Variants in CEP135 Cause Congenital Microcephaly and Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD), a disorder of motile ciliary dysfunction causing chronic respiratory infections, may also rarely present with aspects of non-motile ciliary dysfunction, including retinitis, central nervous system malformations, skeletal dysplasia, and sensorineural hearing loss. However, congenital microcephaly has not been previously associated with PCD.

We identified three children with congenital microcephaly and chronic respiratory disease consistent with PCD. Comprehensive PCD diagnostic testing and whole exome sequencing were performed. Characterization of nasal epithelial cells after expansion and regrowth included reverse transcription polymerase chain reaction, high speed videomicroscopy, and transcript analysis of novel genetic variants.

Three pediatric cases from two families had primary microcephaly from autosomal recessive variants in CEP135. All cases displayed chronic suppurative respiratory symptoms, recurrent otitis media, and bronchiectasis with low nasal nitric oxide. One case had pathogenic, compound heterozygous, loss of function variants, while the other two cases had homozygous variants of uncertain significance. Transcript analyses of CEP135 variants of uncertain significance supported a splicing defect as disease-causing. Regrown nasal epithelial cells demonstrated overall normal ciliary ultrastructure with decreased numbers of full-length axonemes. Ciliary beat pattern was grossly abnormal, and distal axoneme swelling with bulbous-tip structures were identified pre- and post-cellular regrowth.

These cases establish variants in CEP135 as a novel cause of PCD with microcephaly. The TEM findings of bulbous ciliary tips may be a reliable marker of overlapping ciliopathies in patients with aspects of motile and non-motile ciliary dysfunction.