Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.
ciliopathies
molecular diagnosis
primary ciliary dyskinesia
rare respiratory disease
whole genome sequencing
Journal
Pediatric pulmonology
ISSN: 1099-0496
Titre abrégé: Pediatr Pulmonol
Pays: United States
ID NLM: 8510590
Informations de publication
Date de publication:
08 Aug 2024
08 Aug 2024
Historique:
revised:
03
07
2024
received:
22
03
2024
accepted:
22
07
2024
medline:
8
8
2024
pubmed:
8
8
2024
entrez:
8
8
2024
Statut:
aheadofprint
Résumé
Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. 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. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes. WGS was used to screen for pathogenic variants in eight patients with PCD. 7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B. Here, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome.
Sections du résumé
BACKGROUND
BACKGROUND
Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. 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. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes.
METHODS
METHODS
WGS was used to screen for pathogenic variants in eight patients with PCD.
RESULTS
RESULTS
7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B.
CONCLUSION
CONCLUSIONS
Here, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Chief Scientist Office of the Scottish Government Health Directorates
ID : [SGP_1]
Organisme : MRC Whole Genome Sequencing for Health and Wealth Initiative
ID : (MC_PC_15080)
Organisme : MRC
ID : PM
Organisme : MRC
ID : MC_UU_00007/14
Organisme : MRC
ID : MR/Y015002/1
Organisme : European Research Council (ERC)
ID : n°866355
Organisme : MRC Career Development Award
ID : MR/M02122X/1
Organisme : Lister Prize Fellowship
Organisme : NHS Research Scotland fellowship
Organisme : NRS/R+D fellowship from the NHS Lothian R&D office
Informations de copyright
© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.
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