The Role of Genetics in Oral Medicine

The Role of Genetics in Oral Medicine

Olga A. Korczeniewska, BA, PhD

Thomas C. Hart, BA, DDS, PhD

Scott R. Diehl, BS, PhD


History of Genetics and the Human Genome Project

Since the dawn of civilization, humans have been aware of heredity and applied its principles to improve crops and domestic animals. Pedigrees of horses and possibly inherited characteristics were found on a Babylonian tablet more than 6000 years old.1 However, the mechanism by which a genotype resulted in a phenotype was first described only about 150 years ago, when Gregor Mendel discovered independent assortment of traits through his cross‐pollination experiments between variants of the garden pea. Most of the mechanisms of heredity remained a mystery until the nineteenth century, when genetics as a science began. It was the identification of genes, the fundamental units of heredity, which brought genetics into being. In the twentieth century, tremendous strides were undertaken to understand the nature of genes and their function. In 1905, English biologist William Bateson introduced the word “genetics” to describe the study of heredity and the science of variation.2 In 1908, British physician Archibald Garrod applied genetic knowledge to human diseases and disorders. Garrod proposed that the human disease alkaptonuria was caused by “inborn errors of metabolism,” suggesting for the first time that genes had molecular action at the cell level.1 In 1909, Danish botanist, plant physiologist, and geneticist Wilhelm Johannsen introduced the term gene to denote the basic unit of heredity. In 1944, molecular biologist Oswald Avery showed that genes and chromosomes were composed on deoxyribonucleic acid (DNA). Ironically, for most of the twentieth century, clinicians viewed genetics as a somewhat esoteric academic specialty.

A major breakthrough occurred in 1953, when American genetics and biophysicist James D. Watson and British biophysicist Francis Crick and Maurice Wilkins discovered a double helix model for DNA structure.3,4 Watson, Crick, and Wilkins shared the 1962 Nobel Prize in Physiology or Medicine for their discovery. Watson and Crick’s discovery has helped researchers to understand human life more closely. In 1958, American molecular biologist Mathew Meselson and American geneticist Franklin W. Stahl for the first time demonstrated experimentally the strand separation method for DNA replication (semiconservative method).5 In the 1970s, American biologists Allan M. Maxam and Walter Gilbert and English biochemist Frederick Sanger pioneered DNA sequencing techniques, for which Gilbert and Sanger shared the 1980 Nobel Prize in Chemistry. In 1983, American biochemist Kary B. Mullis invented polymerase chain reaction (PCR), a simple technique that allows a specific piece of DNA to be copied billions of times in a few hours.6 In recognition of their invention, Mullis and Michael Smith shared the 1993 Nobel Prize in Chemistry.

On October 1, 1990, an international team of researchers began the Human Genome Project (HGP), which aimed at sequencing and mapping all of the human genes, known as the genome. Completion of the HGP in April 2003 for the first time provided the ability to read nature’s complete genetic blueprint for building a human being.710 Meanwhile, rapid advances in high‐throughput sequencing and bioinformatics analyses made the “$1000 genome” (the cost to read the sequence of nearly a person’s entire DNA sequence of ca. 3 billion DNA bases) a reality. This, in turn, greatly expanded the potential use of DNA sequencing as a tool for diagnostics and prognosis that emphasizes individualized or personalized health care.1113 In 2008, the 1000 Genomes Project was initiated through an international collaboration in which researchers aimed to sequence the genomes of a large number of people from different ethnic groups worldwide. Completion of the 1000 Genomes Project in 2015 enabled the creation of a catalog of genetic variations.14,15

Even though the completion of the HGP and the 1000 Genomes Project as well as the enormous public interest in genomics did not abruptly change or transform the fields of medicine and dentistry, the growing and evolving body of knowledge and information has significantly expanded how we think about and use human genetics in medicine and dentistry. Completion of the HGP has had a profound impact on genetic prediction of individual risks of disease and responsiveness to drugs.16,17 Knowledge of the human genome sequence has enabled the development of designer drugs, based on a genomic approach to targeting molecular pathways disrupted in disease.1719 Genomic medicine holds the ultimate promise of revolutionizing the diagnosis and treatment of many illnesses.20

DNA Makes RNA Makes Protein

Genetics is the study of genes at all levels, including their function in the cell and the ways in which they are transmitted from parents to offspring. Modern genetics focuses on deoxyribonucleic acid (DNA), the chemical substance that genes are made of, and the ways in which it affects the chemical reactions.

