Novel pathogenic variant in ARMC4 identified by whole exome sequencing in a Turkish family with primary ciliary dyskinesia.

INTRODUCTION

Primary ciliary dyskinesia (PCD) is a rare genetic disorder affecting approximately 1:15,000 to 1:30,000 individuals. It is characterized by upper and lower respiratory diseases, otitis media, congenital heart defects, situs inversus, infertility in males, and hydrocephalus. Whole-exome sequencing (WES) has become an important tool for identifying novel pathogenic variants associated with PCD.

METHODS

Trio-based WES was performed in two Turkish siblings with clinically suspected PCD born to healthy consanguineous parents. Candidate variants were validated by Sanger sequencing and functionally assessed using immunofluorescence (IF) analysis of respiratory cilia obtained by nasal brushing biopsy.

RESULTS

A novel homozygous frameshift pathogenic variant in ARMC4 [c.324dupA; p.Arg109Thrfs*19] was identified in both affected siblings. IF analysis demonstrated absence of ARMC4 protein in the ciliary axonemes and distal loss of DNAH5, confirming the functional effect of the variant.

DISCUSSION: These findings expand the mutational spectrum of ARMC4-associated PCD and highlight the importance of combining genetic and functional analyses for accurate diagnosis and variant interpretation in PCD.