Isolated dentinogenesis imperfecta: Novel DSPP variants and insights on genetic counselling

Dentin is the main hard core forming the tooth body, situated beneath enamel and cementum. It is the defender of the sensitive pulp tissue. The main component of dentin is crystalline tissue, organic matrix, and water. Collagen type I predominates in the collagenous protein network of the dentinal configuration [6] The current advancement in the field of molecular genetics allowed unraveling of the pleiotropic action of many genes involved in odontogenesis with their complicated interactive networking and pathways [7]. Dentin defect is the sequela of altered extracellular matrix formation and mineralization. Dentin dysplasia and dentinogenesis imperfecta are inherited monogenic disorders with an autosomal dominant pattern of inheritance [4].

In this study, we identified heterozygous DSPP variants as the cause of DI in our two families. Two new nonsense variants: c.288T > A (p.Tyr96Ter) and c.255G > A (p.Trp85Ter) in the same exon (exon 4) were identified. Both variants are expected to result in early protein truncation and nonsense mediated decay. So far, around 50 different DSPP variants have been described in patients with DI or dentin dysplasia from various ethnic groups [5, 8‐13]. Majority of these variants are located in exon 5 which is likely due to its large size rather than being a hot-spot exon for mutations. Although several protein truncating variants have been reported in the DSPP gene, only one nonsense variant (c.133 C > T, p.Gln45Ter) has been previously described [14, 15]. This variant is located at the splice region of exon 3, three nucleotides before the end of the exon. Several studies have confirmed the splicing effect of this variant leading to skipping of exon 3 [16, 17]. In contrast, the identified variants in our study are located away from the splice site of exon 4 and therefore are not likely to alter splicing. As a result, both of these variants might be considered the first true nonsense variants identified in the DSPP. In view of reported variants, very few were recurrent e.g. the c.52G > T (p.Val18Phe) which was described in 6 unrelated families of Chinese (3 families), Korean, Caucasian, and Finnish origin [18‐21, 9]. Also, the c.53T > A (p.Val18Asp) was reported in three families from Korea [22, 23] and Japan [24]. Other variants were even rarer and found in one family each.

The DSPP gene consists of five exons and encodes the dentin sialophosphoprotein which has two main domains, the amino-terminal dentin sialoprotein (DSP) and carboxyl-terminal dentin phosphoprotein (DPP). Exons 1 to 4 and the anterior part of exon 5 encode for the DSP while the posterior part of exon 5 encodes for DPP. Previous studies have showed that variants in the DSP region, regardless of their type (missense or protein truncating), are associated with DI while protein truncating variants in the DPP are associated with the dentin dysplasia [8, 15, 16]. Interestingly, our two families harbored variants in the DSP region and presented with DI. Therefore, our results are in accordance with such observation and support the presence of phenotype-genotype correlations in patients harboring DSPP variants.

Although DSPP gene seems to be the main causative gene for DI, some reports failed to identify variants in the gene in patients with DI [5, 9]. This led authors to suspect the presence of other etiologies for DI. Recently, heterozygous variants in COL1A2 gene, which usually cause osteogenesis imperfecta type II, III and IV as well as several types of Ehler-Danlos syndrome, were reported in three families with non-syndromic dentinogenesis imperfecta by Lee and co-authors [23]. The study of Lee et al. broadened the spectrum of DI causative genes and highlighted the importance of using whole exome sequencing to unravel novel DI genes [23].

Dentinogenesis imperfecta is known to be associated with pulp obliteration and thin roots. The defective dentin has atypical effect towards external stimulants which might lead to hypertrophied dentin formation and pulp chamber obliteration [24]. As a result, periapical pathosis occurs. The prevalence of periapical lesions is greater in narrow root canals or obliterated. Consequently, loss of teeth due to pathosis is prominent [8]. Elder patients of Family 1 complained of complete pulp obliteration without exhibiting any periapical pathosis.

Genetic counseling and risk assessment are performed under strict ethical considerations taking into account the psychological and socioeconomic class of the counselee. The ethical considerations particularly respecting the counselee’s autonomy and privacy are considered universal that is to say they are protected at all instances regardless of the counselee’s ethnicity and religious beliefs. Over the years, the concept of the counselee’s autonomy has evolved from strict non-directiveness to balanced and well-educated protection of the counselee’s autonomy [25]. This what was followed in the sessions with our families specially Family 1.

In Muslim countries like Egypt, abortion is allowed in case the fetus is proven to be deformed to the degree that the quality of life would be diminished considerably as in multiple congenital anomalies, neurodegenerative diseases or metabolic disorders that have no cure yet among other disorders and this must be done before the end of the fourth month of pregnancy [26]. For a condition like DI where the patients’ complaint is only the yellowish color of the teeth, abortion would be legally and religiously prohibited. However, parents of Family 1, like other parents across the globe, were very concerned and wanted to have kids with normal teeth to avoid subjecting them to bullying from other kids and school colleagues. They were informed about the possibility of pre-implantation genetic (PGD) testing which would save them the hassle of prenatal testing and abortion. However, a major problem with PGD is its high cost which cannot be afforded by majority of parents in our country. Therefore, parents were advised to seek psychological help for for their affected children which is empirical in these cases [27]. On the contrary, the outcome of genetic counseling of Family 2 was very positive as parents were very happy when informed that neither of them carries the DSPP variant and that the recurrence risk has decreased from 50% in each pregnancy to less than 1–2% [28]. However, we are aware that parental gonadal mosaicism was not ruled out in this family.