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

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 281
Author(s):  
Wilfredo De Jesús-Rojas ◽  
Dalilah Reyes-De Jesús ◽  
Ricardo A. Mosquera
Keyword(s):  
Puerto Rican ◽  
Genetic Variants ◽  
Primary Ciliary Dyskinesia ◽  
Founder Mutation ◽  
Clinical Phenotype ◽  
Central Complex ◽  
Genetic Mutations ◽  
Radial Spokes ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

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.

scholarly journals RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

2015 ◽  
Vol 97 (1) ◽  
pp. 153-162 ◽  
Author(s):  
Ludovic Jeanson ◽  
Bruno Copin ◽  
Jean-François Papon ◽  
Florence Dastot-Le Moal ◽  
Philippe Duquesnoy ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Central Complex ◽  
Radial Spokes ◽  
Ciliary Dyskinesia

scholarly journals Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1278
Author(s):  
Michael Glenn O’Connor ◽  
Amjad Horani ◽  
Adam J. Shapiro
Keyword(s):  
Genetic Testing ◽  
North America ◽  
North American ◽  
Primary Ciliary Dyskinesia ◽  
Clinical Phenotype ◽  
The United States ◽  
Diagnostic Process ◽  
The North ◽  
Diagnostic Guideline ◽  
Ciliary Dyskinesia

Primary Ciliary Dyskinesia (PCD) is a rare, under-recognized disease that affects respiratory ciliary function, resulting in chronic oto-sino-pulmonary disease. The PCD clinical phenotype overlaps with other common respiratory conditions and no single diagnostic test detects all forms of PCD. In 2018, PCD experts collaborated with the American Thoracic Society (ATS) to create a clinical diagnostic guideline for patients across North America, specifically considering the local resources and limitations for PCD diagnosis in the United States and Canada. Nasal nitric oxide (nNO) testing is recommended for first-line testing in patients ≥5 years old with a compatible clinical phenotype; however, all low nNO values require confirmation with genetic testing or ciliary electron micrograph (EM) analysis. Furthermore, these guidelines recognize that not all North American patients have access to nNO testing and isolated genetic testing is appropriate in cases with strong clinical PCD phenotypes. For unresolved diagnostic cases, referral to a PCD Foundation accredited center is recommended. The purpose of this narrative review is to provide insight on the North American PCD diagnostic process, to enhance the understanding of and adherence to current guidelines, and to promote collaboration with diagnostic pathways used outside of North America.

scholarly journals Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia

2021 ◽  
Vol 22 (15) ◽  
pp. 8272
Author(s):  
Steven K Brennan ◽  
Thomas W Ferkol ◽  
Stephanie D Davis
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Pulmonary Infections ◽  
Disease Research ◽  
The Past ◽  
Clinical Presentations ◽  
Organ Laterality ◽  
Ciliary Dyskinesia ◽  
Laterality Defects ◽  
Severe Lung Disease ◽  
Severe Lung

Primary ciliary dyskinesia (PCD) is a rare inherited condition affecting motile cilia and leading to organ laterality defects, recurrent sino-pulmonary infections, bronchiectasis, and severe lung disease. Research over the past twenty years has revealed variability in clinical presentations, ranging from mild to more severe phenotypes. Genotype and phenotype relationships have emerged. The increasing availability of genetic panels for PCD continue to redefine these genotype-phenotype relationships and reveal milder forms of disease that had previously gone unrecognized.

scholarly journals Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia

2019 ◽  
Vol 57 (4) ◽  
pp. 237-244 ◽  
Author(s):  
Sylvain Blanchon ◽  
Marie Legendre ◽  
Mathieu Bottier ◽  
Aline Tamalet ◽  
Guy Montantin ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
High Speed ◽  
Genetic Disorder ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Central Complex ◽  
Ciliary Beating ◽  
Recovery Stroke ◽  
Biallelic Mutations ◽  
Ciliary Dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.MethodsWe prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).ResultsSixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.ConclusionQuantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.