All genetic diseases involve errors occurring at the level of the cell, for example DNA replication errors or errors in translation of genes into proteins. These errors often produce single‐gene disorders. Errors occurring during cell division may results in disorders involving entire chromosomes.

Human somatic cells are diploid: they contain two copies of each chromosome, one from the mother and one from the father, for a total of 23 pairs (46 chromosomes). Of the 23 pairs of chromosomes, 22 pairs (numbered 1–22 from largest to smallest) are autosomal chromosomes and 1 pair is sex chromosomes. In a normal male, the sex chromosomes are a Y chromosome from the father and an X chromosome from the mother. Normal females have two X chromosomes. Gametes (egg and sperm cells) are haploid and contain a single copy of chromosomes (23 chromosomes).

Deoxyribonucleic Acid (DNA)

DNA is the genetic blueprint for making all proteins in the body. The discovery of the molecular structure of DNA revealed that it was made of a long chain of nucleotides arranged in two strands, forming a spiral called a double helix. Nucleotides are the building blocks of DNA that are made up of three components: a phosphate group, a 5‐carbon sugar, and a nitrogenous base. The four nitrogenous bases in DNA are adenine (A), guanine (G), cytosine (C), and thymine (T), which is replaced by uracil (U) in ribonucleic acid (RNA). Adenine and guanine are purine bases and cytosine, thymine and uracil, and pyrimidine bases. The information in DNA is stored as a code of these four chemical bases that pair up with each other via hydrogen bonds, such that A pairs with T via a double hydrogen bond and C pairs with G via a triple hydrogen bond. The complementary base pairing is important during DNA replication, in which DNA polymerase enzyme uses a single strand of the double‐stranded DNA molecule as a template for the synthesis of a new, complementary strand, making an identical copy of DNA. Different sequences of nucleotide bases specify different proteins. Therefore, the order of the bases determines the information for building and maintaining an organism.

The majority of human DNA (approximately 3 billion nucleotide pairs per haploid genome) is packaged in the cell nucleus by coiling around a histone protein core to form a nucleosome, which then forms a solenoid that makes up the chromatin loops. Some DNA is also stored in the mitochondria (16,569 nucleotide pairs that encode 9 genes). A small portion of human DNA (1%–2%) encodes functional genes. Humans are estimated to have 20,000–25,000 functional genes, which are sequences of DNA that code for RNA or proteins. The vast majority of the human genome is not as yet informative, which includes pseudogenes (19,000 identified human pseudogenes), or repetitive DNA sequences.9,12,13

From Genes to Proteins

DNA contains instructions for making proteins. It resides and is replicated in the cell nucleus; however, protein synthesis takes place in the cytoplasm. Therefore, information/instructions contained in DNA have to be “transported” into cytoplasm, where they can direct the process of protein synthesis. A series of steps must occur before proteins are made from DNA. First, information contained in a piece of DNA sequence (gene) is transcribed to messenger RNA (mRNA) by RNA polymerase II enzyme. Transcription occurs in the cell nucleus and involves making an mRNA copy of a gene encoded within the DNA template through complementary base pairing. The DNA sequence of a gene has several elements: (1) a start sequence, which begins mRNA transcription; (2) a promoter sequence, which is located upstream (before) the start sequence and contains transcription factor binding sites that act as switches that can turn transcription “on” or “off”; and (3) enhancers or repressors, which are typically 2000 nucleotides long and are located further upstream from a start site. These additional control elements regulate the rate, amplitude, or quantity of transcription by responding to DNA‐binding proteins, hormones, certain types of vitamins, for example retinoic acid, or growth hormones. The body of a gene contains (1) exons, which are coding DNA sequences that produce protein products; (2) introns, which are noncoding sequences separating exons; and (3) a stop sequence that terminates transcription.

