Intarak Narin, Manaspon Chawan, Theerapanon Thanakorn, Prommanee Sasiprapa, Samaranayake Lakshman, Shotelersuk Vorasuk, Porntaveetus Thantrira
Center of Excellence in Genomics and Precision Dentistry, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand.
Oral Dis. 2024 Nov;30(8):5195-5202. doi: 10.1111/odi.14930. Epub 2024 Mar 19.
To investigate the role of Keratinocyte Differentiation Factor 1 (KDF1) in ectodermal dysplasia (ED) and nonsyndromic tooth agenesis (NSTA) and perform a literature review.
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.
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.
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.
研究角质形成细胞分化因子1（KDF1）在外胚层发育不良（ED）和非综合征性牙齿缺失（NSTA）中的作用，并进行文献综述。
采用基因组测序技术在一名泰国NSTA先证者中鉴定基因变异，并通过桑格测序进行验证。使用美国医学遗传学与基因组学学会（ACMG）指南、MetaRNN和AlphaMissense评估致病性。对KDF1/NSTA病例进行全面回顾，以对先证者进行基因型-表型分析。
先证者有多颗牙齿缺失、龋齿和广泛的牙周疾病。深入的表型分析显示，除牙齿缺失外，没有ED的迹象。鉴定出的新型KDF1变异体p.Ile243Leu，被ACMG分类为“可能致病”，并通过MetaRNN和AlphaMissense分析预测为“有害”。总共14例回顾的KDF1病例显示，与ED相关的变异体（8例患者中的3个变异体）聚集在DUF4656结构域内氨基酸251-275区域，而导致NSTA的变异体（6例患者中的4个变异体）通常在该区域的氨基或羧基末端发现。KDF1/NSTA病例平均有15颗牙齿缺失，在下颌骨中的患病率更高。
本研究在泰国人群中鉴定出一种与NSTA相关的新型KDF1变异体。基因型-表型相关性表明KDF1相关NSTA具有独特的模式和牙齿缺失情况。
