New insights in cardiovascular anesthesia: a dual focus on clinical practice and research.

Accumulation of the results of basic and clinical research has advanced the safety and quality of management in cardiovascular anesthesia. To address recent developments in this field, a symposium was held during the 71th Japanese Society of Anesthesiologists annual meetings in 2024, focusing on new advancements in both clinical and basic research in cardiovascular anesthesia. During this symposium, four experts reviewed recent findings in their respective areas of study, covering the following topics: clinical reliability and concerns regarding volatile anesthetics during cardiopulmonary bypass; novel basic and clinical findings regarding the cardioprotective effects of dexmedetomidine; advancements in optimizing blood and hemostasis management during cardiovascular surgery; and innovative strategies for managing postoperative cognitive disorders following cardiovascular and thoracic surgery. Each expert summarized recent novel findings, clinical reliability and concerns, as well as future directions in their respective topics. We believe that this special article provides valuable insights into both clinical practice and basic research in cardiovascular anesthesia while also inspiring anesthesiologists to pursue further research in this field.

Pulmonary vein stump thrombosis and organ infarction after lung lobectomy.

Lung resection surgery, which is performed as a treatment for lung cancer and metastatic lung tumors, is currently conducted via minimally invasive techniques such as video-assisted thoracoscopic surgery and robot-assisted methods. Postoperative complications related to this surgery, such as pulmonary vein thrombosis and cerebral and other organ infarctions, have been increasingly reported. The primary cause of these complications is thrombus formation in the pulmonary vein stump. Statistical data on the site of lung lobectomy have indicated that surgeries involving the left upper lobe are most frequently associated with embolic complications. Although this issue has not received considerable attention in anesthesiology, the importance of prevention and treatment in postoperative management is growing. The role of anesthesiologists in preventing these complications is critical. These roles involve careful fluid management to avoid hypercoagulable states, consideration of early postoperative anticoagulation therapy, assessment of the suitability of epidural anesthesia for postoperative anticoagulation, and improvement of hospital-wide safety systems and monitoring of high-risk patients. Anesthesiologists need to understand the pathology and risk factors involved and play an active role in preventing and treating these complications through effective collaboration with thoracic surgeons and the in-hospital stroke team.

Two Pediatric Cases of Primary Ciliary Dyskinesia Caused by Loss-of-Function Variants in Oral-Facial-Digital Syndrome Gene, OFD1.

Primary ciliary dyskinesia (PCD) is a hereditary disease caused by genes related to motile cilia. We report two male pediatric cases of PCD caused by hemizygous pathogenic variants in the OFD1 centriole and centriolar satellite protein (OFD1) gene. The variants were NM_003611.3: c.[2789_2793delTAAAA] (p.[Ile930LysfsTer8]) in Case 1 and c.[2632_2635delGAAG] (p.[Glu878LysfsTer9]) in Case 2. Both cases had characteristic recurrent respiratory infections. Neither case had symptoms of oral-facial-digital syndrome type I. We identified a variant (c.2632_2635delGAAG) that has not been previously reported in any case of OFD1-PCD.

A peripherally acting µ-opioid receptor antagonist for treating opioid-associated tinnitus: A case report.

BACKGROUND: The use of opioids occasionally causes tinnitus. However, there is a paucity of data regarding the use of peripherally acting µ-opioid receptor antagonists for opioid-associated tinnitus in patients with cancer. ACTUAL CASE: A 74-year-old male with pancreatic cancer complained of abdominal pain. Two days after initiating oxycodone therapy, the patient experienced tinnitus during body movements. Although peripheral tinnitus disappeared after discontinuing oxycodone, it reappeared with hydromorphone or tapentadol administration. POSSIBLE COURSES OF ACTION: Drug cessation is a preferred intervention for drug-induced tinnitus; however, the cessation of opioids may not be feasible in patients with cancer who are already taking opioids. FORMULATION OF A PLAN: Based on the presumed mechanism of peripheral tinnitus, the use of peripherally acting µ-opioid receptor antagonists was planned, and 200 µg/day of naldemedine was prescribed for tinnitus relief. OUTCOME: Tinnitus disappeared immediately after initiating naldemedine, and the pain was well-controlled. The effect was preserved after increasing or switching opioids. LESSONS: The use of peripherally acting µ-opioid receptor antagonists may be an option to treat opioid-associated tinnitus without compromising the analgesic effects. VIEW: Further clinical data regarding the secondary effect of peripherally acting µ-opioid receptor antagonists on opioid-associated complications other than constipation are required.

Point-of-care testing for tranexamic acid efficacy: a proof-of-concept study in cardiac surgical patients.

BACKGROUND: Low-dose tranexamic acid (TXA) has been recently recommended for cardiopulmonary bypass (CPB) to reduce associated complications. Although point-of-care laboratory tests for TXA concentrations are unavailable, a novel TPA-test on the ClotPro® system can measure TXA-induced inhibition of fibrinolysis. We evaluated the performance of the TPA-test in vitro and in patients undergoing surgery requiring CPB. METHODS: Blood samples were obtained from six volunteers for in vitro evaluation of tissue plasminogen activator (tPA)-triggered fibrinolysis and the effects of TXA. This was followed by an observational study in 20 cardiac surgery patients to assess clinical effects of TXA on the TPA-test. RESULTS: Hyperfibrinolysis induced by tPA was inhibited by TXA ≥2 mg L-1 in a concentration-dependent manner, and was completely inhibited at TXA ≥10 mg L-1. In patients undergoing CPB, antifibrinolytic effect was detectable on TPA-test parameters after a 0.1 g bolus of TXA at the end of CPB, and complete inhibition of fibrinolysis was obtained with TXA ≥0.5 g. The antifibrinolytic effects of 1 g TXA on TPA-test parameters were gradually attenuated over 18 h after surgery. However, the fibrinolytic inhibition continued in four patients with estimated glomerular filtration rate (eGFR) ≤30 ml min-1 1.73 m-2. The eGFR had strong correlations with TPA-test parameters at 18 h after surgery (r=0.86-0.92; P<0.0001). CONCLUSIONS: The TPA-test is sensitive to low concentrations of TXA and serves as a practical monitoring tool for postoperative fibrinolytic activity in cardiac surgery patients. This test might be particularly useful in patients with severe renal impairment.

Unique behavioral patterns of wandering colonies of Brevibacillus thermoruber on agar plates.

Brevibacillus thermoruber strain Nabari cells grow as widely spreading dendritic colonies on reasoner's 2A-agar (1.5%) plates at around 55°C but as small motile colonies at 37°C. Motile colonies can be divided into colonies that move in straight or curved lines over long distances (wandering colonies), and colonies that rotate at a fixed location (rotating colonies). The addition of surfactant to the agar medium greatly increased the frequency of wandering colonies and facilitated the study of such colonies. The morphology of the wandering colonies varied: circular at the tip and pointed at the back, lemon-shaped with pointed ends, crescent-shaped, bullet-shaped, fish-like, and so on. A single colony may split into multiple colonies as it moves, or multiple colonies may merge into a single colony. The most surprising aspect of the movement of wandering colonies was that when a moving colony collides with another colony, it sometimes does not make a U-turn, but instead retreats straight back, as if bouncing back. The migration mechanisms of wandering colonies are discussed based on optical microscopic observations of swimming patterns of single cells in water and scanning electron microscopy of the arrangement of bacterial cells in wandering colonies.

Effect of acute normovolemic hemodilution in patients undergoing cardiac surgery with remimazolam anesthesia.

