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

Narin Intarak; Chawan Manaspon; Thanakorn Theerapanon; Sasiprapa Prommanee; Lakshman Samaranayake; Vorasuk Shotelersuk; Thantrira Porntaveetus

doi:10.1111/odi.14930

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

Oral Dis. 2024 Mar 19. doi: 10.1111/odi.14930. Online ahead of print.

Authors

Narin Intarak¹, Chawan Manaspon^{2

3}, Thanakorn Theerapanon¹, Sasiprapa Prommanee¹, Lakshman Samaranayake⁴, Vorasuk Shotelersuk^{5

6}, Thantrira Porntaveetus¹

Affiliations

¹ Center of Excellence in Genomics and Precision Dentistry, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
² Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand.
³ Biomedical Engineering and Innovation Research Center, Chiang Mai, Thailand.
⁴ Faculty of Dentistry, University of Hong Kong, Hong Kong and Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
⁵ Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁶ Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.

PMID: 38501196
DOI: 10.1111/odi.14930

Abstract

Objectives: To investigate the role of Keratinocyte Differentiation Factor 1 (KDF1) in ectodermal dysplasia (ED) and nonsyndromic tooth agenesis (NSTA) and perform a literature review.

Methods: Genome 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.

Results: The 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.

Conclusion: This 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.

Keywords: ectodermal dysplasia; gingival inflammation; oligodontia; periodontitis.