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Bronchiectasis is the abnormal dilation of the airway which may be caused by various etiologies in children. Beyond the more recognized cause of bacterial and viral infections and primary immunodeficiencies, other genetic conditions such as cystic fibrosis and primary ciliary dyskinesia (PCD) can also contribute to the disease. Currently, there is still debate on whether genome sequencing (GS) or exome sequencing reanalysis (rES) would be beneficial if the initial targeted testing results returned negative. This study aims to provide a back-to-back comparison between rES and GS to explore the best integrated approach for the functional and genetics evaluation for patients referred for assessment of bronchiectasis. In phase 1, an initial 60 patients were analyzed by exome sequencing (ES) with one additional individual recruited later as an affected sibling for ES. Functional evaluation of the nasal nitric oxide test, transmission electron microscopy, and high-speed video microscopy were also conducted when possible. In phase 2, GS was performed on 30 selected cases with trio samples available. To provide a back-to-back comparison, two teams of genome analysts were alternatively allocated to GS or rES and were blinded to each other's analysis. The time for bioinformatics, analysis, and diagnostic utility was recorded for evaluation. ES revealed five positive diagnoses (5/60, 8.3%) in phase 1, and four additional diagnoses were made by rES and GS (4/30, 13%) during phase 2. Subsequently, one additional positive diagnosis was identified in a sibling by ES and an overall diagnostic yield of 10/61 (16.4%) was reached. Among those patients with a clinical suspicion of PCD (n = 31/61), the diagnostic yield was 26% ( n = 8/31). While GS did not increase the diagnostic yield, we showed that a variant of uncertain significance could only be detected by GS due to improved coverage over ES and hence is a potential benefit for GS in the future. We show that genetic testing is an essential component for the diagnosis of early-onset bronchiectasis and is most effective when used in combination with functional tools such as TEM or HSVM. Our comparison of rES vs. GS suggests that rES and GS are comparable in clinical diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chau, Lee, Chui, Yu, Fung, Mak, Chau, Siu, Hung, Yeung, Kwong, O'Callaghan, Lau, Lee, Chung and Lee.)

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yu, Chau, Au, Lo, Yeung, Fung, Mak, Chung, Chan, Chung and Kan.)