Analysis of personalized precision diagnosis of 156 children with suspected rare inherited metabolic diseases / 中国热带医学

ABSTRACT

@#Abstract Objective　To explore the accurate diagnosis of children with suspected rare inherited metabolic diseases, and to compare the application value of mass spectrometry and genetic testing in the diagnosis of rare inherited metabolic diseases (IMD). Methods　The clinical information, mass spectrometry, and genetic results of children with suspected rare inherited metabolic diseases admitted to the Department of Pediatrics, the Affiliated Haikou Hospital of Xiangya Medical College, Central South University from March 2017 to December 2021 were analyzed retrospectively. Results　156 children with suspected rare inherited metabolic diseases were detected by mass spectrometry, 67 cases were positive and 89 cases were negative. Children with positive initial examination were retested, and 19 cases were positive. Among the retest positive cases, 13 cases were given genetic testing, and 9 cases were positive and 4 cases were negative. Among the initial negative cases, 54 children with poor therapeutic effect and high clinical suspicion of inherited metabolic diseases completed genetic testing, 15 cases were positive and 39 cases were negative. The results of the two detection methods were compared, the positive rate of mass spectrometry was 19.4%(13/67), and the positive rate of genetic testing was 35.8%(24/67). The continuity correction of Pearson's chi-square test of continuity correction suggested that the results of genetic testing and mass spectrometry were different, and the difference was statistically significant (P<0.05). Taking genetic testing as the gold standard, the sensitivity and specificity of mass spectrometry detection were 37.5% (95%CI19.6%-59.2%) and 90.7% (95%CI76.9%-97.0%), respectively. Among the 24 confirmed cases, 5 cases were diagnosed by gene panel and 19 cases were diagnosed by whole exome sequencing (WES). One case diagnosed by WES had no pathogenic mutation detected by gene panel before diagnosis. The detection of DNM1L gene c.1040C>G and AMN gene c.651+1G>C are novel pathogenic gene variants, which have clinical significance. Conclusions　The ability of mass spectrometry in the diagnosis of inherited metabolic diseases is limited. Genetic testing, especially whole exome sequencing, can be the first choice for individualized diagnosis of suspected rare inherited metabolic diseases. In addition, the new mutation sites found by WES in this study enriched the pathogenic gene mutation spectrum and provided direction for further functional biological experiments.