Founder Mutation in RSPH4A Identified in Patients of Hispanic Descent with Primary Ciliary Dyskinesia
Contract grant sponsors: US National Institute of Health (NIH) Office of the Director; Office of Rare Diseases Research (ORDR); National Heart, Lung, and Blood Institute (NHLBI); (5 U54 HL096458-06); US National Institutes of Health (NIH)—National Heart, Lung, and Blood Institute (NHLBI) (5R01HL071798); T32 Research Training Program “Multidisciplinary Research Training in Pulmonary Diseases” (T32 HL007106); National Human Genome Research Institute (NHGRI); National Center for Advancing Translational Sciences (NCATS) (UL1 TR000083, CFF R026-CR07); ORDR; NHLBI; NHGRI; NCATS. The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Heart Lung and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Communicated by Garry R. Cutting
Correspondence to: Maimoona A. Zariwala, Department of Pathology & Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC 27599. E-mail: email@example.com; Michael R. Knowles, Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599. E-mail: Knowles@med.unc.edu
Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent.