Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting ciliary structure and function. PCD exhibiting dynein regulatory complex subunit 1 (DRC1) exon 1-4 deletion has been reported in several Japanese PCD patients; however, no large scale studies have been performed. Here, we aimed to determine the prevalence and founder effect of this variant in the Korean population. Using an in-house copy number variation tool, we screened for DRC1 exon 1-4 deletion in 20 patients with PCD and exome data of 1435 patients in the Seoul National University Hospital repository. In cases of suspected DRC1 deletion, confirmatory gap-PCR was performed. In a PCD cohort, three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion (NM_145038.5(DRC1): c.1-3952_540 + 1331del27748-bp) while pathogenic variants were found in CCDC39 (N = 1), DNAAF6 (N = 1), DNAH9 (N = 1). In the 1,435-sample exome data, seven patients (0.49%) were confirmed to have DRC1 exon 1-4 deletion. A chimeric sequence including the junction was searched from the 1000 Genomes Project data repository. One Japanese patient (0.96%) was found to have the same DRC1 exon 1-4 deletion, which was absent in other populations. This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis. In summary, the prevalence of PCD based on DRC1 exon 1-4 deletion is particularly high in Korean and Japanese populations, which is attributed to the founder effect. Genetic testing for DRC1 exon 1-4 deletion should be considered as an initial screening tool for Korean and Japanese patients with PCD.

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence.

We aimed to determine a genetic diagnosis in the national primary ciliary dyskinesia (PCD) cohort of Cyprus, an island with a high disease prevalence. We used targeted next-generation sequencing (NGS) of 39 PCD genes in 48 patients of Greek-Cypriot and other ancestries. We achieved a molecular diagnosis in 74% of the unrelated families tested. We identified 24 different mutations in 11 genes, 12 of which are novel. Homozygosity was more common in Greek-Cypriot than non-Greek-Cypriot patients (88% vs. 46.2%, p = .016). Four mutations (DNAH11:c.5095-2A>G, CFAP300:c.95_103delGCCGGCTCC, TTC25:c.716G>A, RSPH9:c.670+2T>C) were found in 74% of the diagnosed Greek-Cypriot families. Patients with RSPH9 mutations demonstrated higher nasal nitric oxide (57 vs. 15 nl/min, p <.001), higher forced expiratory volume in 1 s (-0.89 vs. -2.37, p = .018) and forced vital capacity (-1.00 vs. -2.16, p = .029) z scores than the rest of the cohort. Targeted multigene-panel NGS is an efficient tool for early diagnosis of PCD, providing insight into genetic disease epidemiology and improved patient stratification.

Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous disease with a diverse clinical and genetic spectrum among populations worldwide. Few cases of pediatric PCD have been reported from China. RESEARCH QUESTION: What are the clinical and genotypic characteristics of children with PCD in China? STUDY DESIGN AND METHODS: Clinical characteristics, laboratory findings, and genetic results obtained for 75 patients with PCD were reviewed retrospectively at a single center in China. Genetic sequencing was conducted using whole-exome screening. RESULTS: Patient median age at diagnosis was 7.0 years (range, 2 months-14 years). Of 75 patients, 88% (66/75) had chronic wet cough, 77% (58/75) had recurrent sinusitis, 76% (57/75) had bronchiectasis, 40% (30/75) had neonatal respiratory distress, and 28% (21/75) had coexistent asthma. Notably, postinfectious bronchiolitis obliterans (PIBO) as first presentation was found in 8% of children (6/75). Genes with the highest incidence of mutations were DNAH11 (15/51), followed by DNAH5 (9/51), CCDC39 (5/51), DNAH1 (4/51), and CCNO (3/51). Four genes (DNAI1, HEATR2, RSPH9, and DNAAF3) each were respectively found in two patients, and seven genes (CCDC40, LRRC6, SPAG1, RSPH4A, ARMC4, CCDC114, and DNAH14, a novel gene) each were mutated once. No differences in classical clinical features were observed among patients with commonly observed PCD-associated genotypes. However, three of six PIBO patients carried DNAH1 mutations. INTERPRETATION: Besides typical clinical features, PIBO was observed as the first presentation of pediatric PCD in China. An association of the novel gene DNAH14 with PCD was observed, expanding the PCD genotypic spectrum.

