Molecular Diagnosis for Target Metabolic Diseases of Newborn Screening Using a Gene Panel in Japan


1,2 Hideo Sasai M.D.,Ph.D., 1,2 Hiroki Otsuka M.D., 3 Ryoji Fujiki Ph.D., 3 Osamu Ohara Ph.D., 4 Yoko Nakajima M.D.,Ph.D., 4 Tetsuya Ito M.D.,Ph.D., 5 Masahisa Kobayashi M.D.,Ph.D., 6 Go Tajima M.D.,Ph.D., 7 Osamu Sakamoto M.D.,Ph.D., 8 Shiro Matsumoto M.D.,Ph.D., 8 Kimitoshi Nakamura M.D.,Ph.D., 9 Takashi Hamazaki M.D.,Ph.D., 10 Hisanori Kobayashi M.D.,Ph.D., 10 Yuki Hasegawa M.D.,Ph.D., 1,2 Toshiyuki 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 Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.

4Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan.

5Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.

6Division of Neonatal Screening, NCCHD, Tokyo, Japan.

7Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.

8Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
9Department of Pediatrics, Osaka City Graduate School of Medicine, Osaka, Japan.

10Department 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



Newborn screening (NBS) using tandem mass spectrometry has been performed since 2014 in all over Japan and the target metabolic diseases (TMDs) increased from 6 to at least 19 diseases. Molecular diagnosis for TMDs is not commercially available in Japan and until recently such molecular analyses were mainly performed by pediatricians with “volunteer spirits”. To change the situation, we designed and conducted molecular diagnosis for TMDs using a gene panel.

We designed a gene panel which consists of more than 60 genes covering the TMDs and the related diseases. This research was financially supported by Japan Agency for Medical Research and Development. DNA was purified from patients’ blood at Gifu University and the gene panel analysis was performed at Kazusa DNA Research Institute using the MiSeq or NextSeq (Illumina®). Sanger sequencing was performed to confirm the detected mutations. Pediatric

coauthors in this study are experts responsible to make mutation reports. We analyzed 138 patients who were positively screened during three years (January 2014 to March 2017) and 44 patients who were diagnosed before that period. The number of patients  with TMDs detected by NBS were as follows: Propionic acidemia (35), Hyperphenylalaninemia (19), Methylmalonic acidemia (17), VLCAD deficiency (15), Maple syrup urine disease (13), Methylcrotonylglycinuria (13), Galactosemia (10), primary systemic carnitine deficiency (9), MCAD deficiency (8), Citrullinemia type 1 (7), Glutaric acidemia type 1 (6), CPT2 deficiency (4), Glutaric acidemia type 2 (4), CPS1 deficiency (4), OTC deficiency (4), Multiple carboxylase deficiency (3), Others (11). In most cases, we could find the gene mutations in their corresponding genes and found some common mutations for some TMDs in a Japanese population. Clinical course and severity may differ among patients in some TMDs. One major factor to determine clinical phenotype is of course genotype. Hence, it is important to follow up mutation-defined patients to evaluate efficacy of treatment and management. We will individualize clinical guidelines by genotypes in some TMDs in the near future.

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