RT Journal Article
SR Electronic
T1 Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 237
OP 244
DO 10.1136/jmedgenet-2019-106424
VO 57
IS 4
A1 Sylvain Blanchon
A1 Marie Legendre
A1 Mathieu Bottier
A1 Aline Tamalet
A1 Guy Montantin
A1 Nathalie Collot
A1 Catherine Faucon
A1 Florence Dastot
A1 Bruno Copin
A1 Annick Clement
A1 Marcel Filoche
A1 André Coste
A1 Serge Amselem
A1 Estelle Escudier
A1 Jean-Francois Papon
A1 Bruno Louis
YR 2020
UL http://jmg.bmj.com/content/57/4/237.abstract
AB Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.Methods We prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).Results Sixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.Conclusion Quantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.