Submission Details

The FOXJ1 gene was first reported in relation to primary ciliary dyskinesia in 2019 (Wallmeier et al, PMID: 31630787). The specific disease entity, primary ciliary dyskinesia 43 (MONDO:0032874, OMIM #618699), is one of at least 45 different primary ciliary dyskinesias distinguished by a single monogenic cause. Affected patients generally have onset of symptoms at birth but can be diagnosed as late as during the 5th decade of life (PMID: 34132502). Frequent features among well-characterized patients are noncommunicating hydrocephalus requiring ventriculoperitoneal shunting, neonatal respiratory distress, chronic wet cough, recurrent otitis media, chronic sinusitis, bronchiectasis, and abnormal mucociliary clearance. Unlike other forms of PCD, nasal nitric oxide values are typically within the normal range. Approximately 50% of cases exhibit situs inversus or another form of heterotaxy. Biopsies of the airway epithelium show multiciliated cells with a reduced number of cilia per cell, mislocalization of basal bodies to the cytoplasm rather than docking to the apical membrane, and diverse axonemal defects in ciliary ultrastructure. Ciliary beat pattern may be stiff with reduced amplitude. At least some of the known adult patients exhibit infertility, potentially related to blockage of the abnormal fallopian tube morphology or abnormal sperm morphology and motility (PMID: 31630787, PMID: 34132502). However, the known existence of at least one unpublished family with affected members in multiple generations indicates variable expressivity of the infertility feature (D. Morris, personal communication, October 16, 2025).

This curation has scored nine suspected deleterious pathogenic FOXJ1 variants (seven frameshift and two nonsense), which were collectively reported in twelve probands in five publications (PMID: 31630787, PMID: 34132502, PMID: 33077954, PMID: 37469238, PMID: 37813609). No probands were reported to be from consanguineous parents, and all probands harbored a single heterozygous FOXJ1 variant. Scoring was avoided for three probands who were reported to exhibit hydrocephalus but did not have sufficient additional details available to enable their evaluation for PCD (PMID: 33077954). Nine of the probands had both parental genotypes available and all were found to harbor the variant de novo. All variants were located between codons 237 and 323 in the third and final exon, with multiple independent occurrences of the same variants indicating potential hot spots in this region of FOXJ1. None of the variants were predicted to trigger nonsense-mediated decay, however, two had associated expression data consistent with their absence at the RNA level (PMID: 31630787). Therefore, the molecular mechanism appears to be monoallelic loss-of-function (haploinsufficiency) with an autosomal dominant mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product. While the genetic evidence in this curation has been scored based on the assumption that the known FOXJ1 variants cause PCD through a loss-of-function and/or haploinsufficiency mechanism, an urgent need remains for additional published data to more directly evaluate the mechanism of pathogenicity by which these variants affect FOXJ1 function. An additional reported proband who inherited a missense variant in exon 2 from an unaffected parent (PMID: 33077954) has introduced the possibility that an emerging subset of PCD-associated variants in FOXJ1 may be hypomorphic missense substitutions that preserve fertility and can be transmitted to offspring. However, this variant was not scored due to the unaffected parent and the lack of experimental evidence of impact on FOXJ1 function.

This gene-disease relationship is also supported by experimental evidence that high levels of FOXJ1 expression in humans are specific to tissues known to harbor multi-ciliated cells, particularly the fallopian tube, testis, lung, endocervix, and brain (PMID: 23715323, PMID: 9073514). FOXJ1 levels are severely reduced in multiciliated cells from primary ciliary dyskinesia 42 patients who harbor biallelic variants in the MCIDAS gene, which encodes a positive regulator of FOXJ1 expression. Biochemical studies in zebrafish (PMID: 19011630) and mouse respiratory epithelial cells (PMID: 12818891) indicate that the FOXJ1 gene product functions as a transcription factor (PMID: 9073514) to activate the expression of genes encoding motile ciliary components and induces basal body docking with the apical membrane and the formation of motile cilia during the later stages of respiratory progenitor cell differentiation into multiciliated epithelium. This is consistent with the reduced number of motile cilia and the basal body localization defects observed in the multiciliated cells of human patients and zebrafish with FOXJ1 loss-of-function (PMID: 19011630). A mouse model of FOXJ1 loss-of-function recapitulates additional human patient phenotypes such as heterotaxy, reduced fluid flow, and hydrocephalus (PMID: 9739041).

In summary, there is definitive evidence supporting a gene-disease relationship between variants in FOXJ1 and primary ciliary dyskinesia 43. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This Definitive classification has been approved by the ClinGen Motile Ciliopathy GCEP on October 16, 2025 (SOP Version 11).