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 Clinical and Genetic Analysis of Children with Kartagener Syndrome

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 900 ◽  
Author(s):  
Rute Pereira ◽  
Telma Barbosa ◽  
Luís Gales ◽  
Elsa Oliveira ◽  
Rosário Santos ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Kartagener Syndrome ◽  
Mucus Clearance ◽  
Pathogenic Variants ◽  
Transmission Electron ◽  
Whole Exome ◽  
Dynein Arms ◽  
Organ Laterality ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes’ products. Our work calls the researcher’s attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.

scholarly journals A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Jillian P. Casey ◽  
Patricia Goggin ◽  
Jennifer McDaid ◽  
Martin White ◽  
Sean Ennis ◽  
...  
Keyword(s):  
Case Report ◽  
Developmental Delay ◽  
Primary Ciliary Dyskinesia ◽  
Single Gene ◽  
Ciliary Dyskinesia ◽  
Laterality Defects ◽  
Chromosome Disorder

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 Respiratory Distress in the Newborn with Primary Ciliary Dyskinesia

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 153
Author(s):  
Evans Machogu ◽  
Benjamin Gaston
Keyword(s):  
Respiratory Distress ◽  
Primary Ciliary Dyskinesia ◽  
Chronic Otitis Media ◽  
Situs Inversus Totalis ◽  
Radiographic Findings ◽  
Neonatal Respiratory Distress ◽  
Organ Laterality ◽  
Wet Cough ◽  
Work Up ◽  
Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is inherited in a predominantly autosomal recessive manner with over 45 currently identified causative genes. It is a clinically heterogeneous disorder that results in a chronic wet cough and drainage from the paranasal sinuses, chronic otitis media with hearing impairment as well as male infertility. Approximately 50% of patients have situs inversus totalis. Prior to the development of chronic oto-sino-pulmonary symptoms, neonatal respiratory distress occurs in more than 80% of patients as a result of impaired mucociliary clearance and mucus impaction causing atelectasis and lobar collapse. Diagnosis is often delayed due to overlapping symptoms with other causes of neonatal respiratory distress. A work up for PCD should be initiated in the newborn with compatible clinical features, especially those with respiratory distress, consistent radiographic findings or persistent oxygen requirement and/or organ laterality defects

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.

scholarly journals Late diagnosis of infants with PCD and neonatal respiratory distress

2020 ◽  
Author(s):  
Goutaki Myrofora ◽  
S Halbeisen Florian ◽  
Barbato Angelo ◽  
Crowley Suzanne ◽  
Harris Amanda ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Primary Ciliary Dyskinesia ◽  
List Type ◽  
Term Infants ◽  
Entire Cohort ◽  
Neonatal Respiratory Distress ◽  
Situs Solitus ◽  
History Of ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

AbstractNeonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates are diagnosed timely.We used data from the international PCD cohort study (iPCD), including only participants diagnosed between 2000 and 2019 using current diagnostic criteria. We assessed the proportion of patients with PCD with a history of NRD and their age at diagnosis, stratifying by presence of laterality defects. First we analysed data from the entire cohort and then from a subgroup including children diagnosed using stricter criteria.Among the 1375 patients in the study, 45% had a history of NRD and 42% a laterality defect. Out of the 476 children with definite PCD diagnosis, 55% had a history of NRD and 50% a laterality defect. PCD was diagnosed at a median age of 3.4 years in this group, varying from less than 1 year in Norway and Cyprus to 10 years in Turkey. Overall, 30% of children with PCD were diagnosed during the first 12 months of life. This varied from 13% in those with situs solitus and no NRD, to 21% in those with situs solitus and NRD, 33% in those with situs anomalies but no NRD, and 52% in those with both NRD and situs anomalies.Our results suggest that we need to improve our knowledge of the neonatal presentation of infants with PCD, and apply this knowledge in neonatology so that these patients will receive appropriate care sooner, at the start of their extrauterine life.What is already known on this topic?Many patients with primary ciliary dyskinesia (PCD) present with neonatal respiratory distress (NRD).The neonatal period would therefore be an ideal window of opportunity to diagnose PCD early, before long-term damage to the lungs has occurred.Despite this, PCD is usually diagnosed late in life.What this study adds?55% of children with PCD in this large multinational dataset had a history of NRD.Among these, PCD was diagnosed early in those with laterality defects (median age 0.9 years) but late in those with situs solitus (5.9 years).This suggests that neonatologists and paediatricians do not suspect PCD as a cause of NRD in term infants unless it is accompanied by laterality defects.