Primary ciliary dyskinesia and psychological well-being in adolescence.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease with low prevalence in pediatrics. Health studies have not sufficiently analyzed the role of psychological variables in rare diseases such as PCD. This paper studies the psychological characteristics of a group of pediatric patients diagnosed with PCD compared to their healthy peers. The sample consisted of 48 preadolescents-adolescents, aged 9-18 years (M = 12.96; SD = 2.71), with similar distribution by sex, and 25% of the patients having dyskinesia. Clinical anxiety-depression, self-esteem and psychological well-being were evaluated using questionnaires: the Adolescent Psychological Well-being Scale (BIEPS-J), the Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self-Esteem Scale (RSE). Data were analysed using descriptive, mean comparison (t-test) and diffuse comparative qualitative analysis (QCA). The results show no differences were found between healthy and PCD patients in the variables analyzed, except for social ties showing the latter greater well-being in this aspect. In QCA models, the variables that best explained the high or low levels of well-being were depression and self-esteem, and primary ciliary dyskinesia was not a necessary condition for presenting low levels of well-being. In conclusion, our results highlight the need to explore psychological aspects in pediatric patients with rare diseases.

Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia dysfunction generally inherited as an autosomal recessive disease. Genetic testing is increasingly considered an early step in the PCD diagnostic workflow. We used targeted panel next-generation sequencing (NGS) for genetic screening of 33 Egyptian families with clinically highly suspected PCD. All variants prioritized were Sanger confirmed in the affected individuals and correctly segregated within the family. Targeted NGS yielded a high diagnostic output (70%) with biallelic mutations identified in known PCD genes. Mutations were identified in 13 genes overall, with CCDC40 and CCDC39 the most frequently mutated genes among Egyptian patients. Most identified mutations were predicted null effect variants (79%) and not reported before (85%). This study reveals that the genetic landscape of PCD among Egyptians is highly heterogeneous, indicating that a targeted NGS approach covering multiple genes will provide a superior diagnostic yield compared to Sanger sequencing for genetic diagnosis. The high diagnostic output achieved here highlights the potential of placing genetic testing early within the diagnostic workflow for PCD, in particular in developing countries where other diagnostic tests can be less available.

Validation of pediatric health-related quality of life instruments for primary ciliary dyskinesia (QOL-PCD).

RATIONALE: Having developed the first disease-specific, health-related quality of life (HRQoL) instruments for children with primary ciliary dyskinesia (PCD), we aimed to assess the psychometric performance of quality of life (QOL)-PCD child, adolescent, and parent-proxy versions in terms of reliability and validity across cross-cultural settings and caring for patients with this rare disease. METHODS: Children (n = 71), adolescents (n = 85), and parents (n = 68) from multiple centers in the UK and North America completed age-appropriate QOL-PCD and generic QOL measures: pediatric QOL inventory, COPD assessment test (CAT), and Sino-Nasal Outcome Test 20. Total of 13 children, 13 parents, and 17 adolescents repeated QOL-PCD 10 to 14 days later to assess test-retest reliability. Multitrait analysis evaluated how the items loaded to hypothesized scales: physical, emotional & social functioning, treatment burden, role, vitality, upper and lower respiratory symptoms, and ears and hearing symptoms. Examination of item-to-total correlations led to removal of three, five, and six items, respectively in the prototype child, adolescent and parent-proxy versions; the validated measures now comprise between 34 and 38 items. RESULTS: The QOL-PCD scales had good internal consistency; Cronbach's α for QOL-PCD parent-proxy ranged 0.62 to 0.86. Test-retest reliability demonstrated stability across all scales; for example QOL-PCD adolescent intraclass correlation coefficients ranged 0.71 to 0.89. Significant relationships were found between QOL-PCD scales and similar constructs on generic questionnaires, for example, QOL-PCD adolescent lower respiratory symptoms and the CAT score (r = .64, P < .01); weaker correlations were found between different constructs. CONCLUSION: Age-specific QOL-PCD demonstrated good internal consistency, test-retest reliability, and validity. QOL-PCD offers promising outcome measures for multicenter clinical trials, as well as monitoring symptoms, functioning, and QOL during routine care.

Caregiver burden in children with cystic fibrosis and primary ciliary dyskinesia.

