndrome (PLS)

• Rare autosomal recessive disorder
• Diffuse palmoplantar keratoderma
• Precocious aggressive periodontitis
• Leads to early loss of deciduous and permanent teeth.

Genes Involved in Periodontal Disease

• Gene: Fc-YRIIA
  • Role: Platelet receptor
  • Disease: Chronic periodontitis
• Gene: Interleukin-1 (IL-1α, IL-1β)
  • Role: Proinflammatory response
  • Disease: Periodontitis, Gingivitis, periodontitis, acute apical periodontitis
• Gene: Interleukin-6 (IL-6)
  • Role: Proinflammatory response; bone resorption
  • Disease: Gingivitis, periodontitis, acute apical periodontitis
• Gene: Interleukin-8
  • Role: Immune response
  • Disease: Apical periodontitis, chronic periodontitis
• Gene: Interleukin-10
  • Role: Immune response
  • Disease: Aggressive periodontitis, inflammatory bowel disease, type 1 diabetes; chronic periodontitis
• Gene: Interleukin-37
  • Role: Immune response
  • Disease: Severe periodontitis, tooth loss, stroke
• Gene: Matrix metalloproteinase family (MMP2, 3, 8, 9)
  • Role: Degradation of extracellular matrix
  • Disease: Periodontitis
• Gene: VDR
  • Role: Tooth formation, calcium and phosphate balance
  • Disease: Periodontitis

Personalized Medicine

• Dental and medical care needs examination of patient status, diagnosis and treatment prescription.
• Not all patients respond equally to treatment.
• Treatment response is largely determined by intrinsic genetic factors and behavior.

Personalized Orthodontics

• Genetic tests can supplement clinical and radiographic data, preventing treatment downsides.
• Genetic tests might predict high risk of external apical root resorption.
• Identify patients who will likely "catch up" with skeletal growth.

Variation in the Human Genome

• 99.9% of DNA bases are the same in any two people.
• Variations in 0.1% of the genome create human individuality.
• Variations determine attributes like appearance and disease susceptibility.

Variation Types in the Genome

• Polymorphism
• Deletions
• Insertions
• Chromosome translocations

Polymorphism

• Genetic variation >1%
• Single Nucleotide Polymorphisms (SNPs): Single-base mutations
• SNPs commonly occur in DNA between genes and act as biological markers locating disease-associated genes.
• Most SNPs have no effect on health but can predict drug response, toxin susceptibility, and disease risk.
• SNPs can track disease inheritance patterns.

Tandem Repeat Polymorphisms (VNTRs)

• Polymorphisms consisting of repeated sequences
• Microsatellites/Short Tandem Repeats (STRs) have 1-6 repeats, while minisatellites have 14-100 repeats.
• Repeat number variation due to "slippage" during DNA replication.

SNPs in Linkage Analysis

• Identify SNPs that segregate with diseases using family pedigrees and affected/unaffected family members.
• Fine-mapping isolates candidate genes.

SNPs in Association Studies

• Test if a SNP is enriched in patients compared to healthy controls using patient and control cohorts.

Causes of Human Congenital Anomalies

• Causes of human birth defects (50-60% are of unknown etiology)
• Multifactorial inheritance, chromosomal abnormalities, mutant genes, and environmental agents contribute to congenital anomalies.

Mutations

• Muller's X-ray experiments with fruit flies demonstrated mutation induction.
• Three principal types of mutations:
  • Substitution
  • Deletion
  • Insertion
• Single Base Substitutions: Alter the codon, leading to potential amino acid changes in proteins.
• Deletions/Insertions: These shift the reading frame of the DNA sequence, leading to significant changes in protein structure and potentially nonfunctional proteins.

Mutations (continued)

• Chain termination mutations: Premature termination codons are added or deleted, resulting in truncated proteins.
• Splice mutations: Intron removal from mRNA is altered.
• Regulatory sequence mutations: Alteration of regions like TATA or CAT boxes which affect gene expression.

Single Gene Disorders

• Mutations in single genes can be passed through Mendelian inheritance.
• Inheritance patterns depend on chromosome location and allele dominance/recessiveness.
• Four types: Autosomal dominant, Autosomal recessive, X-linked dominant, X-linked recessive.