PURPOSE: The reduced effects of allogeneic transfusion with acute normovolemic hemodilution (ANH) have been reported. Harvesting a large volume of blood may maximize the effect in patients with low body weight, and the prevention of hypotension is important. Remimazolam is an anesthetic with few circulatory responses. Our aim was to evaluate whether high-volume ANH reduces the need for transfusion in cardiac patients under remimazolam anesthesia. METHODS: In this retrospective single-center study, we enrolled cardiopulmonary bypass (CPB) patients who received remimazolam anesthesia. Changes in hemodynamic parameters were assessed. The numbers of blood transfusions and chest tube outputs were also evaluated. RESULTS: In a total of 51 patients, ANH was performed in 27 patients with a mean body mass index of 23.2 (ANH volume: 740 ± 222 mL). No significant differences were observed in mean blood pressure during blood collection. The intraoperative amount of red blood cell (RBC) transfusion was significantly lower in the ANH group than in the control group (431 ± 678 and 1260 ± 572 mL, p < 0.001). The avoidance rates of RBC were 66.7 and 4.2%, respectively. The multivariate analysis result revealed that ANH correlated with RBC, with an odds ratio of 0.067 (95% confidence interval 0.005-0.84, p < 0.05). The postoperative bleeding at 24 h was significantly lower in the ANH group (455 ± 228 and 797 ± 535 mL, p < 0.01). CONCLUSION: In patients undergoing CPB, ANH reduced intraoperative transfusion amount and postoperative bleeding. Hemodynamic changes during blood collection were minimal under remimazolam anesthesia and high-volume ANH was feasible.

Circulating Extracellular Vesicle Levels in Patients with Coronavirus Disease 2019 Coagulopathy: A Prospective Cohort Study.

Coronavirus disease 2019 (COVID-19) is associated with coagulopathy. However, the underlying mechanisms are not completely understood. We evaluated the association between COVID-19 coagulopathy and extracellular vesicle (EV) levels. We hypothesized that several EV levels would be higher in COVID-19 coagulopathy patients than in non-coagulopathy patients. This prospective observational study was conducted in four tertiary care faculties in Japan. We enrolled 99 COVID-19 patients (48 with coagulopathy and 51 without coagulopathy) aged ≥20 years who required hospitalization, and 10 healthy volunteers; we divided the patients into coagulopathy and non-coagulopathy groups according to the D-dimer levels (≥1 µg/mL and <1 µg/mL, respectively). We used flow cytometry to measure the tissue-factor-bearing, endothelium-derived, platelet-derived, monocyte-derived, and neutrophil-derived EV levels in platelet-free plasma. The EV levels were compared between the two COVID-19 groups as well as among the coagulopathy patients, non-coagulopathy patients, and healthy volunteers. No significant difference was found in EV levels between the two groups. Meanwhile, the cluster of differentiation (CD) 41 + EV levels were significantly higher in COVID-19 coagulopathy patients than in healthy volunteers (549.90 [255.05-984.65] vs. 184.3 [150.1-254.1] counts/µL, p = 0.011). Therefore, CD41+ EVs might play an essential role in COVID-19 coagulopathy development.

Prevalence of preoperative opioid usage and its impact on postoperative outcomes: a retrospective cohort study.

PURPOSE: Preoperative opioid treatment increases postoperative adverse events. This study was aimed to analyze preoperative opioid prevalence in countries with low opioid consumption. Additionally, the effect of low opioid usage on postoperative outcomes was also investigated. METHODS: We conducted this single center retrospective cohort analysis in a Japanese university-affiliated hospital to investigate opioid usage and its impact on the duration of postoperative hospitalization and in-hospital mortality. Adult patients who underwent general anesthesia between 2015 and 2020 were included. We extracted the patients' characteristics, surgical information and postoperative outcomes. Subgroup analysis to address opioid dose effect was performed in high and low dose opioid subgroups. RESULTS: Among 20,306 inpatients, 535 (2.63%) patients used opioids preoperatively. Tramadol was the most frequently used opioid. The median morphine equivalent (MME) dose was 15 mg/day. Median duration of hospitalization was 18 and 9 days in the opioid and non-opioid groups, and in-hospital mortality was 2.06% and 0.42%. Multivariable regression analysis demonstrated that preoperative opioid use was associated with a longer duration of hospitalization and in-hospital mortality. Subgroup analysis demonstrated longer durations of hospitalization in both high (> 30 mg/day MME) and low (≤ 30 mg/day MME) dose opioid groups, while higher in-hospital mortality was seen only in the high dose opioid group. CONCLUSIONS: Preoperative opioid usage was one-tenth of the United States average. Despite its low prevalence and small dosage, preoperative opioid usage was associated with poor postoperative outcomes. Dedicated perioperative interventions to prevent opioid-associated adverse events should be developed even in countries with low opioid consumption.