scholarly journals High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Thorax ◽  
2017 ◽  
Vol 73 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Amelia Shoemark ◽  
Eduardo Moya ◽  
Robert A Hirst ◽  
Mitali P Patel ◽  
Evelyn A Robson ◽  
...  
Keyword(s):  
South Asian ◽  
Situs Inversus ◽  
Diagnostic Tests ◽  
Primary Ciliary Dyskinesia ◽  
Clinical Phenotype ◽  
Phenotypic Variability ◽  
Asian Population ◽  
Missense Variant ◽  
South Asian Population ◽  
Ciliary Dyskinesia

RationalePrimary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.ObjectivesTo determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.MethodsNext-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.ResultsSixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed.ConclusionsThe CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

scholarly journals Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central-Complex and Radial-Spoke Defects

2013 ◽  
Vol 93 (3) ◽  
pp. 561-570 ◽  
Author(s):  
Esther Kott ◽  
Marie Legendre ◽  
Bruno Copin ◽  
Jean-François Papon ◽  
Florence Dastot-Le Moal ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Central Complex ◽  
Loss Of Function ◽  
Radial Spoke ◽  
Ciliary Dyskinesia

scholarly journals Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

2021 ◽  
pp. mbc.E20-12-0806
Author(s):  
Yanhe Zhao ◽  
Justine Pinskey ◽  
Jianfeng Lin ◽  
Weining Yin ◽  
Patrick R. Sears ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Electron Tomography ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Radial Spoke ◽  
Radial Spokes ◽  
Cilia And Flagella ◽  
Tract Infections ◽  
Ciliary Dyskinesia

Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Protein 4 homolog A ( RSPH4A) can lead to primary ciliary dyskinesia (PCD), a life-shortening disease characterized by chronic respiratory tract infections, abnormal organ positioning, and infertility. Despite its importance for human health, the location of RSPH4A in human cilia has not been resolved, and the structural basis of RSPH4A-/- PCD remains elusive. Here, we present the native, three-dimensional structure of RSPH4A-/- human respiratory cilia using samples collected non-invasively from a PCD patient. Using cryo-electron tomography and subtomogram averaging, we compared the structures of control and RSPH4A-/- cilia, revealing primary defects in two of the three radial spokes (RSs) within the axonemal repeat and secondary (heterogeneous) defects in the central pair complex. Similar to RSPH1-/- cilia, the radial spoke heads of RS1 and RS2, but not RS3, were missing in RSPH4A-/- cilia. However, RSPH4A-/- cilia also exhibited defects within the arch domains adjacent to the RS1 and RS2 heads, which were not observed with RSPH1 loss. Our results provide insight into the underlying structural basis for RSPH4A-/- PCD and highlight the benefits of applying cryo-ET directly to patient samples for molecular structure determination. [Media: see text]

Novel Pathogenic DNAH5 Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis

2021 ◽  
Author(s):  
Hong T. Lin ◽  
Anita Gupta ◽  
Kevin E. Bove ◽  
Sara Szabo ◽  
Fang Xu ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Autosomal Recessive ◽  
Neonatal Cholestasis ◽  
Uncertain Significance ◽  
A Subunit ◽  
Axonemal Dynein ◽  
Infantile Cholestasis ◽  
First Time ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

AbstractThe dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.

scholarly journals A Study on the Genetics of Primary Ciliary Dyskinesia

2021 ◽  
Vol 10 (21) ◽  
pp. 5102
Author(s):  
Mohammed T. Alsamri ◽  
Amnah Alabdouli ◽  
Durdana Iram ◽  
Alia M. Alkalbani ◽  
Ayesha S. Almarzooqi ◽  
...  
Keyword(s):  
United Arab Emirates ◽  
Primary Ciliary Dyskinesia ◽  
Coiled Coil ◽  
Conserved Residues ◽  
Respiratory Problems ◽  
Tribal Communities ◽  
Novel Variants ◽  
Jensen Shannon Divergence ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen–Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (DNAH11) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous C1orf127:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.

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