Tooth agenesis is one of the most common developmental anomalies in humans; however, its underlying cause is complex and remains largely unknown. We have previously reported that the prevalence rates of hypodontia and oligodontia, which are subtypes of the condition, in the Japanese population are 6.8% and 0.1%, respectively; we also found that sibling recurrence risks corresponded to 25.0% and 43.8%, respectively. These observations suggest that oligodontia, the more severe tooth agenesis phenotype of the two subtypes, is mostly inherited in a dominant manner1. Multiple congenitally missing teeth have been associated with abnormalities in several genes encoding Msh homeobox 12,3,4,5, ectodysplasin A6,7, axin inhibition protein 28, paired box gene 99, Wnt family member 10A (WNT10A)10,11, and low-density lipoprotein receptor-related protein 6 (LRP6).

To date, 12 functionally null variants of the LRP6 gene have been identified in families with congenital tooth agenesis12,13,14,15. In this study, we performed whole-exome sequencing (WES) as previously described16 using genomic DNA from a Japanese family with congenital tooth agenesis and identified a novel frameshift mutation in LRP6. This study was approved by the Aichi-Gakuin University Committee on the Ethics of Human Experimentation (Nagoya, Japan; approval no. 58), the Institute for Developmental Research (Kasugai, Japan; approval no. 13-07) and IRB of Yokohama City University Graduate School of Medicine (Yokohama, Japan, approval no. A201200014).

A 48-year-old Japanese woman diagnosed with familial oligodontia was referred to our hospital (II-2, Fig. 1A). Clinical examination, including radiographic analysis, confirmed the diagnosis of oligodontia in the proband with 23 missing permanent teeth (Fig. 1B). Subsequently, three other members of her family (I-1, II-1, and III-3) were analyzed, and one of her children (III-3) was diagnosed with oligodontia. However, we could not definitively diagnose her father with congenital tooth agenesis because of severe tooth loss. All of the family members had normal primary dentition, nails, skin, and hair.

Fig. 1: Pedigree of the case patients and permanent tooth number anomalies in the proband.
figure 1

A Family pedigree. The arrow indicates the proband (II-2). Open square, nonaffected male; solid square, affected male; open circle, nonaffected female; solid circle, affected female. B Panoramic radiograph of the proband (II-2) showing the absence of permanent teeth.

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WES detected a heterozygous single-nucleotide insertion in exon 9 of LRP6 (NM_002336.2(LRP6_v001): c.1924dup) (Fig. 2). The variant is not present in Exome　Aggregation Consortium or the 1000 Genome database. Polymerase chain reaction and Sanger sequencing confirmed that our index case patient’s child, III-3, and father, I-1, also carried this insertion. The mutation is predicted to generate a protein with a truncated extracellular domain (NM_002336.2(LRP6_i001): p.(p.Ile642Asnfs11*)).

Fig. 2: LRP6 (low-density lipoprotein receptor-related protein 6 gene) mutation cosegregates with tooth agenesis.
figure 2

A Partial DNA sequence of exon 9 (nucleotide position, 1915–1936) of the LRP6 gene (NM_002336.2) in a nonaffected family member (II-1; Left panel). Heterozygous mutation in the proband (II-2; Right panel). The single base insertion (arrow) leads to an amino acid substitution of Ile to Asn at 642 and introduces a premature stop codon after an unrelated 11-amino acid sequence.

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The Wnt family consists of 19 secreted glycoproteins that regulate homeostasis in various adult tissues and are related to various diseases via the actions of several signaling molecules, such as frizzled receptors and LRP coreceptors17. WNT10A is the causative gene for rare autosomal recessive ectodermal dysplasia presenting with syndromic tooth agenesis18,19. Disfunction of WNT10A is associated not only with recessive syndromic congenital anomalies but also with a dominantly inherited form of selective tooth agenesis20. The LRP5 and LRP6 genes are crucial for various Wnt/β-catenin signaling pathways. Several studies have revealed that loss-of-function mutations in LRP6 cause the autosomal dominant form of selective tooth agenesis (STHAG7: MIM 616724)12,13,14,15. Therefore, the Wnt/β-catenin signaling pathway is considered to be associated with tooth development.

In conclusion, we identified a novel LRP6 variant, c.1924dup, in a Japanese family with tooth agenesis. The gene product of the p.(p.Ile642Asnfs11*) variant is a truncated form of the protein lacking transmembrane and cytoplasmic domains. Moreover, we attempted to screen shared gene variations among case patients using WES data, but promising candidate genes other than LRP6 variant were not identified. Therefore, c.1924dup appears to be a novel causative variant for tooth agenesis in the family investigated. Further studies are needed to determine the precise molecular pathology of Wnt-signaling-related diseases.

HGV database

The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3078.