The transcription process begins with RNA polymerase II enzyme binding to a promoter site on the DNA and pulling a portion of a DNA strand apart. Exposed unmatched DNA bases become a template for the sequence of the primary mRNA transcript. Before the primary mRNA transcript leaves the nucleus it undergoes splicing, in which nuclear enzymes remove sections of the RNA (introns) and the remaining sections (exons) are spliced together to form the functional mRNA. After the gene splicing is complete, mature mRNA transcript leaves the nucleus and migrates into the cytoplasm, where it is translated into a protein. Genes that encode ribosomal RNA (rRNA) and transfer RNA (tRNA) are also transcribed and migrate to the cytoplasm, where they facilitate protein synthesis. Some genes contain alternative splice sites, allowing the primary transcript to be spliced in different ways. Alternative splicing produces different protein products from the same primary transcript. The process of alternative splicing is common, therefore the proteome reflecting the human genome (20,000–25,000 genes) well exceeds the number of genes in the human genome. For example, the AMELX or AMELY gene encodes amelogenin, which is the major protein forming enamel extracellular matrix. In human and other mammals, there are six to eight different isoforms of amelogenin, differing in molecular weights and cross‐reactive with anti‐amelogenin rabbit antibodies. These different amelogenin proteins were shown to be produced by alternative splicing of the AMEL gene and not, as previously believed, by post‐translational modifications.21,22 Another example of the effects of alternative splicing on phenotype is dentinogenesis. The dentin sialophosphoprotein gene (DSPP) encodes two different noncollagenous proteins: (1) dentin sialoprotein and (2) dentin phosphoprotein.23,24 Mutations in type I collagen and/or DSPP genes produce five different patterns of dentinogenesis imperfects (inherited dentin defects).23,24

Translation is the process in which mRNA provides a template for the synthesis of a precise sequence of amino acids known as polypeptide or protein. Translation and protein synthesis occur at a ribosome. A tRNA bound to a particular amino acid contains an anticodon that pairs with a codon in mRNA. During translation, tRNAs and their attached amino acids arrive at the ribosomes. The linear sequence of codons of mRNA determines the order in which amino acids are added into a protein. There are 20 different types of amino acids that are encoded by units of 3 mRNA bases known as codons. Of the 64 possible codons, 3 (UAA, UGA, and UAG) signal the end of a gene and are known as stop codons. The remaining 61 codons are functional codons and specify amino acids. There are 64 possible codons (4 mRNA bases3 triplets = 64) and only 20 amino acids, which means that most amino acids can be encoded by more than one codon. Therefore, genetic code is degenerate. Replication of one strand of DNA to a copy strand of DNA, transcription of DNA into mRNA, and translation of mRNA into proteins are cellular processes critical for biologic activity (Figure 27‐1).

Regulation of Gene Expression

All somatic cells have exactly the same DNA sequence; however, there is a large variety of different cell types making different proteins. This is because cells differ at which genes are actively expressed. For example, muscle cells have a different set of genes that are turned on in the nucleus and a different set of proteins that function in the cytoplasm than do for example nerve cells. In most cells only a small fraction of genes is actively transcribed and most genes are transcribed only in specific tissues at specific points in time. For example, the globin genes are transcribed in the progenitors of red blood cells where they help to form hemoglobin, and the low‐density lipoprotein receptor genes are transcribed in liver cells. Some genes, called housekeeping genes, are transcribed in all cells of the body, as they encode key products necessary for a cell’s maintenance and metabolism. A variety of mechanisms regulate gene expression, which can be broadly divided into transcriptional regulation, post‐transcriptional regulation, and epigenetic mechanisms.