scholarly journals A retrospective review of Achromobacter species and antibiotic treatments in patients with primary ciliary dyskinesia

2021 ◽  
Vol 18 ◽  
pp. 147997312110616
Author(s):  
Mathias G Holgersen ◽  
June K Marthin ◽  
Helle K Johansen ◽  
Kim G Nielsen
Keyword(s):  
Lung Function ◽  
Primary Ciliary Dyskinesia ◽  
Mucociliary Clearance ◽  
Congenital Disease ◽  
Pulmonary Infections ◽  
Opportunistic Pathogens ◽  
Median Length ◽  
Health Records ◽  
Ciliary Dyskinesia

Objectives: Primary ciliary dyskinesia (PCD) is a rare congenital disease with defective mucociliary clearance causing frequent and often persistent pulmonary infections. Achromobacter species are opportunistic pathogens renowned for the difficulty of effective treatments and deteriorating effects on lung function. We aimed to describe the occurrence, treatment, and rate of successful eradication of Achromobacter species in patients with PCD. Methods: We retrospectively reviewed 18 years of historical microbiological samples and 10 years of electronic health records for PCD patients in Denmark. Results: We included 136 patients. Twenty-six patients had isolates of Achromobacter species. On average, 5% of the cohort had at least one annual isolate. Infections became persistent in 38% with a median length of 6.6 years leading to a significant number of antibiotic treatments. Resistance toward tobramycin and ciprofloxacin was prevalent. Overall, successful eradication was achieved in 62% of patients. We found the course of lung function significantly worse during persistent Achromobacter species infection than during the two preceding years, but not different to the course in unaffected age-matched controls. Conclusion The prevalence of Achromobacter species in patients with PCD is in line with what has been reported in cystic fibrosis and can occur transiently, intermittently, or develop into a serious persistent lung infection associated with long-term antibiotic treatment.

scholarly journals Late Diagnosis of Infants with PCD and Neonatal Respiratory Distress

2020 ◽  
Vol 9 (9) ◽  
pp. 2871
Author(s):  
Myrofora Goutaki ◽  
Florian S. Halbeisen ◽  
Angelo Barbato ◽  
Suzanne Crowley ◽  
Amanda Harris ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Primary Ciliary Dyskinesia ◽  
Late Diagnosis ◽  
Appropriate Care ◽  
Neonatal Respiratory Distress ◽  
Situs Solitus ◽  
History Of ◽  
Ciliary Dyskinesia ◽  
Laterality Defects ◽  
Neonatal Presentation

Neonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates receive a timely diagnosis. We used data from the international PCD cohort and assessed the proportion of patients with PCD who had a history of NRD and their age at diagnosis, stratifying by presence of laterality defects. First we analyzed data from all participants diagnosed after 2000, followed by individuals from a subgroup diagnosed using stricter criteria. Among the 1375 patients in the study, 45% had a history of NRD and 42% had laterality defects. Out of the 476 children with definite PCD diagnosis, 55% had a history of NRD and 50% had laterality defects. Overall, 30% of children with PCD were diagnosed during the first 12 months of life. This varied from 13% in those with situs solitus and no NRD, to 21% in those with situs solitus and NRD, 33% in those with situs anomalies but no NRD, and 52% in those with both situs anomalies and NRD. Our results suggest that we need to improve our knowledge of the neonatal presentation of infants with PCD and apply it so that these patients will receive appropriate care sooner.

Discordant organ laterality in monozygotic twins with primary ciliary dyskinesia

1999 ◽  
Vol 82 (2) ◽  
pp. 155-160 ◽  
Author(s):  
Peadar G. Noone ◽  
Deeksha Bali ◽  
Johnny L. Carson ◽  
Aruna Sannuti ◽  
Clay L. Gipson ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Monozygotic Twins ◽  
Organ Laterality ◽  
Ciliary Dyskinesia
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