Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified.To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene.Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in 11 known PCD-causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the receiver operating characteristic curve (AUC) 0.75, 95% CI 0.60–0.90). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97, 95% CI 0.93–1). Finally, WES established an alternative diagnosis in four patients.In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.

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Pathogenic variants identified by whole-exome sequencing in Chinese patients with primary ciliary dyskinesia

10.21203/rs.3.rs-403380/v1 ◽

2021 ◽

Author(s):

Ye Yutian ◽

Huang Qijun ◽

Chen Lipeng ◽

Liang Chunxian ◽

Yuan Fang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Ciliary Dyskinesia ◽

Genetic Factors ◽

Autosomal Recessive Disorder ◽

Chinese Patients ◽

Causative Gene ◽

Pathogenic Variants ◽

Whole Exome ◽

Ciliary Dyskinesia

Abstract Background: The genetic factors contributing to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder, remain elusive for approximately 20–35% of patients with complex and abnormal clinical phenotypes. Our study aimed to identify causative variants of PCD-associated pathogenic candidate genes using whole-exome sequencing (WES). Methods: All patients were diagnosed with PCD based on clinical phenotype or transmission electron microscopy (TEM) images of cilia. WES and bioinformatic analysis were then conducted for patients with PCD. Identified candidate variants were validated by Sanger sequencing. Pathogenicity of candidate variants was then evaluated using in silico software and the American College of Medical Genetics and Genomics (ACMG) database.Results: In total, 15 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1. Moreover, two stop-gain heterozygous variants of DNAAF3 and DNAH1 were classified as pathogenic variants by the ACMG criteria.Conclusions: This study identified novel potential pathogenic genetic factors associated with PCD. Noteworthy, the PCD patients carried multiple rare causative gene variants, thereby suggesting that known causative genes along with other functional genes should be considered for such heterogeneous genetic disorders.

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Whole-exome sequencing identifies a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus

Journal of Human Genetics ◽

10.1038/s10038-018-0540-x ◽

2018 ◽

Vol 64 (3) ◽

pp. 249-252 ◽

Cited By ~ 7

Author(s):

Weizhi Zhang ◽

Dongping Li ◽

Shijie Wei ◽

Ting Guo ◽

Jian Wang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Situs Inversus ◽

Primary Ciliary Dyskinesia ◽

Whole Exome ◽

Ciliary Dyskinesia

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Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

Genome Medicine ◽

10.1186/s13073-019-0702-2 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Elias L. Salfati ◽

Emily G. Spencer ◽

Sarah E. Topol ◽

Evan D. Muse ◽

Manuel Rueda ◽

...

Keyword(s):

Sudden Death ◽

Rare Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Molecular Diagnostic ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

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