Orofacial Genetics for Dentists PDF

Orofacial Genetics for Dentists Farhad Khosrow Shahian, DDS PhD  Why do dentists need to know about genetics? Recent studies indicate that genetics plays a role in the etiology of: - Caries - Periodontal disease - Dental anomalies - Malformation/syndromes (eg. Cleft lip and pa...

Orofacial Genetics for Dentists Farhad Khosrow Shahian, DDS PhD  Why do dentists need to know about genetics? Recent studies indicate that genetics plays a role in the etiology of: - Caries - Periodontal disease - Dental anomalies - Malformation/syndromes (eg. Cleft lip and palate) - Malocclusion - Oral cancer - Many genetics diseases with oral implications Molecular genetics will likely be used to diagnose and treat many of these diseases  Biomarkers for Oral Cancer S100A7 Predictive marker for premalignant oral lesions leukoplakia, Lichen planus, and other dysplastic condition Role in epithelial, breast and Thyroid Cancer as well as Alzheimer's disease.  Genetics and caries Twin studies suggest partial genetic control (20%- 85%). Variation due to etiological variation of caries experience, including population or race-level genetic or environmental differences. Early childhood caries is strongly influenced by maternal health (obesity, diabetes,…)  Genes involved in caries Gene Role Disease Matrix metalloproteinase 20 Early stages of tooth development Caries (MMP20) Ameloblastin (AMBN) Enamel matrix Caries, dental fluorosis Amelogenesis imperfecta, caries, Amelogenin (AMELX) Tooth mineralization hypomineralization Enamelin (ENAM) Enamel matrix Amelogenesis imperfecta, hypomineralization, caries Kallikrein 4 (KLK4) Enamel matrix strengthening Hypomaturation, amelogenesis imperfecta Aquaporin 5 (AQP5) Saliva production Caries Carbonic Anhydrase VI (CA6) Saliva pH regulation Caries Mucin 5 (MUC5B) Inhibits biofilm formation Caries susceptibility  Genetics and Periodontal disease Monogenic congenital syndromes can result in aggressive periodontitis (Papillon-Lefèvre and Chediak-Higashi syndromes) Periodontal disease is a two-step process, requiring both genetic susceptibility followed by a bacterial challenge Genetics plays a role in the etiology of periodontal disease by controlling periodontal structural integrity as well as affecting the host response to subgingival microbiota. 2017 systematic review identified the vitamin D receptor gene, VDR, Interleukin-10, IL-10, and the immunoglobulin platelet receptor gene Fc-γRIIA as the strongest candidates.  Papillon–Lefèvre syndrome (PLS) Rare autosomal recessive disorder Diffuse palmoplantar keratoderma Precocious aggressive periodontitis Leading to premature loss of deciduous and permanent dentition at a very young age. Papillon–Lefèvre syndrome: clinical presentation and management options Basapogu Sreeramulu, Naragani DVN Shyam, Pilla Ajay, Pathipaka Suman Clin Cosmet Investig Dent. 2015; 7: 75–81.  Genes involved in periodontal disease Gene Role Disease Fc-γRIIA Platelet receptor Chronic periodontitis Interleukin-1 (IL-1α, IL-1β) Proinflammatory response Periodontitis Proinflammatory response; bone Gingivitis, periodontitis, acute Interleukin-6 (IL-6) resorption apical periodontitis Apical periodontitis, chronic Interleukin-8 Immune response periodontitis Aggressive periodontitis, Interleukin-10 Immune response inflammatory bowel disease, type 1 diabetes; chronic periodontitis Interleukin-37 Immune response Severe periodontitis, tooth loss, stroke Matrix metalloproteinase family Degradation of extracellular matrix Periodontitis (MMP2, 3, 8, 9) during development, tissue repair Tooth formation, calcium and Periodontitis VDR phosphate balance  “Personalized Medicine” Dental and medical care requires: - Examination and assessment of the patient’s status, diagnosis, and prescription of treatment - Not all patient’s respond equally to treatment - It is believed that an individual’s response to treatment is largely determined by intrinsic genetic factors and behavior (lifestyle, diet, exercise, …)  Personalized Orthodontics Hartsfield 2008; Seminars in Orthodotics Genetic tests can compliment clinical and radiographic data to prevent undesirable treatment outcomes Genetic tests (eg. polymorphic studies) may indicate: - high risk of external apical root resorption - early detection and confirmation of malocclusion - Identify individuals who will likely “catch up” in skeletal growth without treatment or perhaps one who would respond more with a functional appliance  Variation in the Human Genome Person 1 Person 2 = Variations in DNA  Of the 3.2 billion bases, roughly 99.9 percent are the same between any two people. It is the variation in the remaining tiny fraction of the genome, 0.1 percent--roughly several million bases-- that makes a person unique. This small amount of variation determines attributes such as how a person looks or the diseases he or she develops. What are Variation Types in the Genome? Polymorphism Deletions Insertions Chromosome Translocations  Polymorphism Genetic variation that is observed at a frequency of >1% in a population (~90% of all DNA variation) Single nucleotide polymorphisms (SNPs) - Single base mutation which substitutes one nucleotide for another - Most commonly, these variations are found in the DNA between genes. - As biological markers, SNPs locate genes that are associated with disease.  