3.2 Generation and feature of NeoEXOME panel
OMIM database was used to standardize and screen out the diseases and related genes. To design the NBS NGS panel covering monogenic diseases that are severe, actionable, and early onset for the Chinese population, we combined the following categorization of diseases in our study: 1) 248 related genes (249 diseases) that were included in China National Catalog of Rare Diseases. This catalog includes diseases with low incidence, high risk, and strong treatability based on the clinical data; 2) 360 genes (312 diseases) that were included in Preventable and Treatable Rare Diseases in China; 3) 79 genes (71 diseases) that were now in the conventional MS/MS NBS project in China; 4) 71 genes (71 diseases) that were included in the conventional NBS in China; 5) 149 genes (148 diseases) that were recommended by ACMG; 6) 55 genes (57 diseases) that were recommended by the experts of the Chinese NBS Laboratory Committee. Moreover, a list of diseases with high prevalence in the Chinese population based on the database about positive mono-genetic diseases in 40000 ill newborns by MyGenostics was also included. This list included 141 diseases and 94 related genes. Then Venny analysis was conducted to identify and generate the disease-genes panel (named NeoEXOME) in our study (Fig 1A). Our NeoEXOME panel is comprised of 601 genes and 542 kinds of diseases (Supplementary Table1).
The panel covered diseases with multi-systems, including skeletal, respiratory, urinary, immune system, nervous system, cardiovascular system, blood, endocrine system, metabolism, and mitochondria-related diseases (Fig 1B). Among them, diseases of the metabolic system account for the most proportion in our NeoEXOME panel. Besides, the onset age of these gene-related diseases was also collected and shown in Fig 1C. 418 out of 601 gene-diseases were onset in the neonatal period (<1 year), accounting for the largest proportion. 577 out of 601 (96%) gene-diseases were onset in childhood (<18 years).
3.3 Performance of NeoEXOME
Results of “ 1000 Genomes”
Firstly, we validated our panel using the data of unrelated 301 Chinese in the “1000 Genomes Project”. According to the interpretation criteria, 72 were negative, 223 were carrier, and 23 were positive (7.6%). Variants of FLG andGJB2 account for the most frequent mutant genes, with the frequency 47.8% (11/23) and 21.7% (5/23), respectively (Supplementary Table 2).