Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: practice in China

• Published in: Human genetics Vol. 139; no. 4; pp. 473 - 482
• Main Authors: Wang, Huijun, Lu, Yulan, Dong, Xinran, Lu, Guoping, Cheng, Guoqiang, Qian, Yanyan, Ni, Qi, Zhang, Ping, Yang, Lin, Wu, Bingbing, Zhou, Wenhao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2020; Springer; Springer Nature B.V
• Subjects: Alleles; Autosomal recessive inheritance; Biomedical and Life Sciences; Biomedicine; Children; China; Copy number; Critical Illness; Developing countries; Diagnosis; DNA Copy Number Variations; DNA sequencing; Female; Gene Function; Genetic disorders; Genetic screening; Genetic Testing; Genomes; Genomics; Health aspects; Hospital patients; Human Genetics; Humans; Immunosuppressive agents; Infant; Infant, Newborn; Infants; Infants (Newborn); LDCs; Male; Metabolic Diseases; Molecular Medicine; Morbidity; Neonatal intensive care; Neonates; Nucleotide sequencing; Original Investigation; Patients; Pediatrics; Phenotypes; Transplantation; Whole Genome Sequencing; China
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-019-02103-8

Genome sequencing is used to make genetic diagnoses in critically ill infants with rapid turnaround time (TAT). Herein, to delineate the value of a genetic diagnosis, we provide the results from 130 pediatric patients in a large, comprehensive children’s hospital in China. This study was performed using an optimized trio genome sequencing (OTGS) test. The sequencing depth for patients was 40–50 × and for their parents, it was 8–10 × . Patients from the pediatric or neonatal intensive care unit (PICU/NICU) with complicated clinical features were enrolled between June 2018 and December 2018, each with a phenotype suggesting an underlying genetic disorder. OTGS testing identified pathogenic variants in 62 of 130 individuals, resulting in a diagnosis rate of 47.7%. The TAT varied from 72 to 120 h, with an average of 94 h and a median of 90 h. Of the 62 infants with diagnoses, 48 (77.4%) had pathogenic single-nucleotide variants (SNVs), 12 (19.4%) had pathogenic copy number variations (CNVs) or structure variants (SVs), and 2 (3.2%) had small deletions in one allele plus pathogenic variants in another allele of autosomal recessive genes. Therapeutic strategies for 48.4% (30/62) of the diagnosed patients were modified and included transplantation, dietary recommendations, or change of drugs, which avoided morbidity and improved prognosis. This study provided high-capacity OTGS testing in detecting SNVs and chromosomal abnormalities with fast response, higher diagnostic yield, and lower cost. OTGS demonstrates the potential to be the first-tier of genetic testing used in critically ill infants in developing countries.