Within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function. Most SNPs have no effect on health or development. Help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families.  SNPs Are the Most Common Type of Variation At least 1 percent of Most of the population the population G to C Common Variant sequence sequence SNP site  Tandem Repeat Polymorphisms Tandem repeats or variable number of tandem repeats (VNTR) are a class of polymorphism, consisting of variable length of sequence motifs that are repeated in tandem in a variable copy number. Based on the size of the tandem repeat units: Microsatellites or Short Tandem Repeat (STR) repeat unit:1-6 (dinucleotide repeat: CACACACACACA) Minisatellites repeat unit: 14-100 Number of repeats is highly variable due to “slippage” during DNA replication.  SNPs in linkage analysis identify SNP that segregate family pedigree together with the disease + ~ location fine mapping SNP typing using DNA of affected and unaffected family members candidate gene  SNPs in association studies to test whether a particular SNP allele is enriched in patients compared to healthy controls Causes of human congenital anomalies  Mutations Muller – Mutation of fruit flies by X-rays 3 types – Substitution – Deletion – Insertion  Mutations Single Base Substitutions – alter the triplet codon – one amino acid to be replaced Deletions and insertions – if a single base pair is deleted or inserted, the entire frame of the DNA strand gets shifted Single base substitutions – proteins produced Frame shift mutations – no proteins  Mutations Chain termination mutations – – Termination codons can be added prematurely or be deleted Splice Mutations – – These interfere with the way introns are removed from the messenger RNA. Mutations in regulatory sequences – These affect the TATA box and the CAT box regions of the gene.  Single gene disorders Mutations found in single genes can be transmitted through mendelian inheritance. Mendelian inheritance/Single Gene Traits – Patterns of single gene inheritance depend on chromosomal location and dominance or recessiveness of the phenotype associated with the allele – 4 types of inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive  Mendelian Disorders Dental Disorders – Amelogenesis imperfecta – Dentinogenesis imperfecta – Familial hypodontia – Some ectodermal dysplasias – Other syndromes with dental defects Craniofacial Disorders – Cleidocranial Dysostosis – Nevoid Basal Cell Carcinoma Syndrome – Craniosynostosis Syndromes – Oro-facial Clefting Syndromes  Mendelian Disorders Systemic disorders that may affect dental care Sickle cell anemia: - Susceptibility to dental infections, Delayed eruption and hypoplasia of the dentition secondary to their general underdevelopment. - hypercementosis and osteoporosis of the jaw - general anesthesia is hazardous in sickle cell patients because of severe anemia and a crisis may be precipitated. - Acute infections should be treated immediately since they may precipitate a sickling crisis. - Patients are more prone to developing osteomyelitis because of hypovascularity Cystic fibrosis: - antibiotics side effects  Inheritance – Single gene disorders Autosomal dominant – one gene or allele is defective and the other complementary allele is normal – Rare – Patient usually heterozygous – Parent affected – New mutation (mutation in an egg or sperm) – Achondroplasia, Osteogenesis imperfecta – Porphyria variegata – one couple (1688) – ½ the children affected – irrespective of sex How do autosomal dominant diseases stay in the population? Variable Expressivity Late Onset High Recurrent Mutation Rate Incomplete Penetrance  Variable Expressivity Marfan syndrome is an autosomal dominant disease caused by a mutation in collagen formation. It affects about 1/60,000 live births. Symptoms of Marfan syndrome include: - Skeletal/Dental: Narrow jaws and high-arched palate, arachnodactyly (long fingers and toes), extreme lengthening of the long bones, scoliosis, rib and sternum abnormalities, … - Optical: ectopia lentis, a dislocation of the lens into the anterior chamber of the eye. - cardiovascular abnormalities: Including dissecting aneurysms, Also seen with Ehlers-Danlos syndrome. Mitral valve prolapse and artificial heart valves- endocarditis? *Each patient may express all of the symptoms, or only a few.  The disease is maintained in the population through recurrent mutations and the reproduction of less severely affected individuals with normal individuals. The extent of severity of affected does not affect the severity of expression in the next generation, that is, the offspring of mildly affected individuals range from mildly affected to severely affected, with equal probability.  