Inherited Variation

Transcriptional Regulation of Gene Expression

Gene expression is initiated by transcription factors binding to a promoter region of a gene. General transcription factors are used by all genes, and specific transcription factors initiate transcription of only certain genes at specific points in time. Transcription factors contain DNA‐binding motifs that allow them to interact with specific DNA sequences. Basal transcription levels can be modulated by binding of transcription factors to other regulatory regions such as enhancers and silencers, located thousands of bases away from the transcribed gene. Enhancers do not directly interact with a transcribed gene, but are bound by specific transcription factors (activators) that bind to a second class of specific transcription factors (co‐activators) that in turn bind to general transcription factor complex, enhancing the expression of specific genes at specific points in time. Silencers repress the transcription of genes. Mutations in genes encoding transcription factors as well as mutations in enhancer, silencer, or promoter sequences can result in faulty expression of vital genes, leading to genetic disease. For example, tooth agenesis (oligodontia or hypodontia) is caused by mutations in one or more transcription factors (e.g., MSX1, MSX2, DLX5, PAX9) that may result in inhibition, arrest, or retarded tooth development.2528

Schematic illustration of central dogma of molecular biology: from DNA through mRNA to protein.

Figure 27‐1 Central dogma of molecular biology: from DNA through mRNA to protein. Majority of human DNA resides in the cell nucleus and is organized in chromosomes. Chromosomes contain thousands of genes that are sequences of nucleotides along the chromosome (colored blocks). Genes on a chromosome are separated by noncoding DNA (black blocks). Each genes contains exons, which are coding DNA sequences that produce proteins (red blocs in the primary mRNA transcript), and introns, which are noncoding sequences separating exons (blue lines in the primary mRNA transcript). The primary mRNA transcript is transcribed from the DNA blue print in the nucleus. The primary mRNA contains both exons and introns and undergoes splicing to create mature mRNA transcript. Splicing occurs in the nucleus and involves removal of introns by nuclear splicing enzymes and splicing exons together. Mature mRNA leaves the nucleus and translocate into the cytoplasm to serve as a template for making proteins. In the cytoplasm, the mature mRNA is read in triplicates of nucleotides (codons) that are translated into amino acids (building blocks of proteins) (colored circles).

A number of morphoregulatory master genes encoding highly conserved transcription factors such as HOX (homeotic) genes, PAX genes, and T‐Box genes have been identified. These transcription factors are highly conserved from fish to humans and bind with specific nucleic acid sequence motifs with high affinity. They are major regulators of animal development.29 Mutations in either the FOXC1 or the PITX2 homeobox genes have been found in 40% of Axenfeld–Rieger syndrome (ARS), an autosomal dominant developmental disorder with anomalies of the anterior segment of the eyes, iris hypoplasia, tooth anomalies, craniofacial dysmorphogenesis, cardiac defects, limb anomalies, pituitary anomalies, intellectual disabilities, and neurosensory defects (Figure 27‐2).30

Post‐transcriptional Regulation of Gene Expression

This form of gene regulation includes mechanisms of RNA processing (splicing), mRNA transport, mRNA stability, and translation. For example, alterations in RNA splicing may result in different isoforms of a gene. MicroRNA regulation is another mechanism of post‐transcriptional regulation. MicroRNAs (miRNA) are 17–27 nucleotide‐long RNA molecules that are not translated into proteins. MiRNAs can downregulate the expression of genes they are complementary to by binding to their mRNA transcript. MiRNAs play a crucial role in the control of gene expression. Dysregulation of miRNA expression results in grossly aberrant gene expression, leading to disease,3136 and altered miRNA expression has been associated with the progression of cancer.37,38

Photo depicts clinical presentation of Axenfeld–Rieger syndrome (ARS). Mutations in PITX2 (pituitary homeobox transcription factor 2) and/or FOXC1 (forkhead box transcription factor C1) result in ARS, which represents a spectrum of diseases and disorders, including those of the dentition.

Figure 27‐2 Clinical presentation of Axenfeld–Rieger syndrome (ARS). Mutations in PITX2 (pituitary homeobox transcription factor 2) and/or FOXC1 (forkhead box transcription factor C1) result in ARS, which represents a spectrum of diseases and disorders, including those of the dentition (i.e., extreme dental hypoplasia, as shown in this figure).

Source: Courtesy of Dr. Carl Allen.

Epigenetic Control

Epigenetic mechanisms play an essential functional role in the regulation of transcription. Genetic control of gene expression depends on changes in DNA sequence. Epigenetic changes are heritable (from cell to daughter cell, or from parent to child) changes that do not depend on changes in genome sequence. Epigenetic controls are post‐translational modifications of chromosomal proteins, such as methylation and acetylation, which regulate human conditions via gene–gene and gene–environment influences.

