Abstract
BACKGROUND: Tooth agenesis (TA) is a congenital abnormality that may present as syndromic or nonsyndromic. Considering its complex genetic aetiology, the aim of this study was to uncover the pathogenic mutants in patients with nonsyndromic TA and analyse the characteristics of these mutants. METHODS: Exome sequencing was performed to detect pathogenic variants in 72 patients from 43 unrelated families with nonsyndromic TA. All candidate variants were validated using Sanger sequencing. Bioinformatics and conformational analyses were performed to determine the pathogenic mechanisms of the mutants. RESULTS: The following eight mutations (six novel and two known) in six genes were identified in eight families: WNT10A [c.742C > T (p.R248*)], LRP6 [c.1518G > A (p.W506*), c.2791 + 1G > T], AXIN2 [c.133_134insGCCAGG (p.44_45insGQ)], PAX9 [c.439C > T (p.Q147*), c.453_454insCCAGC (p.L154QfsTer60)], MSX1 [c.603_604del (p.A203GfsTer10)] and PITX2 [c.522C > G (p.Y174*)]. Bioinformatics and conformational analyses showed that the protein structures were severely altered in these mutants, and indicated that these structural abnormalities may cause functional disabilities. CONCLUSIONS: Our study extends the mutation spectrum in patients with nonsyndromic TA and provides valuable data for genetic counselling. The pathogenic mechanisms of TA in patients/families with unknown causative variants need to be explored further.