Polydactyly Often in genes for structural proteins Often associated with advanced paternal age  Late Onset Some autosomal dominant diseases do not express themselves until later in life. Huntington disease Age of onset varies from the teens to the late sixties Most of the individuals born with the defective allele will develop the disease by the time they are 70. The disease is progressive with death usually occurring between four and twenty-five years after the first symptoms develop. Poor Coordination, Involuntary Movements, Depression, Short-Term Memory Loss, Slight Lack of Emotion (Apathy) Emotional changes often are the first symptoms.  It is caused by the expansion of an unstable trinucleotide repeat sequence, CAG, in the coding region of the gene. Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. Trinucleotide repeat disorders are the result of extensive duplication of a single codon. What is inherited at birth in Huntington disease is a gene with several repeats and the instability that allows somatic recombination and extension.  Myotonic dystrophy Progressive muscle wasting and weakness beginning in their 20's or 30’s. The muscle wasting and weakness develop in their lower legs, hands, neck and face. The expression is delayed due to unstable trinucleotide sequences (CTG) of DMPK gene. This unstable sequence lies in a non-translated region of the gene. Alleles with greater than 37 repeats are unstable and additional trinucleotide repeats may be inserted during cell division in mitosis and meiosis.  High Recurrent Mutation Rate Achondroplasia: major causes of dwarfism. Motor skills may not develop as quickly as their normal siblings, but intelligence is not reduced. It occurs in about 1/10,000 live births. Like many autosomal dominant diseases, individuals homozygous for the mutant allele do not survive to term. 85% of the cases are the result of new mutations, where both parents have a normal phenotype. The mutation rate for achondroplasia may be as much as 10 times the "normal" mutation rate in humans. This high recurrent mutation is largely responsible for keeping the mutant gene in the population at its present rate.  Incomplete Penetrance The proportion of people who show symptoms from the mutation is called the penetrance of the gene. Not all individuals carrying a deleterious gene express the associated trait. Complete penetrance: The presence of a genetic mutation always results in disease (FGFR3 mutation results in achondroplasia/dwarfism). Incomplete penetrance: Mutations that have less than 100 percent penetrance (BRCA1 gene mutation results in 80% of women to develop breast cancer).  Crouzon Syndrome Autosomal dominant; complete penetrance; Many cases are due to sporadic mutation; increased risk with higher paternal age Premature craniosynostosis, may be present at birth Coronal fuses first in most cases – changes in head and facial form  Crouzon Syndrome Midfacial and maxillary hypoplasia Orbital proptosis (protrusion of orbital contents) Brachycephaly (flat-head) Clinically normal hands Measurable alteration in proportions of the bones of the hand – shortened proximal phalanx of the first and second fingers, terminal phalanx of the first finger (short thumbs) Hands in Crouzon Syndrome Cleidocranial Dysplasia  Cleidocranial Dysplasia Multiple unerupted teeth Delayed dental eruption Supernumerary teeth Characteristic facial phenotype –frontal bossing, hypertelorism, delayed closure of the fontanels Hypoplastic/absent clavicles Cementum deficient on roots Autosomal dominant inheritance CBFA1 gene (RUNX2) – a transcription factor involved in osteoblast differentiation. Cleidocranial Dysplasia  Autosomal Recessive Parents of affected offspring have 25% recurrence risk Each parent contributes a mutated copy of the gene Often associated with genes for enzymes Phenotype is often not variable Both sexes – homozygous Extremely rare – heterozygous are normal  Inheritance – Single gene disorders Consanguineous marriages – Chance that cousins will carry the same genes is 1 in 8 – The rarer the disease  more probability of consanguineous marriage of parents. – Eg – Alkaptonuria Most common autosomal recessive disorder – Cystic fibrosis – 1 in 22 is a carrier.  Amelogenesis Imperfecta Mutations in the AMELX, ENAM, MMP20, and KLK-4 Amelogenesis imperfecta can have different inheritance patterns depending on the gene that is altered. Most cases are caused by mutations in the ENAM gene and are inherited in an autosomal dominant pattern. Amelogenesis imperfecta is also inherited in an autosomal recessive pattern; this form of the disorder can result from mutations in the ENAM or MMP20 gene. About 5% of amelogenesis imperfecta cases are caused by mutations in the AMELX gene and are inherited in an X- linked pattern In most cases, males with an X-linked form of this condition experience more severe dental abnormalities than affected females. Amelogenesis imperfecta – hypoplastic type