Mendelian Disorders - Dental Disorders

• Amelogenesis imperfecta
• Dentinogenesis imperfecta
• Familial hypodontia
• Ectodermal dysplasias
• Syndromes with dental defects

Mendelian Disorders - Craniofacial Disorders

• Cleidocranial dysostosis
• Nevoid Basal Cell Carcinoma Syndrome
• Craniosynostosis syndromes
• Orofacial clefting syndromes

Mendelian Disorders - Systemic Disorders

• Sickle cell anemia: susceptibility to dental infections, delayed eruption/hypoplasia, hypercementosis, osteoporosis, crisis risk.
• Cystic fibrosis: antibiotics side effects, etc.

Inheritance - Single Gene Disorders - Autosomal Dominant

• One defective gene or allele; other is normal, meaning that one copy of a mutated gene is sufficient to cause the disorder.
• Usually heterozygous
• Parent can be affected
• Can be new mutation (egg/sperm)
• ½ the children affected regardless of sex (common in autosomal dominant disorders). (Note: examples of autosomal dominant disorders mentioned in the text are achondroplasia, Osteogenesis imperfecta, and Porphyria variegata – one couple (1688))

How do Autosomal Dominant Diseases Stay in the Population?

• Variable Expressivity
• Late Onset
• High Recurrent Mutation Rate
• Incomplete Penetrance

Variable Expressivity (Example: Marfan Syndrome)

• Marfan syndrome results from collagen mutations, found in about 1/60,000 live births.
• Variable clinical expression (varying symptoms), not all with the gene will expressed them equally).
• Skeletal/dental features including jaw shape, arched palate, long fingers/toes, long bones, scoliosis.
• Optical abnormalities: dislocated lens
• Cardiovascular anomalies including aneurysms.

Late Onset (Example: Huntington Disease)

• Huntington disease symptoms arise later in life (teens-late 60s).
• Death usually occurs about 20-25 years after symptoms appear.
• Symptoms include poor coordination, involuntary movements, depression, short-term memory loss, apathy, and other emotional changes.
• Caused by expansion of an unstable trinucleotide repeat sequence (CAG) in the coding region of the gene responsible for the HTT protein.

High Recurrent Mutation Rate (Example: Achondroplasia)

• Achondroplasia is a major cause of dwarfism.
• Motor skills may develop more slowly than normal siblings, but intelligence is unaffected.
• Occurs in 1/10,000 live births.
• Homozygous individuals usually do not survive to term.
• The majority of cases (85%) are due to new mutations.
• High mutation rate in achondroplasia compared to normal populations is a main driver in maintaining the condition in the population.

Incomplete Penetrance

• Often associated with the proportion of people showing symptoms from the mutation.
• Not all who carry a deleterious gene display affected traits, like in some cases of achondroplasia/dwarfism or BRCA1 (breast cancer). A genetic mutation may or may not be expressed

Crouzon Syndrome

• Autosomal dominant, complete penetrance, sporadic mutations, increased paternal age risk.
• Premature craniosynostosis (skull sutures fuse prematurely).
• Changes to craniofacial form, like midfacial and maxillary hypoplasia, orbital proptosis, brachycephaly, and clinically normal hands except for slight hand bone proportions.

Cleidocranial Dysplasia

• Multiple unerupted teeth, delayed eruption, supernumerary teeth; characteristic face features (frontal bossing, hypertelorism, delayed closure of fontanels) and clavicular hypoplasia/absence.
• Cementum deficiency on the roots.
• Autosomal dominant inheritance, involving CBFA1 (RUNX2) transcription factor for osteoblast differentiation.

Autosomal Recessive

• Parents of affected children have a 25% risk of recurrence.
• Each parent contributes mutated gene copies for this mode of inheritance.
• Rare. Often associated with genes for enzymes and variable expression patterns.
• Typically homozygous conditions (both parents pass on affected genes) meaning that both parents must be carriers.
• Heterozygous unaffected individuals, are extremely common in autosomal recessive disorders
• Examples include alkaptonuria and cystic fibrosis (more common).

Amelogenesis Imperfecta

• Mutations in AMELX, ENAM, MMP20, and KLK-4 genes result in different inheritance patterns.
• Most cases (autosomal dominant) are due to ENAM gene mutations.
• Amelogenesis imperfecta can also have autosomal recessive inheritance due to ENAM and MMP20 mutations.
• X-linked cases are less common. Males with X-linked cases tend to experience more severe dental abnormalities than affected females.

Polydactyly

• Often due to mutations in genes involved in structural proteins.
• Sometimes associated with advanced paternal age.

This quiz explores the genetic factors influencing dental health, focusing on mutations, genetic susceptibility to conditions like caries and periodontal disease, and the role of specific genes. Test your knowledge on the relationship between genetics and oral health, including SNP typing and gene expression in dental development.