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.

Background: Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant syndrome, which is caused by the heterozygous germline loss-of-function variants in CTNNB1. Methods:We evaluated the clinical and genetic findings of 24 previously undescribed Chinese patients affected by CTNNB1-related disorders and explored the possible ethnicity-related phenotypic variations.Results: Twenty-one loss-of-function variants were identified within these 24 NEDSDV patients, including 14 novel CTNNB1 variants and 7 recurrent ones.The prominent clinical manifestations in our cohort are developmental delay/intellectual disability (100%), motor delay (100%), speech impairment (100%), dystonia (87.5%) and microcephaly (69.6%). The common facial dysmorphisms were consistent with previous reports, including wide nasal bridge (58.3%), bulbous nose (45.8%), long philtrum (45.8%) and thin upper lip (45.8%). In addition, 19 patients (79.2%) in our cohort had mild visual defects, while one affected individual (4.2%) had familial exudative vitreoretinopathy. Notably, we discovered that 20 patients (83.3%) exhibited various behavioral abnormalities, which is described in Chinese patients for the first time. Conclusion:We provided the largest known Chinese cohort with pathogenic CTNNB1 variants, which not only helps to expand the variant spectrum of CTNNB1 gene, but further delineates the typical phenotype of this disorder in Chinese population.

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