Tooth agenesis related to a novel KDF1 variant: A case report and literature review

Abstract

AbstractObjectivesTo investigate the role of Keratinocyte Differentiation Factor 1 (KDF1) in ectodermal dysplasia (ED) and nonsyndromic tooth agenesis (NSTA) and perform a literature review.MethodsGenome sequencing was used to identify genetic variants in a Thai, NSTA proband and validated through Sanger sequencing. Pathogenicity was assessed using ACMG guidelines, MetaRNN and AlphaMissense. A comprehensive review of KDF1/NSTA cases informed genotype–phenotype analysis of the proband.ResultsThe proband revealed multiple missing teeth, caries and extensive periodontal disease. Deep phenotyping showed no signs of ED beyond tooth agenesis. The identified novel KDF1 variant, p.Ile243Leu, was classified as ‘likely pathogenic’ by ACMG and predicted as ‘detrimental’ by MetaRNN and AlphaMissense analyses. A total of 14 reviewed KDF1 cases revealed ED‐associated variants (3 variants in 8 patients) clustering in the region of amino acids 251–275, within the DUF4656 domain, while NSTA‐causing variants (4 variants in 6 patients) were typically found in amino‐ or carboxy‐termini to this region. KDF1/NSTA cases exhibited an average of 15 missing teeth, with a higher prevalence in the mandible.ConclusionThis study identifies a novel KDF1 variant‐related NSTA in Thai people. The genotype–phenotype correlates suggest a distinctive pattern and tooth agenesis of KDF1‐related NSTA.