INTRODUCTION: Caregiver burden impacts both the social and economic framework of society. Cystic fibrosis (CF) causes significant caregiver burden, but the current data is scarce. In the case of primary ciliary dyskinesia (PCD), even less is known. This study aims to compare the caregiver burden of the parents of patients with CF and PCD. METHODS: Patients with CF and PCD between the ages of 6 to 13 and their parents were included. Patients' clinical information and parents' demographics were recorded. Caregiver burden was measured with Zarit Caregiver Burden Scale (ZCB), while the quality of life (QOL) was measured with CFQOL-revised (CFQOL-R) and PCD QOL questionnaire as the patients' age and diagnosis indicated. RESULTS: A total of 63 patients, 44 with CF (69%) and 85 caregivers (35 mothers, 6 fathers, and 22 mother-father dyads) participated in the study. Caregiver burden was significantly higher in mothers of the CF group with a mean ZCB of 30.5 ± 10.7 when compared to the PCD group with a mean ZCB of 21.93 ± 8.26 (P = .006). This was similar in fathers with mean ZCB of 27.5 ± 9.21 in the CF group and 20.36 ± 7.43 in the PCD group (P = .03). In correlation analyses, mothers' caregiver burden moderately and inversely correlated with CFQOL-R subscales in the CF population. CONCLUSION: Caregiver burden is significantly higher in the CF population when compared to PCD. It is correlated with pulmonary functions and QOL in patients with CF.

Prevalence of chronic rhinosinusitis in bronchiectasis patients suspected of ciliary dyskinesia.

BACKGROUND: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. METHODS: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed. RESULTS: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV1 ) at the time of referral than those without CMD (CMD+ , 91 ± 3.7%; CMD- , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72). CONCLUSION: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.

Síndrome de Kartagener / Kartagener Syndrome

Introducción: El síndrome de Kartagener es una variación clínica de la discinesia ciliar primaria, se caracteriza por la triada clásica de sinusitis crónica, bronquiectasia y situs inversus (total o parcial), catalogada como enfermedad rara de herencia autosómica recesiva. Objetivo: Analizar las manifestaciones clínicas, análisis complementarios y tratamiento de los pacientes diagnosticados con síndrome de Kartagener en la República del Ecuador. Presentación de caso: Paciente femenina, de nacionalidad ecuatoriana, con manifestaciones clínicas de la tríada del síndrome de Kartagener y rasgo de infertilidad, con antecedente de sinusitis crónica desde 14 años de edad. Los estudios imagenológicos de rayos X de tórax y tomografía axial computarizada de tórax y senos paranasales confirmaron las manifestaciones de síndrome de Kartagener, que representa el séptimo caso reportado en el país. Se analizaronn las características clínicas de la serie de siete casos reportados en el Ecuador hasta el presente, correspondiente al período 2015-2018 y exámenes complementarios realizados para el diagnóstico de certeza y diferencial. Conclusiones: Se presentó el séptimo caso de síndrome de Kartagener diagnosticado en el Ecuador y se analizó la serie de una totalidad de 7 pacientes reportados en el país entre 2015-2018(AU)

Introduction: Kartagener syndrome is a clinical variation of primary ciliary dyskinesia, characterized by the classic triad of chronic sinusitis, bronchiectasis and situs inversus (total or partial), classified as a rare autosomal recessive inheritance disease. Objective: To analyze the clinical manifestations, complementary tests and treatment of patients diagnosed with Kartagener syndrome in the Republic of Ecuador. Case presentation: Female patient, of Ecuadorian nationality, with clinical manifestations of the Kartagener syndrome triad and infertility trait, with a history of chronic sinusitis since 14 years of age. Imaging studies of thorax, x-rays and computed tomography of chest and paranasal sinuses confirmed the manifestations of Kartagener syndrome, which represents the seventh case reported in the country. Respiratory evolution and therapeutic management are exposed. In this context, we analyze the clinical characteristics of the series of seven cases reported in Ecuador up to the present, corresponding to the period 2015-2018 and complementary tests performed for the certainty and differential diagnosis. Conclusions: The seventh case of Kartagener syndrome diagnosed in Ecuador is presented, and the series of a totality of 7 patients reported in the country between 2015-2018 is analyzed(AU)

