Gene panel study for target metabolic diseases of newborn mass screening in Japan – fatty acid oxidation defects –

1,2Hideo Sasai M.D.,Ph.D., 1Yasuhiko Ago M.D., 1,2,3Hiroki Otsuka M.D., 4Junichi Hosokawa M.D.,Ph.D., 4Ryoji Fujiki Ph.D., 4Osamu Ohara Ph.D., 5Yoko Nakajima M.D.,Ph.D., 5Tetsuya Ito M.D.,Ph.D., 6Kei Hara M.D.,Ph.D., 7Masahisa Kobayashi M.D.,Ph.D., 8Go Tajima M.D.,Ph.D., 9Osamu Sakamoto M.D.,Ph.D., 10Shiro Matsumoto M.D.,Ph.D., 10Kimitoshi Nakamura M.D.,Ph.D., 11Takashi Hamazaki M.D.,Ph.D., 12Hisanori Kobayashi M.D.,Ph.D., 12Yuki Hasegawa M.D.,Ph.D., 1,2Toshiyuki Fukao M.D.,Ph.D.

1Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.

2Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan.

3Department of Neonatal Medicine, Gifu Prefectural General Medical Center, Gifu, Japan; 4Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan. 5Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan. 6Department of Pediatrics, Kure Medical Center, Kure, Japan.

7Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.

8Division of Neonatal Screening, NCCHD, Tokyo, Japan.

9Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.

10Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

11Department of Pediatrics, Faculty of Medicine, Osaka City University, Osaka, Japan.

12Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Japan.

Corresponding author:

Hideo Sasai

Department of Pediatrics, Graduate School of Medicine, Gifu University 1-1 Yanagido, Gifu, 501-1194, Japan

Tel +81-58-230-6386

FAX +81-58-230-6387




Nationwide newborn screening (NBS) using tandem mass spectrometry (MS/MS) has been conducted in Japan since 2014. The number of NBS-target diseases then increased from 6 diseases to at least 19 diseases, which included VLCAD deficiency, MCAD deficiency, TFP deficiency, primary systemic carnitine deficiency, CPT2 deficiency, CPT1 deficiency, CACT deficiency, and Glutaric acidemia type 2. Before expanding pilot NBS using MS/MS in 2000s, fatty acid oxidation defects (FAODs) had been thought to be very rare in Japan.


We have been performing a study in which we have provided mutation analysis for NBS- positive patients with the use of AMED (Japan Agency for Medical Research and Development) grant and have followed up these patients after mutation confirmation since January 2014. Since November 2017, mutation analysis for some diseases has been performed using Japanese public medical insurance instead of AMED research grant.

We designed a gene panel covering the target metabolic diseases (TMDs) and the related diseases. Gene panel analysis was performed at Kazusa DNA Research Institute using the MiSeq or NextSeq (Illumina®). We are planning follow-up study every two years for mutation-defined patients.


More than 240 cases were enrolled in this gene panel study during four years (January 2014 to April 2018). Among them, the number of NBS-positive patients was 183 cases in total, 50 cases of FAODs: VLCAD deficiency (17), MCAD deficiency (13), primary systemic carnitine deficiency (9), Glutaric acidemia type 2 (4), CPT2 deficiency (4), CPT1 deficiency (2), TFP deficiency (1). In most cases, we could find the gene mutations in their corresponding genes. We have also started the first clinical follow-up study for patients identified in 2014-2015.


In some TMDs, clinical course and severity may vary from patient to patient. One major factor determining the clinical phenotype is, of course, the genotype. It is therefore important to follow up patients who have defined mutations to evaluate the effectiveness of treatment and management. In the near future, we will personalize clinical guidelines in part by genotype in several TMDs.

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