Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Gileles-Hillel A

PROVIDER: S-EPMC7792814 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Gileles-Hillel Alex A Mor-Shaked Hagar H Shoseyov David D Reiter Joel J Tsabari Reuven R Hevroni Avigdor A Cohen-Cymberknoh Malena M Amirav Israel I Brammli-Greenberg Shuli S Horani Amjad A Kerem Eitan E Breuer Oded O

ERJ open research 20201001 4

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 measu ...[more]

PMID: 33447612

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Project description:BackgroundIt is estimated that 1-13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a "gold standard" diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability.MethodsUK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC.Results16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort.ConclusionsGenetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.

Dataset Information

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

Publications

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

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