Functional Evaluation and Genetic Landscape of Children and Young Adults Referred for Assessment of Bronchiectasis.

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.

Childhood bronchiolitis obliterans in Hong Kong-case series over a 20-year period.

BACKGROUND AND OBJECTIVE: Bronchiolitis obliterans (BO) is a rare but serious condition. The natural history and outcomes remain poorly understood. In this clinical review, we aimed to describe the clinical characteristics and outcomes of children diagnosed with BO in Hong Kong (HK). METHODS: This was a retrospective study of pediatric patients with BO under the care of six respiratory units in HK from January 1996 to December 2015. Information was retrieved from medical records. RESULTS: Fifty-six patients were included with a male predominance (67.9%). The median age at diagnosis was 1.98 years (interquartile range [IQR]: 0.84-4.99 years). Postinfectious BO (PIBO) was the commonest cause (64.3%) followed by posthematopoietic stem-cell transplant (21.4%). Adenovirus (63.2%) was the commonest causative pathogen among PIBO. The median follow-up duration was 9.7 years (IQR: 2.9-14.3 years). Twenty-five patients (44.6%) could achieve symptom-free recovery at the time of follow-up. Five (8.9%) and three (5.4%) were oxygen or ventilator dependent, respectively. There were two deaths, both had posttransplant BO. Patients who developed BO after transplant had significantly worse lung function than those with PIBO. There were no risk factors significantly associated with worse clinical outcomes (oxygen/ventilator dependence or death) by logistic regression. Among patients with PIBO, coinfection at presentation was significantly associated with persistent symptoms at follow-up (p = .028). CONCLUSIONS: The most common cause of childhood BO in HK is postinfectious and coinfection at presentation was associated with persistent symptoms at follow-up. Further studies are needed to better elucidate disease progression, treatment options and long term outcomes.

CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation. METHOD: Using our in-house next-generation sequencing (NGS) pipeline for childhood bronchiectasis, we identified disease-causing CFTR mutations in CF patients in Hong Kong. After identifying p.I1023R in multiple patients, haplotype analysis was performed with genome-wide microarray to ascertain the likelihood of this being a founder mutation. We also assessed the processing and gating activity of the mutant protein by Western hybridization and patch-clamp test. RESULTS: Molecular diagnoses were confirmed in four patients, three of whom shared a missense mutation: CFTR:c.3068T>G:p.I1023R. The results suggested that p.I1023R is a founder mutation in southern Han Chinese. In addition, the processing and gating activity of the mutant protein was assessed by gel electrophoresis and a patch-clamp test. The mutant protein exhibited trafficking defects, suggesting that the dysfunction is caused by reduced cell surface expression of the fully glycosylated proteins. CONCLUSION: Together with other previously reported mutations, the specific founder mutation presented herein suggests a unique CFTR mutation spectrum in the southern Chinese populations, and this finding has vital implications for improving molecular testing and mutation-specific treatments for Chinese patients with CF.

Expanded Prader-Willi syndrome due to chromosome 15q11.2-14 deletion: report and a review of literature.

We report on a male infant with de novo unbalanced t(5;15) translocation resulting in a 17.23 Mb deletion within 15q11.2-q14 and a 25.12 kb deletion in 5pter. The 15q11.2-q14 deletion encompassed the 15q11.2-q13 Prader-Willi syndrome (PWS) critical region and the recently described 15q13.3 microdeletion syndrome region while the 5pter deletion contained no RefSeq genes. From our literature review, patients with similar deletions in chromosome 15q exhibit expanded phenotype of severe developmental delay, protracted feeding problem, absent speech, central visual impairment, congenital malformations and epilepsy in addition to those typical of PWS. The patient reported herein had previously unreported anomalies of mega cisterna magna, horseshoe kidney and the rare neonatal interstitial lung disease known as pulmonary interstitial glycogenosis. Precise breakpoint delineation by microarray is useful in patients with atypical PWS deletions to guide investigation and prognostication.

Maternally inherited Leigh syndrome: an unusual cause of infantile apnea.

INTRODUCTION: Leigh Syndrome is an uncommon cause of infantile apnea. CASE SUMMARY: We report a 5-month-old girl with sudden respiratory arrest followed by episodic hyper- and hypo-ventilation, encephalopathy, and persistent lactic acidosis. Computed tomography of the brain revealed symmetric low densities over the basal ganglia, internal capsule, thalami, and midbrain. Cardiac echocardiogram was suggestive of hypertrophic cardiomyopathy. DISCUSSION: Diagnosis of Leigh syndrome due to T8993G mutation was confirmed with polymerase chain reaction and direct DNA sequencing of mitochondrial genome. To our knowledge, this is the first report of proven maternally inherited Leigh syndrome in Hong Kong.

Improvement in quality of life after adenotonsillectomy in a child with Prader Willi syndrome.

INTRODUCTION: We report a child with Prader Willi syndrome who developed obstructive sleep apnea (OSA). This patient underwent surgical treatment for OSA. There was improvement not only on her OSA but in her quality of life score as well. This report highlights the need for a comprehensive assessment in the management of patients with Prader Willi syndrome.