JCK-AP session 5-1 (II-JCKAP5-1)
Miscellaneous 1

[II-JCKAP5-1-4] The TMEM260 c.1617del variant is identified as the most frequent single gene determinant for persistent truncus arteriosus in Japanese population

^○Tadashi Inoue^1,2, Ryuta Takase², Keiko Uchida^1,3, Kazuki Kodo^1,4, Kenji Suda², Yoriko Watanabe^2,5, Masaya Kunimatsu^1,6, Reina Ishizaki¹, Hiroyuki Akagawa⁷, Hiroyuki Yamagishi^1,8 (1.Department of Pediatrics, Keio University School of Medicine, Tokyo, 2.Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, 3.Department of Physiology, Tokyo Medical University, Tokyo, 4.Department of Pediatrics, Tokyo Metropolitan Otsuka Hospital, Tokyo, 5.Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Fukuoka, 6.Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 7.Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, 8.Tokyo Metropolitan Children's Medical Center, Tokyo)

キーワード：outflow tract defects, exome sequencing, heart development

Objective: Persistent truncus arteriosus (PTA) is the most severe form of cardiac outflow tract (OFT) defects observed in nearly 20% of Asian population with 22q11.2 deletion, however its genetic etiology remains to be fully understood. We focused on TMEM260 as a genetic cause of PTA and aimed to elucidate the frequency of TMEM260 variants in the Japanese PTA patients and the pathology associated with OFT development. Methods: Exon sequencing of TMEM260 was performed on 26 Japanese PTA patients from our genome bank. The variant protein was subjected to Western blotting and immunostaining. To elucidate the regulatory mechanism of Tmem260 expression during OFT development, enhancer analysis was performed using transgenic mice. Results: The TMEM260 c.1617del variant was identified in 3 of 26 (12%) cases in autosomal recessive fashion. This genotype was a rare polymorphism found only in Japanese and Korean populations. In vitro analysis showed that the variant TMEM260 protein which truncates the C-terminal region exhibited abnormal aggregation. In vivo analysis showed that Tmem260 mRNA is expressed in the OFT of mouse embryos, and that a 0.8 kb genomic region in intron 3 functions as its enhancer. Conclusions: The TMEM260 c.1617del variant, named as "Keio-Tohoku Variant", was revealed as a major genetic cause of PTA in the Japanese population excluding the 22q11.2 deletion syndrome. The pattern and regulation for expression of TMEM260 are compatible with PTA. Genetic testing and counseling for TMEM260 should be considered for patients with PTA in Asian population.