Pretranscriptional Regulation of Gene Expression

DNA is wrapped around histone proteins forming chromatin (a highly organized and densely packaged structure). Chromatin remodeling enzymes alter the folding and basic structure of chromatin, making it more open. Euchromatin is an open structure accessible to transcription factors and therefore transcriptionally active. Histone acetylation is a dynamic epigenetic modification that regulates gene expression. This lysine modification is reversibly controlled by histone acetyltransferases, which add acetyl groups to lysine residues of histones, and deacetylases, which remove the acetyl groups from lysine residues. Addition of acetyl groups reduces histone binding to DNA, helping decondense the chromatin and promoting transcription.

DNA methylation is another epigenetic mechanism that plays an important role in gene regulation.39 It is controlled by DNA methyl transferase enzymes (DNMTs) that add methyl groups to the DNA molecule. Methylation can change the activity of a gene and, when located in a gene promoter, it typically suppresses transcription of that gene.

Additionally, gene actions depend on interaction with the environment. Monozygotic (MZ) twins are genetically identical. However, as MZ twins develop and age they become phenotypically discordant, for example they differ in susceptibilities to diseases and even in anthropometric measurements. Epigenetic regulation can explain phenotypic discordance in MZ twins. Studies of a large cohort of MZ twins found that while they are epigenetically (DNA methylation and histone acetylation profiles) indistinguishable early in life, older MZ twins differ drastically in their overall content and genomic distribution of 5‐methylcytosine DNA and histone acetylation, and therefore in their gene expression profiles.40,41 Epigenetic control of gene expression provides an explanation for how different phenotypes (e.g., arthritis, osteoporosis, periodontal disease, fibromyalgia, Alzheimer’s disease and other forms of dementia) can originate from the identical genotype.


All genetic variation results from a process known as mutation, which is defined as a permanent change in the DNA sequence that can range in size from a single DNA base pair affecting a single gene to a large segment of a chromosome affecting many genes. The effects of gene mutations on health vary depending on where they occur and whether they alter the function of essential proteins. Mutations can be classified into hereditary and acquired (somatic) mutations.42 Hereditary mutations are inherited from a parent and are present in every cell of the body throughout a person’s life. Hereditary mutations are also called germline mutations because they are present in a parent’s gametes (either egg or sperm) and therefore in each cell of an offspring that grows out of the fertilized egg.42 Acquired (somatic) mutations occur at some point during a person’s life and are present only in some cells. They can occur as a result of environmental exposures such as ultraviolet radiation from the sun, or as a result of an error made in DNA replication during cell division. Acquired mutations cannot be passed to the next generation.42

De novo (new) mutations can be either hereditary or somatic. De novo hereditary mutations arise when a mutation occurs in a person’s egg or sperm cell but is not present in any of the other cells, or when a mutation occurs in the fertilized egg shortly after fertilization. The de novo hereditary mutations are present in every cell of a growing embryo. De novo hereditary mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not, and there is no family history of the disorder.42

Mosaicism occurs when a somatic mutation occurs in a single cell early in embryonic development when the embryo includes several cells, but is not present in a parent’s egg or sperm cells, or in the fertilized egg. As cells divide, the cell containing the mutation will give rise to altered cells, while other cells will not. Mosaicism may or may not cause health problems, depending on the type of mutation and the number of cells affected.42

Mutations are also classified based on their size, ranging from changes of a single base (point mutations or single nucleotide polymorphisms, abbreviated SNPs; Figure 27‐3), to insertions and deletions of two or more bases up to a dozen or more bases, or copy number variations (CNVs) up to chromosomal rearrangements involving millions of DNA bases.

Schematic illustration of A. Molecular composition of DNA. DNA is composed of a phosphate–sugar backbone and four nitrogenous bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Adenine always pairs with thymine and guanine always pairs with cytosine. The order of bases determines information encoded in a gene. Nucleotides are read in triplicates called codons and each codon codes for one amino acid (building blocks of proteins). B. Five major types of mutations. Silent mutations result in no change in the encoded amino acid sequence, as multiple codons can code for the same amino acid.

