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

Gileles‐Hillel, Alex; Mor‐Shaked, Hagar; Shoseyov, David; Reiter, Joel; Tsabari, Reuven; Hevroni, Avigdor; Cohen‐Cymberknoh, Malena; Amirav, Israel; Brammli‐Greenberg, Shuli; Horani, Amjad; Kerem, Eitan; Breuer, Oded

doi:10.1183/23120541.00213-2020

Cited by 18 publications

(9 citation statements)

References 41 publications

(48 reference statements)

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“…A study from Israel included predominantly Arab individuals and reported mutations in DNAH11 [ 38 ] to be the most common cause of PCD. A study of five children from two unrelated consanguineous Palestinian families revealed novel mutations in DNAAF11/LRRC6 (c.436G>C), which also affected families in this study [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

et al. 2023

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Diagnostic testing for primary ciliary dyskinesia (PCD) started in 2013 in Palestine. We aimed to describe the diagnostic, genetic, and clinical spectrum of the Palestinian PCD population.Individuals with symptoms suggestive of PCD were opportunistically considered for diagnostic testing: nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM), and/or PCD genetic panel or whole exome testing. Clinical characteristics of those with a positive diagnosis were collected close to testing including FEV1GLI z-scores, and BMI z-scores.Sixty-eight individuals had a definite positive PCD diagnosis, 31 confirmed by genetic and TEM results, 23 by TEM results alone, and 14 by genetic variants alone. Forty-five individuals from 40 families had seventeen clinically actionable variants, and 4 had variants of unknown significance in 14 PCD-genes. CCDC39, DNAH11, andDNAAF11were the most commonly mutated genes. 100% of variants were homozygous. Patients had median age of 11.2 years at diagnosis, were highly consanguineous (93%) and 100% of Arabic descent. Clinical features included persistent wet cough (99%), neonatal respiratory distress (84%), and situs inversus(43%). Lung function at diagnosis was already impaired (FEV1z-score median −1.90 (−5.0 to 1.32)) and growth was mostly within the normal range (z-score mean= −0.36 (−3.03 to 2.57). 19% individuals had finger clubbing.Despite limited local resources, detailed geno- and phenotyping forms the basis of one of the largest national PCD populations globally. There was notable familial homozygosity within the context of significant population heterogeneity.

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Section: Discussionmentioning

confidence: 99%

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

et al. 2023

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“…In the last few years, since the guidelines were published, more studies have demonstrated the effectiveness of PCD diagnosis by genetic testing, including with WES/whole genome sequencing (WGS) 15–18. Recently, Shoemark and colleagues found that in a cohort of patients with severe bronchiectasis, pathogenic or likely-pathogenic variants were identified in motile ciliopathy genes in 17/142 (12%) individuals by WES 19.…”

Section: Discussionmentioning

confidence: 99%

Stepwise genetic approach for the diagnosis of primary ciliary dyskinesia in highly consanguineous populations

Gatt,

Golan Tripto,

Levanon

et al. 2024

Arch Dis Child

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BackgroundThe American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia (PCD) consider the presence of a bi-allelic pathogenic variant confirmatory for the diagnosis of PCD, with genetic testing recommended when other confirmatory diagnostic tests are less accessible. We present our experience with genetic testing as first line with a proposed algorithm for high consanguinity populations.MethodsPatients with a suspected diagnosis of PCD underwent genetic testing according to a diagnostic algorithm composed of three steps: (1) patients with a previously known causative familial/Bedouin tribal pathogenic variant completed direct testing for a single variant; (2) if the initial test was negative or there was no known pathogenic variant, a PCD genetic panel was completed; (3) if the panel was negative, whole exome sequencing (WES) was completed.ResultsSince the implementation of the protocol, diagnosis was confirmed by genetic testing in 21 patients. The majority of them were of Bedouin origin (81%) and had a positive history of consanguinity (65%). Nine patients (43%) had a sibling with a confirmed diagnosis. Most patients (15/21, 71%) were diagnosed by direct pathogenic variant testing and the remainder by genetic panel (19%) and WES (10%). Disease-causing variants were found in nine genes, withDNAL1(24%) andDNAAF3,DNAAF5,ZMYND10(14% each) as the most prevalent ones.ConclusionsIn highly consanguineous regions, a stepwise genetic testing approach is recommended. This approach may be particularly useful in areas where the ability to obtain confirmatory diagnostic tests through other modalities is less accessible.

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“…Panels covering greater numbers of PCD genes will have greater detection rates [ 50 ] ( Figure 2 ). It is expected that the routine use of newer sequencing methods, such as whole exome sequencing (which offers better coverage), will likely replace panels with limited numbers of genes [ 51 ].…”

Section: Pcd Diagnostic Testingmentioning

confidence: 99%

Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

2021

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Primary Ciliary Dyskinesia (PCD) is a rare, under-recognized disease that affects respiratory ciliary function, resulting in chronic oto-sino-pulmonary disease. The PCD clinical phenotype overlaps with other common respiratory conditions and no single diagnostic test detects all forms of PCD. In 2018, PCD experts collaborated with the American Thoracic Society (ATS) to create a clinical diagnostic guideline for patients across North America, specifically considering the local resources and limitations for PCD diagnosis in the United States and Canada. Nasal nitric oxide (nNO) testing is recommended for first-line testing in patients ≥5 years old with a compatible clinical phenotype; however, all low nNO values require confirmation with genetic testing or ciliary electron micrograph (EM) analysis. Furthermore, these guidelines recognize that not all North American patients have access to nNO testing and isolated genetic testing is appropriate in cases with strong clinical PCD phenotypes. For unresolved diagnostic cases, referral to a PCD Foundation accredited center is recommended. The purpose of this narrative review is to provide insight on the North American PCD diagnostic process, to enhance the understanding of and adherence to current guidelines, and to promote collaboration with diagnostic pathways used outside of North America.

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

Cited by 18 publications

References 41 publications

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

Stepwise genetic approach for the diagnosis of primary ciliary dyskinesia in highly consanguineous populations

Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

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