Primary Ciliary Dyskinesia Diagnostic Challenges: Understanding the Clinical Phenotype of the Puerto Rican RSPH4A Founder Mutation

Abstract

Primary ciliary dyskinesia (PCD) is a rare, heterogeneous ciliopathy resulting in chronic oto-sino-pulmonary disease, bronchiectasis, newborn respiratory distress, and laterality defects. PCD diagnosis can be achieved by following diagnostic algorithms that include electron microscopy, genetics, and ancillary testing. Genetic mutations in more than 45 genes, including RSPH4A, can lead to PCD. RSPH4A mutations located on chromosome six, affect radial spokes and results in central complex apparatus abnormalities. The RSPH4A [c.921 + 3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. Additionally, there are further diagnostic challenges present in the Puerto Rican population to diagnose PCD. We describe the demographics, clinical features, and RSPH4A genetic variants in 13 patients with clinical PCD affecting 11 Puerto Ricans from unrelated families.

Keywords: Puerto Rico; RSPH4A; cilia; founder mutation; primary ciliary dyskinesia.

Figure 1

Ciliary biopsy findings of RSPH4A subjects. A total of 11 samples were submitted for electron microscopy, representative images of abnormal findings are shown. (a) Normal ciliary configuration [9 + 2]; (b) Abnormal peripheral microtubule configuration, [7 + 2]; (c) Single microtubule outside the 9 outer doublet rings [9 + 1]; (d) Extra central microtubule, [9 + 3]; (e) Electron dense material in central area surrounded by eight outer doublets [8 + 0]; (f) Single microtubule in position of the central pair [9 + 1]. (g,h) Abnormal microtubule organization and configuration, with displacement of peripheral doublets [9 + 0]; (i) Supernumerary central microtubules, [9 + 5]. (j) Central displacement of a peripheral doublet [8 + 4].

Figure 2

High-Resolution chest CT scans (HRCT) of PCD patients with positive RSPH4A genetic variants. (a) 15-year-old male homozygous for RSPH4A [c.921 + 3_921 + 6del (Intronic)] founder mutation shows a tree-in-bud pattern at left lower lobe (LLL), lingula, right lower lobe (RLL), right middle lobe (RML), right upper lobe (RUL). HRCT showed bilateral ground-glass appearance but no bronchiectasis. (b) 51-year-old male, homozygous for RSPH4A [c.921 + 3_921 + 6del (Intronic)] founder mutation who also had a heterozygous Variant of Unknown Significance (VUS) in DNAH5 c.1250C > G (p.Thr417Ser). HRCT showed bibasilar bronchiectasis and parenchymal scarring tissue more evident at the LLL. (c) 13-year-old male with two pathogenic heterozygous genetic variants in RSPH4A [c.921 + 3_921 + 6del (Intronic)] and RSPH4A [c.1103T > G (p.Val368Gly)] and one heterozygous VUS in DNAH8 [c.9839A > T (p.Gln3280Leu)]. HRCT showed cylindrical and varicose bilateral bronchiectasis, multiple centrilobular nodules, and tree-in-bud opacities. (d) A 33-year-old female with one heterozygous RSPH4A [c.902A > C (p.Gln301Pro)] VUS who showed extensive bilateral bronchiectasis, reticular-nodular infiltrates with tree-in-bud changes at RML and RLL. Case 4 also had an heterozygous VUS on DNAAF3 [c.1672G > T (p.Glu558*)] and DNAH11 [c.11678C > T (p.Thr3893Met)]. All four cases had central apparatus abnormalities on the cilia ultrastructure examined by electron microscopy.