FOXJ1 – Primary Ciliary Dyskinesia

Forkhead box J1 (FOXJ1) is a transcription factor essential for motile cilia biogenesis and left–right axis specification. Heterozygous loss-of-function variants in FOXJ1 have been established as an autosomal dominant cause of primary ciliary dyskinesia (PCD), a disorder marked by recurrent respiratory infections, bronchiectasis, infertility, organ laterality defects and, uniquely, obstructive hydrocephalus.

Multiple independent reports have described five unrelated probands carrying truncating or missense variants in FOXJ1: a Chinese child with de novo c.734_735ins20 (frameshift) presenting PCD and hydrocephalus (PMID:37469238), a Japanese adult with c.709del (p.Arg237GlyfsTer5) and classical PCD features (PMID:37813609), two patients in a multi-patient cohort harboring c.929_932del (p.Phe315LeufsTer18) and c.945del (p.Phe315LeufsTer18) with hydrocephalus (PMID:34132502), and a three-generation heterotaxy family with c.1129del (p.Leu377TrpfsTer76) showing dominant-negative effects and situs abnormalities (PMID:37692537).

Inheritance is autosomal dominant with de novo occurrence in four cases and segregation of the c.1129del variant through two additional affected relatives in a three-generation pedigree. The variant spectrum is predominantly truncating (five LoF alleles) with one missense (p.Gln135Glu), consistent with haploinsufficiency and dominant-negative effects. No recurrent or population-specific founder alleles have been reported.

Functional studies have demonstrated that truncating FOXJ1 variants fail to induce motile cilia in vitro and cannot activate downstream targets such as ADGB. A knock-in mouse model of c.1129del recapitulates human phenotypes including hydrocephalus, situs inversus and disrupted tracheal ciliary ultrastructure, supporting a dominant-negative mechanism (PMID:37692537).

There are no reported studies disputing the causative role of FOXJ1 variants in PCD or assigning alternative primary phenotypes. All available data show concordance between genotype, ciliary dysfunction, and clinical presentation.

Collectively, genetic and experimental evidence support a Strong gene–disease relationship for FOXJ1 and autosomal dominant PCD with hydrocephalus. Clinicians should consider FOXJ1 testing in patients with PCD who present hydrocephalus or laterality defects to enable precise diagnosis and management.

References

• Molecular Genetics & Genomic Medicine • 2023 • A novel heterozygous variant of FOXJ1 in a Chinese female with primary ciliary dyskinesia and hydrocephalus: A case report and literature review. PMID:37469238
• Molecular Genetics & Genomic Medicine • 2021 • Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus. PMID:34132502
• Translational Pediatrics • 2023 • Novel dominant-negative FOXJ1 mutation in a family with heterotaxy plus mouse model. PMID:37692537
• Internal Medicine (Tokyo, Japan) • 2024 • FOXJ1 Variants Causing Primary Ciliary Dyskinesia with Hydrocephalus: A Case Report from Japan. PMID:37813609

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