Founder Mutation in RSPH4A Identified in Patients of Hispanic Descent with Primary Ciliary Dyskinesia

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.

[1]  M. Rosenfeld,et al.  Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline , 2018, American Journal of Respiratory and Critical Care Medicine.

[2]  M. Rosenfeld,et al.  Mutations in CCDC39 and CCDC40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms , 2013, Human mutation.

[3]  S. Lindberg,et al.  The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans , 2013, Nature Genetics.

[4]  Emily H Turner,et al.  Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. , 2013, American journal of human genetics.

[5]  S. Amselem,et al.  Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. , 2012, American journal of human genetics.

[6]  Kate S. Wilson,et al.  Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. , 2012, American journal of human genetics.

[7]  E. Ziętkiewicz,et al.  Mutations in Radial Spoke Head Genes and Ultrastructural Cilia Defects in East-European Cohort of Primary Ciliary Dyskinesia Patients , 2012, PloS one.

[8]  M. Rosenfeld,et al.  Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure , 2011, Thorax.

[9]  H Omran,et al.  Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children , 2009, European Respiratory Journal.

[10]  F. Roudot-thoraval,et al.  A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia , 2009, European Respiratory Journal.

[11]  Haibo Zhou,et al.  Increased nasal epithelial ciliary beat frequency associated with lifestyle tobacco smoke exposure , 2009, Inhalation toxicology.

[12]  J. Carson,et al.  Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome , 2009, Genetics in Medicine.

[13]  Colin A. Johnson,et al.  Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. , 2009, American journal of human genetics.

[14]  D. Hughes Primary ciliary dyskinesia. , 2008, Paediatrics & child health.

[15]  Heymut Omran,et al.  Genetic defects in ciliary structure and function. , 2007, Annual review of physiology.

[16]  J. Martínez-Cruzado,et al.  Reconstructing the population history of Puerto Rico by means of mtDNA phylogeographic analysis. , 2005, American journal of physical anthropology.

[17]  C. O’Callaghan,et al.  Central microtubular agenesis causing primary ciliary dyskinesia. , 2004, American journal of respiratory and critical care medicine.

[18]  M. Hazucha,et al.  Primary ciliary dyskinesia: diagnostic and phenotypic features. , 2004, American journal of respiratory and critical care medicine.

[19]  M. Chilvers,et al.  Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia☆ , 2003, Journal of Allergy and Clinical Immunology.

[20]  C. Lalueza-Fox,et al.  MtDNA from extinct Tainos and the peopling of the Caribbean. , 2001, Annals of human genetics.

[21]  M. Hazucha,et al.  Germline mutations in an intermediate chain dynein cause primary ciliary dyskinesia. , 2001, American journal of respiratory cell and molecular biology.