Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

Yiallouros, Panayiotis K.; Kouis, Panayiotis; Kyriacou, Kyriacos; Evriviadou, Aigli; Anagnostopoulou, Pinelopi; Matthaiou, Andreas M.; Tsiolakis, Ioannis; Pirpa, Panayiota; Michailidou, Kyriaki; Potamiti, Louiza; Loizidou, Maria A.; Hadjisavvas, Andreas

doi:10.1002/humu.24196

Cited by 9 publications

(8 citation statements)

References 54 publications

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“…However, it was already suspected that the previously understood leading causes of PCD may be heavily biased towards European/north American populations, as these are the so-far best studied. The emerging view, that specific ethnicities carry characteristic PCD gene variants, concurs with previous reports of different human populations carrying their own specific mutational landscape and predominant PCD disease variants [4][5][6][7] . Overall, this study highlights a need for new understanding about the most at-risk communities.…”

supporting

confidence: 88%

Primary ciliary dyskinesia: a big data genomics approach

Mitchison

Smedley

2022

The Lancet Respiratory Medicine

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supporting

confidence: 88%

Primary ciliary dyskinesia: a big data genomics approach

Mitchison

Smedley

2022

The Lancet Respiratory Medicine

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“…In this study we have identified a mutation in CFAP300 causative for PCD in Finland and analysed the effect of the mutation on motile cilia formation and function. The main defect in axonemal cross-sections was the lack of dynein arms as described in previous studies (Fassad et al, 2018;Höben et al, 2018;Zietkiewicz et al, 2019;Aprea et al, 2021;Bolkier et al, 2021;Yiallouros et al, 2021). Furthermore, we detected misorientation of the basal feet of the airway cilia, which we believe is most likely to be a secondary defect due to the lack of cilia motility and is also seen in PCD cases due to mutations in other genes.…”

Section: Discussionsupporting

confidence: 81%

“…Although we were unable to confirm the axonemal defects in this patient, the residual movement could be due to different levels of dynein arm formation as has been shown in previous studies (Fassad et al, 2018;Aprea et al, 2021;Yiallouros et al, 2021). Variable cilia beat frequency has also been reported for variant c.98_106del (0-9.1 Hz, Yiallouros et al, 2021). All the CFAP300 mutations reported to date are listed in Table 2.…”

Section: Discussionmentioning

confidence: 48%

“…In a patient with a homozygous stop gain mutation c.361C>T (p.Arg121*) in CFAP300, DNAI1, DNAI2 and DNALI1 were reported to be missing in cilia and TEM reported only ODA defect (Aprea et al, 2021). In frame deletion c.98_106del (p.Arg33_Arg35del) in six patients of Greek-Cypriot population was associated with IDA and ODA loss in most cilia cross-sections based on TEM and there was an extremely stiff CBP (Yiallouros et al, 2021). The c.198_200delinsCC frameshift variant identified in this study caused lack or truncation of IDA or ODA in all axonemal cross sections based on TEM of patient II-1 and lack of DNAH5, DNAI1 and DNAH7 suggesting a severe defect in dynein arm assembly.…”

Section: Discussionmentioning

confidence: 91%

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CFAP300 mutation causing primary ciliary dyskinesia in Finland

Schultz

Elenius²,

Fassad³

et al. 2022

Front. Genet.

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Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.

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“…There seems to be a genotype/phenotype correlation in PCD, with subjects carrying mutations, e.g. in the genes CCDC40 [ 6 ] or CCNO [ 7 ], displaying worse lung function outcomes and individuals with mutations in, for example, DNAH9 , RSPH1 and RSPH9 showing milder respiratory phenotypes, as reported in small cohorts [ 1 , 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

et al. 2022

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Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

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Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

Cited by 9 publications

References 54 publications

Primary ciliary dyskinesia: a big data genomics approach

Primary ciliary dyskinesia: a big data genomics approach

CFAP300 mutation causing primary ciliary dyskinesia in Finland

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

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