Amelogenesis and Dentinogenesis Imperfecta Panel

Amelogenesis imperfecta (AI) is a heterogeneous group of conditions characterized by inherited developmental defects in the formation of enamel affecting both primary and permanent teeth. Affected teeth are abnormally thin, soft, fragile, pitted or grooved, discolored and prone to rapid wear and breakage, associated with early tooth loss, eating difficulties, and pain. Based on the clinical and radiographic features of the enamel defects as well as on the mode of inheritance pattern, AI has been divided into different subtypes, which can be grouped into four major forms. These include hypoplastic AI (type I) and hypomaturation AI (type II), which is further subdivided into hypocalcified (type III) and hypomaturation/hypoplastic/taurodontism (type IV) (Witkop et al. 1988. PubMed ID: 3150442; Smith et al. 2017. PubMed ID: 28694781). Type I hypoplastic AI is characterized by thin but mineralized enamel or, in extreme cases, the complete absence of enamel (secretion stage related defect). Type II hypomineralized AI gives rise to enamel that is of full thickness but is weak and fails prematurely (maturation stage-related defect). Type III hypocalcified AI, which is caused by incomplete removal of protein from the enamel matrix, may present with brittle enamel that can be easily scraped or chipped away by attrition. Type IV hypomaturated-hypoplastic with taurodontism AI is characterized by insufficient transport of calcium ions into the developing enamel and produces soft enamel (Witkop et al. 1988. PubMed ID: 3150442; Crawford et al. 2007. PubMed ID: 17408482; Smith et al. 2017. PubMed ID: 28694781). The frequency of amelogenesis imperfecta varies between populations, and it is estimated to range from 1 in 700 to 1 in 14,000 (Smith et al. 2017. PubMed ID: 28694781).

Dentinogenesis imperfecta is a hereditary dentin defect which is characterized by severe hypomineralization of dentin and altered dentin structure. Prevalence of dentinogenesis imperfecta is estimated to be ~1/6,000 to 1/8,000 (Dure-Molla et al. 2015. PubMed ID: 25118030).

This panel includes genes associated with amelogenesis imperfecta, enamel dysplasia, or dentinogenesis imperfecta. These disorders are genetically heterogenous and can be inherited in an autosomal dominant, autosomal recessive, and X-linked manner. A 2017 study reported that of the AI families with a known pathogenic variant, 132 (48.9%) had autosomal dominant AI, 109 families had findings associated with autosomal recessive inheritance (40.4%) and 31 families were identified with X linked inheritance (11.5%) (Smith et al. 2017. PubMed ID: 28694781). All types of variants have been reported in the genes within this panel, including missense, nonsense, small deletions, duplications, insertions, indels, splicing, and regulatory variants. Copy number variants have also been reported in several of these genes.

Enamel or dentin defects can also present as clinical features of syndromic disorders. For example, Jalili Syndrome is an autosomal recessive disorder characterized by cone-rod dystrophy and amelogenesis imperfecta and is associated with pathogenic variants in the CNNM4 gene (Jalili et al. 1988. PubMed ID: 3236352; Jalili et al. 2010. PubMed ID: 20706282; Parry et al. 2009. PubMed ID: 19200525). Pathogenic variants in LTBP3 have been associated with autosomal recessive dental anomalies and short stature (Huckert et al. 2015. PubMed ID: 25669657). Pathogenic variants in FAM20C have been reported in individuals with Raine syndrome and enamel dysplasia (Fradin et al. 2011. PubMed ID: 20825432). Pathogenic variants in SLC10A7 have been associated with autosomal recessive short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS) (Ashikov et al. 2018. PubMed ID: 29878199; Dubail et al. 2018. PubMed ID: 30082715). Furthermore, COL17A1 variants are associated with the autosomal recessive condition junctional epidermolysis bullosa (JEB); in addition, JEB patients often present with hypoplastic, pitted enamel (Wright et al. 1993. PubMed ID: 8297258), and heterozygous carriers of some pathogenic variants in this gene sometimes have AI in the absence of any skin phenotype (McGrath et al. 1996. PubMed ID: 8669466; Poulter al. 2014. PubMed ID: 24319098; Prasad et al. 2016. PubMed ID: 26502894).

Due to insufficient epidemiological data on amelogenesis and dentinogenesis imperfecta, it is difficult to estimate prevalence; however, analysis of published AI disease-causing variants identified in 270 families revealed that four genes included in this panel account for ~60.4% of AI cases. Variants were most commonly identified in FAM83H (19.3% of cases), followed by FAM20A (15.2%), ENAM (14.2%), and AMELX (11.5%) (Smith et al. 2017. PubMed ID: 28694781). Therefore, this entire panel is expected to identify a molecular finding for more than 50% of clinically diagnosed AI.

Furthermore, this panel can identify copy number variants in genomic regions/genes included in this panel. For example, gross deletions/duplications greater than 100 bp have been reported in AMELX, AMBN, AMTN, CNNM4, COL1A1, COL1A2, COL17A1, DLX3, DSPP, FAM20A, FAM20C, GPR68, LAMA3, LAMB3, ROGDI, SLC10A7, SLC13A5, SLC24A4, and WDR72 (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides at least 96.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).