Autosomal dominant variants inFOXJ1causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus

Abstract

Background Primary ciliary dyskinesia (PCD) is a mostly autosomal recessive, genetic disease of abnormal motile cilia function, resulting in bronchiectasis, infertility, organ laterality defects, and chronic otolaryngology disease. Though motile, ependymal cilia influencing cerebrospinal fluid flow in the central nervous system share many aspects of structure and function with motile cilia in the respiratory tract, hydrocephalus is rarely associated with PCD. Recently, pathogenic variants in FOXJ1 (Chr 17q25.1) were identified causing PCD associated with hydrocephalus, reduced respiratory cilia number, axonemal microtubule disorganization, and occurring in a de novo, autosomal dominant inheritance pattern. Method Two patients with chronic oto‐sino‐pulmonary disease and hydrocephalus underwent candidate testing of FOXJ1. Coding region and splice junctions were sequenced and analyzed under the auspices of Genetic Disorders of Mucociliary Clearance Consortium. Results Upon sequencing of the entire coding region and splice‐junctions, heterozygous, pathogenic variants in FOXJ1 were discovered in exon 3 of two patients: an 11‐month‐old female with situs inversus totalis (NM_001454.4: c.945delC (p.Phe315Leufs*18)) and a 51 year‐old male, post‐double lung transplantation (NM_001454.4: c.929_932delACTG (p.Asp310Glyfs*22)). FOXJ1 variants were not detected in the available parents and the siblings of these probands. Conclusion FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus. Physicians treating patients with hydrocephalus and chronic oto‐sino‐pulmonary disease should be aware of this PCD association and test for FOXJ1 variants.

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit

“…Nasal nitric oxide testing was performed per standardized protocol, as previously described, 15 for patients seen at the MUHC or HSC. Ciliary TEM was performed on a case‐by‐case basis in the clinical laboratory of the MUHC, HSC, CHEO, or in the central GDMCC research laboratory, as previously described 16–18 …”

Insights into Personalised Medicine in Bronchiectasis

“…It predominantly affects the respiratory tract ciliated epithelium. Generally, PCD is an autosomal recessive disorder however other modes of inheritance are also described (x-chromosomal [ 15 ] and autosomal dominant [ 16 , 17 ]). The underlying cilia may be drastically decreased in number but retain normal function or be defective in their utility.…”

The role of cilia for hydrocephalus formation

“…Surgical intervention was not required in any of the cases. In contrast, in all reported FOXJ1 affected patients, surgical relief of intracranial pressure was necessary (Shapiro et al, 2021; Wallmeier et al, 2019). De novo loss of function pathogenic variants in FOXJ1 cause RGMC with obstructive hydrocephalus and aqueduct stenosis, next to respiratory symptoms, subfertility, and situs anomalies in some (Shapiro et al, 2021; Wallmeier et al, 2019).…”

“…Interestingly, in the subgroup of affected individuals with defect in multiciliogenesis (RGMC), the prevalence of hydrocephalus compared to the healthy population is severely increased (Amirav et al, 2016). So far, all reported individuals with de novo loss of function variants in FOXJ1 suffer from hydrocephalus (Shapiro et al, 2021; Wallmeier et al, 2019). MCIDAS mutant individuals also exhibit enlarged ventricles.…”