Truncating mutations in exons 20 and 21 of <i>OFD1</i> can cause primary ciliary dyskinesia without associated syndromic symptoms.

Abstract

Primary ciliary dyskinesia (PCD) is a motile ciliopathy, whose symptoms include airway infections, male infertility and <i>situs inversus</i>. Apart from the typical forms of PCD, rare syndromic PCD forms exist. Mutations of the X-linked <i>OFD1</i> gene cause several syndromic ciliopathies, including oral-facial-digital syndrome type 1, Joubert syndrome type 10 (JBTS10), and Simpson-Golabi-Behmel syndrome type 2, the latter causing the X-linked syndromic form of PCD. Neurological and skeletal symptoms are characteristic for these syndromes, with their severity depending on the location of the mutation within the gene. To elucidate the role of motile cilia defects in the respiratory phenotype of PCD patients with C-terminal OFD1 mutations. Whole-exome sequencing in a group of 120 Polish PCD patients, mutation screening of the <i>OFD1</i> coding sequence, analysis of motile cilia, and magnetic resonance brain imaging. Four novel hemizygous <i>OFD1</i> mutations, in exons 20 and 21, were found in men with a typical PCD presentation but without severe neurological, skeletal or renal symptoms characteristic for other <i>OFD1</i>-related syndromes. Magnetic resonance brain imaging in two patients did not show a molar tooth sign typical for JBTS10. Cilia in the respiratory epithelium were sparse, unusually long and displayed a defective motility pattern. Consistent with the literature, truncations of the C-terminal part of <i>OFD1</i> (exons 16-22) almost invariably cause a respiratory phenotype (due to motile cilia defects) while their impact on the primary cilia function is limited. We suggest that exons 20-21 should be included in the panel for regular mutation screening in PCD.