Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia

Author:

Black Holly A.12ORCID,de Proce Sophie Marion1,Campos Jose L.3,Meynert Alison3,Halachev Mihail3,Marsh Joseph A.3,Hirst Robert A.4,O'Callaghan Chris4,Shoemark Amelia5,Toddie‐Moore Daniel1, ,Santoyo‐Lopez Javier6,Murray Jennie23,Macleod Kenneth7,Urquhart Don S.78,Unger Stefan78ORCID,Aitman Timothy J.1,Mill Pleasantine3ORCID

Affiliation:

1. Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

2. South East of Scotland Genetics Service Western General Hospital Edinburgh UK

3. MRC Human Genetics Unit, MRC Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

4. Department of Respiratory Sciences, Centre for PCD Diagnosis and Research University of Leicester Leicester UK

5. School of Medicine, Division of Molecular and Clinical Medicine University of Dundee Dundee UK

6. Edinburgh Genomics Edinburgh UK

7. Department of Paediatric Respiratory and Sleep Medicine Royal Hospital for Sick Children Edinburgh UK

8. Department of Child Life and Health University of Edinburgh Edinburgh UK

Abstract

AbstractBackgroundPrimary 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.MethodsWGS was used to screen for pathogenic variants in eight patients with PCD.Results7/8 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.ConclusionHere, 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.

Publisher

Wiley

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