Dataset Information

Autosomal dominant variants in FOXJ1 causing 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.

SUBMITTER: Shapiro AJ

PROVIDER: S-EPMC8372090 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is a type of ciliary dyskinesia that is usually caused by autosomal recessive inheritance and can manifest as recurrent respiratory infections, bronchiectasis, infertility, laterality defects, and chronic otolaryngological disease. Although ependymal cilia, which affect the flow of cerebrospinal fluid in the central nervous system, have much in common with respiratory cilia in terms of structure and function, hydrocephalus is rarely associated with PCD. Recently, variants of Forkhead box J1 (FOXJ1) have been found to cause PCD combined with hydrocephalus in a de novo, autosomal dominant inheritance pattern.MethodsWe performed DNA extraction, whole-exome sequencing (WES) analysis, and mutation analysis of FOXJ1 and analyzed the patient's clinical and genetic data.ResultsThe patient was a 4-year-old female exhibiting normal growth and development. At 3 years and 2 months of age, the patient experienced hand shaking and weakness in the lower limbs. Cardiac ultrasonography showed a right-sided heart, and cranial magnetic resonance imaging showed obstructive hydrocephalus. The nasal nitric oxide level was 54 nL/min. WES indicated a de novo, heterozygous variant of FOXJ1, c.734-735 ins20. This variant was novel, not included in the Human Gene Mutation and Genome Aggregation Database, and likely pathogenic according to the American College of Medical Genetics and Genomics, causing earlier termination of amino acid translation. The patient underwent a neuroendoscopic third ventriculostomy after the diagnosis of obstructive hydrocephalus. Six months after the operation, the patient's motor deficits had improved.ConclusionThis is the first report of a de novo, autosomal dominant pattern of FOXJ1 causing PCD combined with hydrocephalus in China. The patient's clinical symptoms were similar to those previously reported. WES confirmed that a novel variant of FOXJ1 was the cause of the PCD combined with hydrocephalus, expanding the spectrum of the genotypes associated with this condition. Physicians should be aware of the correlation of hydrocephalus and PCD and test for FOXJ1 variants.