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Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study
Author(s) -
Sun Yu,
Peng Jing,
Liang Desheng,
Ye Xiantao,
Xu Na,
Chen Linlin,
Yan Dan,
Zhang Huiwen,
Xiao Bing,
Qiu Wenjuan,
Shen Yiping,
Pang Nan,
Liu Yingdi,
Liang Chen,
Qin Zailong,
Luo Jingsi,
Chen Fei,
Wang Jingmin,
Zhang Zhixin,
Wei Haiyan,
Du Juan,
Yan Huifang,
Duan Ruoyu,
Wang Junyu,
Zhang Yu,
Liao Shixiu,
Sun Kun,
Wu Lingqian,
Yu Yongguo
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24347
Subject(s) - exome sequencing , biology , global developmental delay , intellectual disability , cohort , genetic testing , genetic diagnosis , genetics , bioinformatics , medicine , phenotype , gene
Genome sequencing (GS) has been used in the diagnosis of global developmental delay (GDD)/intellectual disability (ID). However, the performance of GS in patients with inconclusive results from chromosomal microarray analysis (CMA) and exome sequencing (ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test before enrollment. Reanalysis of their CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 21%. Seven cases could have been solved with reanalysis of ES data. Thirteen families were missed by previous CMA/ES due to improper methodology. Two remained unsolved after ES reanalysis due to complex variants missed by ES, and a CNV in untranslated regions. Follow‐up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this undiagnosed GDD/ID cohort, detecting a wide range of variant types of different sizes in a single workflow.