In August 2021, Beijing Children's Hospital affiliated to Capital Medical University published a research paper entitled "Newborn screening with targeted sequencing: A multi-center investigation and a pilot clinical study in China" in the journal Journal of Genetics and Genomics. The next generation of newborn screening programs for targeted sequencing of high-throughput genes and their clinical applications have been reported internationally. The program, abbreviated as "NESTS (NewbornScreening with TargetedSequencing)", means to "cage" the existing newborn screening program together and "gather" the genes of severe teratogenic, disabling and fatal genetic diseases in China. Researchers Hao Chanjuan, Dr. Ruolan Guo and Dr. Xuyun Hu of Beijing Children's Hospital are the co-first authors of the paper, and Professors Li Wei, Professor Ni Xin and Researcher Hao Chanjuan are the co-corresponding authors of the paper.
Vice President Li Wei
Newborn screening ("new screening") began in the 1960s to screen asymptomatic newborns for interventional congenital genetic metabolic diseases such as phenylketonuria. At present, different countries and regions implement different screening schemes that use biochemical or mass spectrometry to detect metabolite or enzyme activity according to the characteristics of diseases in the region and health economics, but most of these schemes only cover a few or dozens of diseases. Due to the different methods and techniques used, the heel blood collection of newborns is repeated, sometimes as many as 8 to 10 blood spots, and there are usually problems such as uneven test quality control, lack of genetic level and clinical diagnosis, and lack of effective management of those who are screened positive. Whether it is possible to collect only 1 to 2 blood spots, group these screening programs together, cover more single-gene genetic diseases, and implement closed-loop management, this is a topic that the team led by Professor Li Wei began to tackle in August 2015.
Over the course of six years, the team has developed a targeted sequencing solution based on next-generation sequencing technology (NGS), NESTS (Figure A). Based on the investigation of the situation of children with hereditary rare diseases admitted to Beijing Children's Hospital for many years, combined with the rare disease database, Panel containing 465 known pathogenic genes for the characteristics of hereditary rare diseases in China was designed for screening 596 serious genetic diseases with early onset, relatively high incidence and intervention. Through the Multi-center Collaboration Group of the Women's and Children's Specialized Medical Association of Futang Children's Medical Development Research Center established since 2013, a retrospective screening of 11,484 infants (Figure B) distributed in 8 maternal and child health care institutions in different regions of China found that the initial screening positive rate of NESTS was 7.85%. Further follow-up of newborns with positive initial screening found that the clinical diagnosis rate was 12.07%. According to this calculation, the diagnosis rate of ungene genetic diseases in nexus neonates is 0.95%, indicating that ungenic genetic diseases account for a large proportion of neonatal birth defects.
A. NESTS project R&D flow chart; B. The 40 genes and regional distributions with the highest initial screening positive frequency in the 11,484 samples in the study. (IM: Inner Mongolia; QH: Qinghai; HB: Hubei; SD: Shandong; BJ: Beijing; GZ: Guizhou; GX: Guangxi)
Subsequently, the research team further recruited 3,923 newborns at Shunyi Women's and Children's Hospital of Beijing Children's Hospital for the clinical evaluation trial of NESTS. With the help of the intelligent decision support system for neonatal genetic diseases, the cycle of new screening reports can be controlled within 11 days; and the implementation effect of NESTS and closed-loop management are comprehensively evaluated, and through the questionnaire survey of 220 parents of newborns who have received NESTS testing, 91.4% of the respondents believe that they can benefit from nests testing, and 95.2% of the respondents believe that through genetic counseling, the anxiety about the test results is alleviated, and they can accept feedback on the information of pathogenic gene carriers.
The results of the study show that under the closed-loop management of the whole process, especially the support of professional genetic diagnosis and counseling teams, and the pediatric grading diagnosis and treatment system, the AI-assisted NESTS scheme is feasible as a first-line solution for the new screening, and has good socioeconomic benefits. The promotion and application of this program is expected to change the current status quo of new screening clinical practice in China. The State Council's "Decision on Optimizing Fertility Policies to Promote Long-term Balanced Population Development" pointed out that it is necessary to expand the scope of newborn disease screening diseases and promote early screening, early diagnosis and early treatment of hereditary rare diseases to effectively reduce the rate of birth defects in China. It is reported that Beijing Children's Hospital affiliated to Capital Medical University has included NESTS into the achievement transformation project, and its promotion and application will play an important role in the tertiary prevention of birth defects in China.
(Correspondent: Hu Xuyun)