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Clinical and Genetic Analysis of Children with Kartagener Syndrome

1
Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (UP), Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2
Multidisciplinary Unit for Biomedical Research (UMIB), ICBAS-UP, 4050-313 Porto, Portugal
3
Department of Pediatrics, Maternal Child Center of the North (CMIN), University Hospital Center of Porto (CHUP), Largo da Maternidade de Júlio Dinis, 4050-651 Porto, Portugal
4
Department of Molecular Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (UP), Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
5
Bioengineering and Synthetic Microbiology Group, Institute of Health Research and Innovation (IBMC/i3S), University of Porto (UP), Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
6
Center of Medical Genetics Dr. Jacinto de Magalhães (IGMJM), University Hospital Centre of Porto (CHUP), Praça Pedro Nunes 88, 4050-106 Porto, Portugal
7
Center for Predictive and Preventive Genetics, Institute for Molecular and Cell Biology (IBMC), Institute of Health Research and Innovation (i3S)-UP, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
8
UniGene- IBMC/i3S, UP, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
*
Author to whom correspondence should be addressed.
Cells 2019, 8(8), 900; https://doi.org/10.3390/cells8080900
Received: 25 June 2019 / Revised: 5 August 2019 / Accepted: 13 August 2019 / Published: 15 August 2019
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Abstract

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes’ products. Our work calls the researcher’s attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families. View Full-Text
Keywords: primary ciliary dyskinesia; situs inversus; whole-exome sequencing; CCDC40; DNAH5; DNAH7 primary ciliary dyskinesia; situs inversus; whole-exome sequencing; CCDC40; DNAH5; DNAH7
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MDPI and ACS Style

Pereira, R.; Barbosa, T.; Gales, L.; Oliveira, E.; Santos, R.; Oliveira, J.; Sousa, M. Clinical and Genetic Analysis of Children with Kartagener Syndrome. Cells 2019, 8, 900.

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