Figure 27‐3 A. Molecular composition of DNA. DNA is composed of a phosphate–sugar backbone and four nitrogenous bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Adenine always pairs with thymine and guanine always pairs with cytosine. The order of bases determines information encoded in a gene. Nucleotides are read in triplicates called codons and each codon codes for one amino acid (building blocks of proteins). B. Five major types of mutations. Silent mutations result in no change in the encoded amino acid sequence, as multiple codons can code for the same amino acid. In missense mutations, a single nucleotide change results in a change of encoded amino acid. Nonsense mutations occur when a single nucleotide change results in the formation of a stop codon (TAA, TAG, and TGA), leading to premature termination of translation and therefore a shortened protein product. Frame‐shift mutations (insertions or deletions) shift a reading frame by shifting nucleotide positions in each triplet codon. They result in a change of the encoded amino acid sequences from the point of mutation. Mutated nucleotides are highlighted in yellow and affected amino acids are highlighted in pink.

Single Nucleotide Polymorphisms

SNPs are the most common type of genetic variation among humans. As the name implies, a SNP is a single base pair change in the DNA sequence at a particular location, for example a SNP may replace a cytosine (C) nucleotide for a thymine (T) nucleotide in a certain stretch of DNA. The frequency of SNPs is on average one in every 1000 nucleotides, resulting in approximately 4–5 million SNPs in a person’s genome.42 SNPs within a gene or its regulatory region may affect the function of the gene and thus have a more direct role in disease. Some SNPs may affect an individual’s response to certain drugs, susceptibility to environmental factors, and risk of developing a particular disease. Most SNPs have no effect on health or development.42 Depending on the effects of an SNP on the encoded amino acid, SNPs can be classified as synonymous (silent) or nonsynonymous. A synonymous SNP occurs when a single base pair change does not result in a change in the amino acid in the protein encoded by a gene. Nonsynonymous SNPs can be further classified as missense or nonsense. A missense SNP occurs when a change in one DNA base pair results in the substitution of one amino acid for another in the protein made by a gene. Examples of human conditions caused by missense mutations are hemoglobinopathies such as sickle cell anemia (typically caused by a single missense mutation resulting in a substitution of valine for glutamic acid at position 6 of the β‐globin) and osteogenesis imperfecta. A nonsense SNP occurs when a change in one DNA base pair results in a stop codon prematurely signaling the cell to stop building a protein. This may result in a shortened protein that may function improperly or not at all.43 SNPs can act as biologic markers, helping scientists locate genes associated with a disease. Genome‐wide association studies (GWAS) have been used to scan markers (SNPs) across genomes of many people to find genetic variations associated with a particular disease (Figure 27‐4). GWAS are particularly useful in finding genetic variations contributing to common, complex diseases, such as asthma,44,45 cancer,46 diabetes,47 and heart disease.48

Insertions and Deletions

Insertion and deletion mutations result in a change of the number of DNA bases in a gene by either adding or removing a piece of DNA, respectively. These mutations can range in size from small (insertion or deletion of a single or a few base pairs) to large (entire gene insertion or deletion). Insertions and deletions are also known as frame‐shift mutations, as they can affect the codon reading frame depending on the number of nucleotides inserted or deleted. Depending on the size and location, insertions and deletions can affect protein function.

Schematic illustration of genome-wide association study (GWAS). GWAS aim at comparing frequencies of a large number of SNPs between cohorts of age- and sex-matched cases and controls. For this reason, DNA is isolated from each individual and genotypes of SNPs are determined on microarrays and subjected to statistical analysis to determine if some alleles are significantly more frequent in either cases or controls.

Figure 27‐4 Genome‐wide association study (GWAS). GWAS aim at comparing frequencies of a large number of SNPs between cohorts of age‐ and sex‐matched cases and controls. For this reason, DNA is isolated from each individual and genotypes of SNPs are determined on microarrays and subjected to statistical analysis to determine if some alleles are significantly more frequent in either cases or controls. The results of GWAS are usually represented as a “Manhattan” plot (shown at the foot of the figure), where each dot represents an SNP, the horizontal axis indicating chromosomes and the vertical axis indicating the statistical significance of disease association. A P‐value <5 ×10‐8 (horizontal line) is generally considered as being statistically significant at the genome‐wide level.

