Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia

Abstract

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.

Keywords: Kartagener syndrome; RSPH4A; cilia; sequencing.

Figure 1. Electron Micrographs Findings

A total of 871 ciliary cross sections were scored from 7 PCD families (8 subjects) with biallelic mutations in RSPH4A, and representative images are shown. (A) Normal axonemal structure including central apparatus [9+2] (50% of cilia images); (B) Complete absence of the central apparatus [9+0] (9% of cilia images) or (C) electron dense material in central area [9+0] (9% of cilia images); (D) Translocation of outer doublet to replace the central pair [8+1] (11% of cilia images); (E) Translocation of outer doublet into central region [8+4] (1% of cilia images); (F) A single microtubule in the center instead of a central pair [9+1] (5% of cilia images); (G) Eccentric 9 outer doublets with 9+2 arrangement (3% of cilia images); (H) Central pair off-center with 9+2 arrangement (3% cilia images); (I, J) Extra singlet or multiple microtubules in center of the cilia (6% of cilia images); (K) Multiple single microtubules outside the 9 outer doublet ring (1% of cilia images); (L) Other abnormalities includes 8 outer doublets with or without a normal central apparatus; 7 outer doublets with a central pair and 2 single microtubules in the center; 8 outer doublets with 2 central pairs; 8 outer doublets with 4 central single microtubules; 8 outer doublets without a central pair and 1 doublet outside of the outer ring (2% of cilia images).