Characterising the nutritional status of children with primary ciliary dyskinesia.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare, heterogeneous genetic disorder where impaired mucociliary clearance is caused by dysfunctional motile cilia leading to bronchiectasis. There is limited evidence characterising the nutritional status of children with PCD, although lower body mass index (BMI) z-score has been associated with worse lung function (FEV1). METHODS: All children (n = 43) with PCD, aged <16 years, from a single tertiary centre were prospectively enrolled. Information on clinical phenotype and nutritional status including bioelectrical impedance spectroscopy (BIS) phase-angle was collected. RESULTS: There was a weak positive association between height-for-age z-score (HAZ) and FEV1 z-score (n = 28, r = 0.4, p = 0.049). Those with a low fat free mass index (<-2 z scores) had a lower BMI z score (-1.3 ± 1.2 vs. 0.8 ± 0.7, p = 0.0002). BIS phase angle identified more patients at nutritional risk than using moderate malnutrition cut-offs of either HAZ or BMI ≤ -2 z scores alone (21% vs. 4.6% vs. 6.9% respectively). PCD patients had a higher incidence of vitamin D insufficiency (<50 nmoL/L) (54%) and deficiency (<30 nmoL/L) (26%) than healthy children. CONCLUSIONS: We have characterised the nutritional phenotype of a cohort of children with PCD. Monitoring vitamin D levels is important in PCD patients. There is a weak association between lung function and nutritional status, and measures of BIS phase-angle. The use of BIS phase-angle may allow for early identification of at risk children and may therefore be of benefit for nutritional assessments in the clinical setting. These findings will help inform a future nutritional intervention strategy in children with PCD.

Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype-phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.

The prevalence of the defining features of primary ciliary dyskinesia within a cri du chat syndrome cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD) and cri du chat syndrome (CdCS) are distinct disorders that can co-occur due to a common genetic locus on chromosome 5p. Chronic respiratory symptoms associated with PCD can occur in CdCS and are typically attributed to hypotonia, dysphagia, and aspiration. The prevalence of PCD among individuals with CdCS is not known. METHODS: An online survey assessing common features of PCD was distributed to members of the 5P Minus Society, a cri du chat patient advocacy group. Respondents who met criteria for elevated risk of PCD (at least 3 symptoms or other features highly suggestive of PCD) were offered PCD genetic testing. RESULTS: For the 123 respondents (median age 10.1 years with IQR 5.5-17.3 years; from 33 U.S. states and 10 other countries) chronic respiratory symptoms associated with PCD were prevalent, including unexplained neonatal respiratory distress, year-round nasal congestion beginning in infancy, and year-round, wet cough beginning in infancy in 35%, 32%, and 20% of respondents, respectively. Fifteen respondents (12%) met criteria for elevated risk for PCD and completed genetic analysis; however, none were diagnostic for PCD. A PCD clinical center evaluated an additional subject with CdCS who met criteria for likely PCD and had negative genetics, but had diagnostic electron microscopy of the respiratory cilia (missing outer dynein arms). CONCLUSION: Clinicians should be aware of the genetic connection between CdCS and PCD. Non-informative genetic testing does not rule out PCD. CdCS patients with chronic respiratory symptoms may benefit from referral to specialized PCD diagnostic centers.

A review of Meckel-Gruber syndrome--incidence and outcome in the state of Qatar.

Meckel-Gruber (MKS) syndrome is a lethal autosomal abnormality diagnosed most commonly from classical findings on ultrasound scan after the late first trimester. There are few reports of cases followed up antenatally until delivery. We report here one of the largest series of 19 cases diagnosed antenatally from as early as 11 weeks gestation with 5 born alive. Of the 12 cases followed up antenatally, 7 were stillbirths while 5 were live births. The absence of obvious polycystic kidneys and severe oligohydramnios were prognostic features consistent with a live birth; however, mortality was 100% within a few weeks of delivery. The incidence of 2/1000 live births in the local population is similar to that reported from similar groups where consanguinity is more than 40%. The recurrence rate was high with 50% of the parous patients having had an affected baby. We conclude that diagnosis in early pregnancy does not require the classical triad of encephalocele, polydactyly and polycystic kidneys as some of these features do not manifest on imaging until much later.