Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Abstract

Non-syndromic tooth agenesis (ns-TA) is one of the most common dental anomalies characterized by the congenital absence of at least one permanent tooth (excluding third molars). Regarding the essential role of genetic factors in ns-TA aetiology, the present study aimed to identify novel pathogenic variants underlying hypodontia and oligodontia. In a group of 65 ns-TA patients and 127 healthy individuals from the genetically homogenous Polish population, the coding sequences of 423 candidate genes were screened using targeted next-generation sequencing. Pathogenic and likely pathogenic variants were identified in 37 (56.92%) patients, including eight nucleotide alternations of genes not previously implicated in ns-TA (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22 and TP63). However, since only single variants were detected, future research is required to confirm and fully understand their role in the aetiology of ns-TA. Additionally, our results support the importance of already known ns-TA candidate genes (AXIN2, EDA, EDAR, IRF6, LAMA3, LRP6, MSX1, PAX9 and WNT10A) and provide additional evidence that ns-TA might be an oligogenic condition involving the cumulative effect of rare variants in two or more distinct genes.

Characterization of novel MSX1 variants causally associated with non‐syndromic oligodontia in Chinese families

“…We summarized and analyzed the genotype–phenotype relationships of NSTA caused by MSX1 variants reported in 1996–2022 (Abid et al., 2017; Adachi et al., 2021; AlFawaz et al., 2015; Arte et al., 2013; Bergendal et al., 2011; Biedziak et al., 2022; Bonczek et al., 2018; Ceyhan et al., 2014; Chishti et al., 2006; Daw et al., 2017; De Muynck et al., 2004; Kamamoto et al., 2011; Keskin et al., 2022; Kim et al., 2006; Kimura et al., 2014; Ma et al., 2020; Mitsui et al., 2016; Mostowska et al., 2006, 2012; Mu et al., 2013; Şahan & Akan, 2021; Tatematsu et al., 2015; Vastardis et al., 1996; Wong et al., 2014; Xin et al., 2018; Xuan et al., 2008; Xue et al., 2016; Yamaguchi et al., 2014; Yang et al., 2020; Yue et al., 2022; Zheng et al., 2021). In brief, we identified 46 patients with 44 MSX1 variants, including the patients in this study (Table S1).…”

Classification, Symptoms, Diagnosis, and Treatment of Oral Genetic Disorders

“…nc/4.0/ -http://creativecommons.org/licenses/by ( EDARADD, KREMEN1, and BMP4. Pathogenic or likely pathogenic nucleotide changes were observed in 56.92% of those affected, including eight nucleotide alterations of genes not previously implicated in non-syndromic tooth agenesis (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22, and TP63) [33].…”

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective

“…It was first discovered as a candidate gene in an NSTA individual in 2001 ( Schneider et al, 2001 ) and was first identified in an X-linked inherited NSTA family in 2006 ( Tao et al, 2006 ). To date, 45 mutations in EDA have been linked to NSTA ( Schneider et al, 2001 ; Tao et al, 2006 ; Tarpey et al, 2007 ; Fan et al, 2008 ; Han et al, 2008 ; Li et al, 2008 ; Rasool et al, 2008 ; Mues et al, 2009 ; Song et al, 2009 ; Ayub et al, 2010 ; Mues et al, 2010 ; Arte et al, 2013 ; He et al, 2013 ; Nikopensius et al, 2013 ; Yang et al, 2013 ; Lee et al, 2014 ; Sarkar et al, 2014 ; Zhang et al, 2015 ; Gaczkowska et al, 2016 ; He et al, 2016 ; Shen et al, 2016 ; Bock et al, 2017 ; Martins et al, 2017 ; Yamaguchi et al, 2017 ; Zeng et al, 2017 ; Martínez-Romero et al, 2019 ; Parveen et al, 2019 ; Zhang et al, 2021a ; Biedziak et al, 2022 ; Yu et al, 2022 ), with missense mutations accounting for the majority (39/45). In addition, deletion mutations (3/45), altered splicing (2/45), and non-sense mutation (1/45) were also found in NSTA cases.…”

“…The EDAR gene is a 425-kb segment located on chromosome 2q11-13. In total, 24 EDAR variants have been identified in NSTA since 2013 ( Arte et al, 2013 ; Chen et al, 2017 ; Yamaguchi et al, 2017 ; Zeng et al, 2017 ; Jonsson et al, 2018 ; Mumtaz et al, 2020 ; Zhang et al, 2020 ; Zhang et al, 2021a ; Zhang et al, 2021b ; Biedziak et al, 2022 ; Yu et al, 2022 ; Zhao et al, 2022 ). As an integral component of the EDA/EDAR/NF-κB signaling pathway, EDAR binds to EDA through the extracellular LBD upstream and interacts with EDARADD through the intracellular death domain downstream.…”