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 20 publications

(13 citation statements)

References 41 publications

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“…In Case 3, a patient with features of reduced generation of motile cilia and hydrocephalus, no pathogenic variants would been identified in a panel-based approach, even with targeted sequencing of potential candidates for known RGMC loci. The diagnostic rate of 100% in our small study is higher than previous reports, in which 60-70% of cases received a genetic diagnosis based on the known PCD gene panels (1,5,12,13,20), 75% on extended NGS panels (44) and 68-94% by WES (45)(46)(47)(48).…”

Section: Discussioncontrasting

confidence: 71%

High diagnostic rate of whole genome sequencing in primary ciliary dyskinesia

Black,

Marion de Proce,

Campos

et al. 2024

Preprint

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AimPrimary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in more than 50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, sub-fertility and laterality defects in some cases. Given overlapping clinical features and genetic heterogeneity, diagnosis can be difficult and often occurs late. Of those tested, an estimated 30% of genetically screened PCD patients still lack a molecular diagnosis. Here, we aimed to identify how readily a genetic diagnosis could be made in a clinically diagnosed population using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as identify novel PCD candidate genes.MaethodsWGS was used to screen for variants causing PCD in 8 clinically diagnosed PCD patients, sequenced as trios where parental samples were available.ResultsSeven of the eight cases (87.5%) had homozygous or biallelic variants inDNAH5,DNAAF4orDNAH11that were classified as pathogenic or likely pathogenic. Three of the variants were deletions, ranging from 3kb to 13kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded a high genetic diagnostic rate from this clinically diagnosed population, in part through detection of structural variants as well as identification of ade novovariant in a novel PCD geneTUBB4B.ConclusionA molecular diagnosis allows for appropriate clinical management for cases and their families, including prediction of phenotypic features correlated to genotype. Here, WGS uplifted genetic diagnosis in cases of clinically diagnosed PCD by identifying structural variants and novel modes of inheritance in new candidate genes. Our study suggests that WGS could be a powerful part of the PCD diagnostic toolkit to increase the current molecular diagnostic yield from 70%. It provides important new insight into our understanding of fundamental biology of motile cilia as well as of variation in the non-coding genome in PCD.SummaryWhole genome sequencing (WGS) yielded a high genetic diagnostic rate (100%) in eight Scottish patients with clinically diagnosed primary ciliary dyskinesia (PCD) by detection of large structural variants, homology modelling and identification of a novel disease gene with a dominant mode of inheritance. Prioritised WGS may facilitate early genetic diagnosis in PCD.

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Section: Discussioncontrasting

confidence: 71%

High diagnostic rate of whole genome sequencing in primary ciliary dyskinesia

Black,

Marion de Proce,

Campos

et al. 2024

Preprint

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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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“…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 20 publications

References 41 publications

High diagnostic rate of whole genome sequencing in primary ciliary dyskinesia

High diagnostic rate of whole genome sequencing in primary ciliary dyskinesia

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

Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

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