Copy Number Variations

CNVs are a type of genetic variation characterized by a variable number of copies of gene(s). The human genome has two copies of most genes (one copy from each parent). In some cases the number of copies vary, and one, three, or more copies of a gene are present. CNVs account for a significant amount of genetic differences between individuals. Much of the variation due to CNV does not affect health and development, but some variations may affect a person’s risk of developing a disease or response to certain drugs. Examples of disorders caused by CNVs include Williams–Beuren syndrome (an autosomal dominant condition caused by deletion of the 7q11.23 locus), Gaucher disease (an autosomal recessive condition caused by deletion of the NPHP1 gene), and intellectual disability (an X‐linked condition caused by duplication of the HUWE1 gene). CNVs in the CYP2D6 gene can affect the response to about 30 drugs, including opioids, tamoxifen, and antipsychotics.49

Chromosomal Rearrangements

Chromosomal mutations can range from changes in chromosomal structure when fragments of chromosomes get rearranged, missing, or duplicated to changes in chromosome numbers (aneuploidy). Chromosomal rearrangements include translocations, duplications, deletions, and inversions. Translocations occur when a fragment of one chromosome breaks off and attaches to another chromosome. Translocations can be balanced (no genetic material is gained or lost in a cell) or unbalanced (there is a gain or loss of genetic material in a cell). Duplications occur when a part of a chromosome is copied too many times, resulting in extra copies of genetic material from the duplicated segment. Chromosomal deletions result in loss of genetic material anywhere along the chromosome. Aneuploidy refers to a gain or loss of chromosomes from the normal 46.

Changes in chromosome structure or the number of chromosomes lead to problems with the growth, development, and function of the body’s system. Examples of conditions caused by changes in chromosome number include Down syndrome (trisomy 21), which results from the presence of an extra copy of chromosome 21, and Turner syndrome (monosomy of the X chromosome), which is caused by a deletion of one of the X chromosomes in a female. Conditions caused by chromosomal rearrangement include William syndrome, which is caused by a deletion of a region on chromosome 7 (7q11.23, the Williams–Beuren syndrome critical region) containing the elastin gene, and Potocki–Lupski syndrome, caused by duplication of a region on chromosome 17 (17p11.2).


Most diseases have a genetic component and it is believed that genes play a role in over 10,000 human diseases.50,51 It is estimated that approximately 1 in 10 people in the United States—almost 30 million people—has a rare disease, equivalent to the number of people who have diabetes. Although individually rare on a population level, over 5000 single‐gene disorders (called Mendelian disorders because they follow predictable inheritance patterns) have been identified.51 Thousands of these disorders have some phenotypic effect on the oral cavity/craniofacial complex and are therefore seen by dentists. For many of these conditions, (e.g., most forms of amelogenesis imperfecta and isolated cleft palate), the major clinical findings are seen in the oral cavity. For others (e.g., syndromic forms of dentinogenesis imperfecta and syndromic forms of orofacial clefting), the condition may manifest dental as well as significant extraoral findings (e.g., vascular, bone, kidney), meaning these conditions are best managed by an interdisciplinary healthcare team. For some of these conditions the dental findings are the most apparent, and the dentist may be the first to recognize that a genetic condition exists in an individual and/or family.52 Dentists may be the first healthcare provider to detect certain genetic disorders due to their seeing patients across critical times of growth and development.53 Thus, it is important for dental health professionals to have an understanding of basic genetic concepts.54

As our understanding of the genetic basis of diseases improves, the amount of clinically relevant genetic information increases. Web‐based databases that continually catalog and update this information are important resources that allow clinicians to rapidly scan the available information and identify resources to help manage patients (Table 27‐1). Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and can help develop differential diagnoses.51 This database offers overviews of information on all known Mendelian disorders and over 15,000 genes. It focuses on the relationship between phenotype and genotype and is updated daily. Clinicians can use the database to enter clinical findings and help check and develop a differential diagnosis for genetic conditions of interest. Table 27‐2 lists information from the OMIM database for many of the conditions discussed in this section.

