Exome sequencing as the first‐tier test for pediatric respiratory diseases: A single‐center study

Abstract

The high clinical and genetic heterogeneity makes it difficult to reach a confirmative diagnosis of suspected pediatric respiratory inherited diseases. Many patients with monogenic respiratory disorders could be missed without genetic testing. We performed a single‐center study in Beijing Children's Hospital to demonstrate the clinical utility of exome sequencing (ES) as a first‐tier test by evaluating the diagnostic yields of ES for inherited diseases with respiratory symptoms. A total of 107 patients were recruited in this study. We identified 51 pathogenic or likely pathogenic variants in 37 patients by ES (with or without copy number variants sequencing). The overall diagnostic yield was 34.6% (37/107). The most frequent disorders in our cohort were primary immunodeficiency disease (PIDs) (18/37, 48.6%) and primary ciliary dyskinesia (PCD) (9/37, 24.3%). We further reviewed the directive outcomes of genetic testing on the 37 positive cases. Our study demonstrated the effectiveness of ES as a first‐tier test in China for diagnosing monogenic diseases of the respiratory system. In the era of precision medicine, ES as a first‐tier test can rapidly make a molecular diagnosis and direct the intervention of the positive cases in pediatric respiratory medicine.

High diagnostic rate of whole genome sequencing in primary ciliary dyskinesia

“…Currently genetic testing for PCD sits as an additional step to confirm diagnosis by both European and American guidelines (8,21,22). As shown here, and elsewhere, genetic testing can accurately diagnose PCD where standard clinical procedures are unavailable, impractical or inconclusive (45–47,51) Importantly, a delayed PCD diagnosis is associated with worse prognosis (52,53). A clinical diagnosis of PCD requires specialised, invasive testing, and frequently necessitates travel over considerable distances to specialist centres.…”

“…Suggested clinical criteria for genetic testing in PCD could include term babies who become unwell at >12 hours of age with respiratory disease, lobar collapse, situs inversus and/or an unexpectedly high or prolonged oxygen requirement (54,55). Increasing availability, reducing costs and recognised clinical utility of NGS platforms such as WGS in the neonatal and paediatric intensive care unit setting would be consistent with such indications (50,51,54,(56)(57)(58)(59). Moreover, either WES or WGS would help rule out other confounding clinical presentations such as primary immune deficiency disorders (PIDs), with overlapping symptoms of frequent, often severe, airway infections as well as recurrent otitis media, and sinusitis (60)(61)(62).…”

Whole-exome sequencing as the first-tier test for patients in neonatal intensive care unit: a Chinese single-center study

“…WES has become a primary clinical diagnostic tool for children suffering from developmental delays, intellectual disabilities, respiratory disease [ 10 , 19 ], and more. Recent discussions have highlighted its use in NICU settings and among neonatal populations in China, viewing it from various perspectives [ 2 , 9 , 12 , 13 ].…”

“…WES has become a primary clinical diagnostic tool for children suffering from developmental delays, intellectual disabilities, respiratory disease [10,19], and more.…”

“…For example, a study from China on the largest cohort of neonates with congenital heart defects demonstrated that next-generation sequencing facilitated precise genetic diagnoses, enabling earlier intervention by specialists [ 9 ]. A study at Beijing Children’s Hospital [ 10 ] revealed that exome sequencing as an initial test for pediatric respiratory diseases had a diagnostic yield of 34.6%, proving its efficacy in rapidly diagnosing and guiding treatment. Additionally, a prospective study [ 11 ] showed that using whole-exome sequencing (WES) as a primary test in infants suspected of monogenic disorders could streamline the diagnostic process, offering a higher diagnostic yield than standard approaches.…”