Genetic Basis of Dental Agenesis: Non-Syndromic Hypodontia

Review Article

J Dent & Oral Disord. 2021; 7(4): 1171.

Genetic Basis of Dental Agenesis: Non-Syndromic Hypodontia

Karamini A1,2*, Chavli A1,2 and Kritis A1,2

¹Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece

²cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece

*Corresponding author: Alexia Karamini, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece; cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), Thessaloniki, Greece

Received: July 20, 2021; Accepted: August 11, 2021; Published: August 18, 2021


Tooth agenesis or hypodontia is one of the most prevalent developmental anomalies of the human dentition which affects up to 8% of the Caucasian population. It is a quite heterogenous condition which describes the congenital absence of one or more teeth and can occur either with a syndrome (syndromic hypodontia) or without (non-syndromic hypodontia). Hypodontia still constitutes a challenging clinical problem. Our insight on the cause of tooth agenesis is increasing as a result of recent advances in the field of molecular biology and human genetics. Further research is needed to establish a genotype phenotype correlation and to fully understand the pathogenesis of tooth agenesis. This review presents the genes and signaling pathways associated with nonsyndromic hypodontia, based on the most current literature and provides an overview of novel genes that seem to contribute to dental agenesis.

Keywords: Dental agenesis; Oligodontia; Hypodontia; Genetics; Molecular biology


Tooth development begins during embryonic day 9-11, from the oral epithelium under the governance of signal transduction pathways [1,2]. These pathways establish a crosstalk between two adjacent tissues, the mesenchymal stem cells originating from cranial neural crest cells and the primitive epithelium lining the stomatodeum. Genes associated with dental development encode signal transducers, transcription and decisive factors of cell proliferation and differentiation [3]. This constant mesenchymeepithelium interaction throughout tooth development regulates growth, determines differentiation and pattern formation [4,5]. The type of genes involved as well as their expression affect tooth primordium in such a way that its development may be arrested at the bud or cap or bell stage, or even be altogether abolished [1].

Among dental abnormalities of human dentition, tooth agenesis is the most common, defined as absence of development of one or more teeth [2,6,7]. In this congenital condition, permanent dentition is not fully formed to an extent that varies from 2.2% to 10.1%, depending on factors such as race and nationality. Third molars are the most affected. Upper lateral incisors, mandibular second premolars and maxillary second premolars come next. Agenesis involving first and second molars is very rare [8]. One of the most frequently presented forms of hypodontia is maxillary lateral incisors agenesis [9].

Hypodontia is a clinically challenging problem. One to six teeth are absent with considerable variation in both expressivity and penetrance. Oligodontia represents the congenital absence of six or more teeth and anodontia refers to absence of all teeth [4,6,7,10]. To this classification absence of third molars is not considered.

Up to 8% of Caucasian population have tooth agenesis, mostly in incisors and/or premolars, only 0.25% have oligodontia, whereas anodontia is very rare [10,11]. Hypodontia mainly appears due to genetic causes and can occur, either along with other genetic conditions due to a clinical syndrome or as a non-syndromic form [1]. However, other factors may also be involved in tooth agenesis pathogenesis such as infectious diseases, trauma of the dental region, drug use during pregnancy and chemo or radiotherapy [12]. Non- syndromic hypodontia may be sporadic, or familial, concerning mostly the secondary dentition [4,13-15]. It is inherited in an autosomal-dominant, autosomal recessive, or X-linked mode [6,7,10,16]. Environmental and genetic factors may cause sporadic cases of 1 to 3 missing teeth, again not considering third molars. Hypodontia may be the only abnormality attributed also to nonsporadic cases [4]. Familial non-syndromic hypodontia is presented with significant heterogeneity [6]. More specifically, family members with the condition may be characterized with different location, symmetry and number of teeth involved [16]. Known mutations influence all major signaling transduction pathways and typically entail characteristic phenotypes in teeth affected [2].

Genes in Teeth Development

Tooth morphogenesis involves more than 300 genes. The number and structure of teeth is determined to a great extent by genetic and environmental factors. These factors are multilevel and progressive [7]. Although hypodontia is not considered a wide public health problem, it may be responsible for speech and masticatory difficulties, esthetic problems and malocclusion [17]. Advancements in molecular biology such as the now complete human genome sequences and gene mapping techniques on families known to have hypodontia/ oligodontia have contributed a lot in the detection of the genetic factors associated with tooth agenesis [16].

The genes’ regulatory role throughout the development of the tooth organ and the relation with all major signal transduction cascades and transcription factors mediating these signaling pathways has been identified [1,18]. Changes in the nucleotides in the identified genes lead to malfunctions in proteins as well as altered structure and/or interactions. As a result, tissues may not play their role correctly and lead to missing teeth, due to the breakdown in the signaling cascade [4]. Several genes have a pronounced effect on tooth development (MSX1, PAX9, WNT10, EDA, AXIN2, LEF1, LTBP3), while others’ influence is moderate (DLX1, DLX2, GLI2, GLI3) [1].

Mutations in axis inhibition protein 2 (AXIN2), muscle segment homeobox 1 (MSX1), paired box gene 9 (PAX9) and wingless-type MMTV integration site family, number 10 (WNT10A) are identified to have a strong relationship with isolated tooth agenesis [4]. MSX1 and PAX9 were the first genes with detected mutations in isolated tooth agenesis [2,6]. Detection of similar dominant mutations in AXIN2 gene followed and lately, mutations in isolated tooth agenesis have been confirmed in EDA and WNT10A. EDA encodes a signal molecule ectodysplasin which plays a role in the epithelium. Mutations in WNT10A were detected for the first time in patients with recessive Odonto-Onycho-Dermal Dysplasia (OODD) and Schopf-Schulz-Passarge Syndrome (SSPS). WNT10A’s impact on tooth agenesis depends on its expression in the epithelial signaling centers (Figure 1) [2]. Frameshift and nonsense mutations are mainly involved and lead to major modification of the primary structure of the protein.