Like all healthcare providers, dentists are facing an increase in the application of genetic knowledge in clinical practice. The ability to take a family history to construct a three‐generation pedigree can be important to make a correct diagnosis for both dental and nondental conditions. Disorders of the teeth and periodontium can be inherited. Seemingly isolated dental defects may have extraoral health consequences. Making a correct diagnosis is crucial for a discussion of phenotypic consequences, management, and genetic counseling for recurrence risks. Recurrence is the risk of having a second child in a later pregnancy affected by the same disease or health condition. Sometimes clinical evaluation is enough to establish a diagnosis, but at other times genetic testing is needed.

The decrease in cost to sequence DNA has resulted in increased sequencing of the exome (focusing on the 2% of the genome that codes for proteins) and genome (the entire 3 billion base pairs of DNA). Such sequencing has revealed pathogenic variants underlying conditions such as amelogenesis imperfecta,55 tooth agenesis,56 latent transforming growth factor–beta‐binding protein 3 (LTBP3)‐related disorders,57 and genes not previously known to be involved in tooth development. LTBP3 pathogenic variants are associated with amelogenesis imperfecta, short stature, and predisposition to thoracic aortic aneurysms and dissections.58 Thus, the association of amelogenesis imperfecta and short stature should prompt consideration of referral for cardiac evaluation. Other dental phenotypes may also prompt referral for evaluation. For example, oligodontia can be associated with colon cancer.59 The finding of amelogenesis imperfecta and gingival hyperplasia in an individual may suggest referral for renal imaging.60 Knowledge of the underlying genetic defect can be important in developing treatment plans, such as dental treatment for amelogenesis imperfecta (

Table 27‐1 Genetic resources.

Resource URL Use
Online Mendelian Inheritance in Man (OMIM) Type in phenotypic features for a list of disorders that include those features
GeneReviews Provides overviews of many genetic disorders, including diagnosis, management, and recurrence risks
Genetic Alliance Network of disease‐specific advocacy organizations, universities, private companies, government agencies, and public policy organizations
Genetic and Rare Disease Information Center (GARD) Provides information on specific genetic disorders to the public, including healthcare professionals, patients, and families
National Organization of Rare Diseases Patient advocacy organization focused on individuals with rare diseases and the organizations and clinicians that serve them
American College of Medical Genetics and Genomics


Locate a geneticist
National Society of Genetic Counselors

Genetic Counsellor Registration Board

Australasian Society of Genetic Counsellors

Locate a genetic counselor
Genetic Testing Registry



Locate a testing facility
Clinical Trials Locate a clinical trial worldwide

As shown in Figure 27‐3, a variety of DNA nucleotide sequence changes can occur. With the availability of inexpensive DNA sequencing, many thousands of human genomes have been sequenced, revealing hundreds of thousands of DNA sequence variants. The challenge is to determine which of these are important and have a biologic or phenotypic consequence when present. When a sequence change is identified, it must be evaluated to determine whether the change, or variant, produces a phenotype and is therefore pathogenic. Guidelines have been published to aid in the interpretation of sequence variants.61 A five‐scale classification system is used: pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign. The term mutation and polymorphism are no longer used in order to be clearer regarding the functional consequence of identified variants. In general, the term pathogenic variant is now used instead of the term mutation. As more individuals have their genomes sequenced, variants may be reclassified. A recent study found that approximately 25% of variants of uncertain significance have been reclassified over time, including upgrades and downgrades.62

Table 27‐2 Examples of dental‐craniofacial genetic conditions from the Online Mendelian Inheritance in Man (OMIM) database. Information includes syndrome name, associated OMIM syndrome number, mode of inheritance, and tooth/oral findings. The name of each specific gene(s) involved in the etiology, gene symbol, chromosomal location, and OMIM gene number are included.

Source: HUGO Gene Nomenclature Committee Approved Gene Nomenclature. HGNC Database, February 2020.

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Type Syndrome OMIM Number for Syndrome Inheritance Overview of Craniofacial‐Oral‐Dental Features Gene Name Gene Symbol Chromosomal Location

Nov 28, 2021 | Posted by in General Dentistry | Comments Off on The Role of Genetics in Oral Medicine
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