Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone Full Length Article Whole-exome sequencing in a Japanese pedigree implicates a rare non- synonymous single-nucleotide variant in BEST3 as a candidate for mandibular prognathism Takashi S. Kajii a, ⁎ , Akira Oka b , Fumio Saito c , Jun Mitsui d , Junichiro Iida c a Section of Orthodontics, Department of Oral Growth and Development, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan b Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan c Department of Orthodontics, Division of Oral Functional Science, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan d Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan ARTICLEINFO Keywords: Genetics Whole-exome sequencing Bestrophin 3 Mandibular prognathism Endochondral growth Japanese ABSTRACT Mandibular prognathism is a phenotype of facial deformity seen in populations around the world, but with higher incidence among East Asian populations. Five genome-wide nonparametric linkage analyses and a genome-wide association study to identify susceptibility loci of the phenotype have shown inconsistent results. To explore variants related to mandibular prognathism, we undertook whole-exome sequencing in a Japanese pedigree. The pedigree was ascertained as mandibular prognathism. The pedigree comprised 15 individuals from 4 generations. Four afected individuals across 2 generations and 5 unafected individuals were chosen for whole-exome sequencing. Five non-synonymous single-nucleotide variants (SNVs) of UBASH3B, OR6M1, OR8D4, OR8B4, and BEST3 genes were detected in all 4 afected individuals, but in none of the 5 unafected individuals. A non-synonymous SNV of the BEST3 gene, Chr12(GRCh37):g.70048878G > T, NM_032735.2:c.1816C > A, p.(L606I), was identifed as rare missense variant. BEST3 is located on chromosome 12q15 and encodes bestrophin 3 from the bestrophin family of anion channels. The 4 other non-synonymous SNVs of UBASH3B, OR6M1, OR8D4, and OR8B4 were not considered plausible candidates for mandibular prognathism. Our whole-exome sequencing implicates a rare non-synonymous SNV of BEST3 as a candidate for mandibular prognathism in the Japanese pedigree. 1. Introduction Mandibular prognathism (Online Mendelian Inheritance in Man [OMIM] #176700), a skeletal Class III malocclusion in orthodontics, is a morphological disorder of the face (phenotype) that occurs in popu- lations throughout the world but with higher incidence among East Asian populations [1]. The prevalence is less than 1% in Caucasians [2] while approximately 10% in Japanese [3]. The phenotype can induce defciencies in speech articulation and low efciency of mastication. Not only orthodontic treatment but also orthognathic surgery is fre- quently necessary to treat adult mandibular prognathism. The majority of cases of mandibular prognathism evidently represent a multifactorial phenotype attributed to the interactions of susceptibility genes with environmental factors [4–6]. The results of a genome-wide linkage analysis of mandibular prog- nathism identifed chromosomes 1p36, 6q25, and 19p13.2 as showing suggestive linkage to mandibular prognathism in Japanese and Korean families [7]. Supplementary association studies on 1p36 of the sus- ceptibility locus suggested MATN1 (matrilin 1, cartilage matrix protein) (164 Korean patients and 132 controls) [8] and EPB41 (erythrocyte membrane protein band 4.1) (211 Han Chinese patients and 224 con- trols) [9] as candidate genes for the phenotype. However, another linkage analysis of Brazilian families [10] did not reveal any suggestive linkages between the phenotype and 1p36, 6q25, or 19p13.2. On the other hand, a genome-wide linkage analysis of Colombian Hispanic families [11] showed 5 susceptibility loci: 1p22.1; 3q26.2; 11q22; 12q13.13; and 12q23 with suggestive linkage to mandibular prog- nathism. A supplementary association study [12] of multiracial 44 https://doi.org/10.1016/j.bone.2019.03.004 Received 10 September 2018; Received in revised form 12 February 2019; Accepted 4 March 2019 Abbreviations: GWAS, genome-wide association studies; ANB, point A-the Nasion-point B; SNP, single-nucleotide polymorphism; SNV, single-nucleotide variant; EGFR, epidermal growth factor receptor; PDGF, platelet-derived growth factor ⁎ Corresponding author at: Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan. E-mail address: takkajii@mac.com (T.S. Kajii). Bone 122 (2019) 193–198 Available online 05 March 2019 8756-3282/ © 2019 Elsevier Inc. All rights reserved. T