Development and first results of the BEAT-PCD international Primary Ciliary Dyskinesia gene variant database: CiliaVar

Abstract

PCD can be diagnosed by bi-allelic pathogenic mutations in one of >50 ciliary genes. ~ 60% of patients with an identified genetic cause have private mutations not previously reported in another patient. Increasing numbers of variants of unknown significance (VUS, i.e. unknown if they are pathogenic) are identified. As clinical genetic testing is increasingly used for PCD, there is a need to develop a public access resource to identify if variants have previously been reported to be associated with disease.

Our aim was to establish an online open database registering gene mutations and specific combinations of variants causing PCD.

A panel of clinicians and geneticists with expertise in PCD identified database fields to link each variant with the associated diagnostic, clinical and genetic evidence supporting pathogenicity. A literature search was conducted to identify published mutations causing PCD. Database curators checked mutation nomenclature and classification of variants was carried out following ACMG guidelines.

624 papers were identified. Following abstract review 235 papers yielded 1,282 PCD patients. Additionally, 201 PCD cases from a diagnostic centre were entered to pilot the database. 1214 mutations were included in CiliaVar. The majority of mutations (52%) were in 4 genes DNAH5, DNAH11, CCDC39, CCDC40. The most common variants reported are CCDC40: c.248del (n=41 patients) and DNAI1: c.48+2dupT (n=49). 21% of the distinct variants are classified as VUS.

The online open database CiliaVar will improve access to PCD variant information to improve the diagnosis of PCD.

Acknowledgments: BEAT-PCD ERS clinical research collobaration