An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia

• Published in: Human genetics Vol. 139; no. 10; pp. 1273 - 1283
• Main Authors: Shamseldin, Hanan E., Al Mogarri, Ibrahim, Alqwaiee, Mansour M., Alharbi, Adel S., Baqais, Khaled, AlSaadi, Muslim, AlAnzi, Talal, Alhashem, Amal, Saghier, Afaf, Ameen, Waleed, Ibrahim, Niema, Yang, Jason, Abdulwahab, Firdous, Hashem, Mais, Chivukula, Raghu R., Alkuraya, Fowzan S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2020; Springer; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cilia; Diagnosis; Dyskinesia; Gene Function; Human Genetics; Medical colleges; Metabolic Diseases; Molecular Medicine; Movement disorders; Neonates; Nitric oxide; Original Investigation; Patient compliance; Phenotypes; Primary ciliary dyskinesia
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-020-02170-2

Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (
n
 = 58), neonatal respiratory distress (NRD) (
n
 = 2), laterality defect (LD) (
n
 = 6), and combined LD/SPI (
n
 = 15). Biallelic likely deleterious variants were also encountered in
AKNA
and
GOLGA3
, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in
ITCH
, and a pathogenic variant in
CEP164
causing Bardet–Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help “democratize” the diagnosis of PCD, which is currently limited to highly specialized centers.