Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis

Kohei Murakami; Shingo Kikugawa; Shoji Seki; Hidetomi Terai; Takako Suzuki; Masaki Nakano; Jun Takahashi; Yukio Nakamura

doi:10.1055/s-0041-1726282

Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis

J Pediatr Genet. 2021 Apr 14;11(4):287-291. doi: 10.1055/s-0041-1726282. eCollection 2022 Dec.

Authors

Kohei Murakami^{1

2}, Shingo Kikugawa³, Shoji Seki⁴, Hidetomi Terai⁵, Takako Suzuki^{1

6}, Masaki Nakano¹, Jun Takahashi¹, Yukio Nakamura¹

Affiliations

¹ Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
² Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime, Japan.
³ DNA Chip Research Inc., Minato-ku, Tokyo, Japan.
⁴ Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Japan.
⁵ Department of Orthopedics, Osaka City University Graduate School of Medicine, Osaka, Japan.
⁶ Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, Chiyoda, Tokyo, Japan.

Abstract

Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.

Keywords: congenital scoliosis; de novo variants; exome sequencing.