Long Duration of Action of Tranexamic Acid After Cardiac Surgery in a Hemodialysis Patient: A Case Report.

A 61-year-old woman with chronic renal dysfunction was scheduled to undergo aortic valve replacement. After a bolus of 1 g tranexamic acid (TXA), the TPA (tissue-plasminogen activator)-test result with the ClotPro system demonstrated extensive inhibition of fibrinolysis. Plasma TXA level decreased from 71 to 25 µg/dL at 6 hours postoperatively; however, no further decrease was observed. Although TXA levels dropped to 6.9 µg/dL after hemodialysis on postoperative day (PoD) 1, fibrinolytic shutdown on the TPA-test remained unchanged until PoD 2. In dialysis patients, low-dose TXA <1 g may be considered for reducing seizure and thromboembolic complications after cardiac surgery.

Antenatal mgnesium sulfate and ritodrine increased potassium levels in preterm infants: A cohort study.

BACKGROUND: Ritodrine and magnesium sulfate are administered to prevent preterm labor. Magnesium sulfate is also administered to prevent preeclampsia. These drugs have been reported to increase potassium levels in pregnant women and neonates. The aim of this study was to investigate the relationship between potassium levels in preterm infants and antenatal treatment. METHODS: This prospective cohort study was conducted at Saiseikai Suita Hospital. Preterm infants born at <35 weeks' gestation between October 2012 and September 2014 were recruited and divided into four groups based on the antenatal treatment their mothers received. Serum and urine electrolyte levels at birth and serum potassium levels 1 day after birth were measured. RESULTS: The mothers of 16 infants received no antenatal treatment (condition C); the mothers of 29 infants received antenatal ritodrine (R); the mothers of seven infants received magnesium sulfate (M); and the mothers of 15 infants received both magnesium sulfate and ritodrine (M + R). At birth, potassium levels were similar among the four groups. However, potassium levels a day after birth were significantly higher in the M + R group than in the other groups: median (min.-max.) mEq/L 4.8 (3.8-6.2), 4.8 (3.6-6.0), and 4.4 (3.8-5.9) vs. 5.8 (4.9-7.2), in the C, R, and M groups versus the M + R group, respectively (P < 0.01). Significantly more infants in the M + R group exhibited a fractional excretion of potassium of <10% compared with those in the other groups. CONCLUSION: The increased potassium levels we observe in preterm infants of mothers who received antenatal magnesium sulfate and ritodrine administration on postnatal day 1 warrant monitoring by neonatologists.

A comparison of the ClotPro system with rotational thromboelastometry in cardiac surgery: a prospective observational study.

Viscoelastic coagulation tests have been increasingly used for hemostasis management in cardiac surgery. The ClotPro system is a novel viscoelastic device based on principles of rotational thromboelastometry. We aimed to compare ClotPro with ROTEM and plasma coagulation assays in cardiopulmonary bypass (CPB) patients. Blood samples were collected from 25 CPB patients at (1) baseline, (2) start of CPB, (3) end of CPB, and (4) end of surgery. The EX-test, IN-test, HI-test, FIB-test parameters on ClotPro were compared with corresponding ROTEM assay (EXTEM, INTEM, HEPTEM, and FIBTEM). Standard plasma coagulation assays and endogenous thrombin generation (TG) were simultaneously evaluated. Pearson correlation analyses showed moderate correlations between clotting times (CTs) (r = 0.63-0.67; p < 0.001, respectively), and strong correlations with maximal clot firmness (MCF) (r = 0.93-0.98; p < 0.001, respectively) between ClotPro and ROTEM. EX-test and IN-test MCF parameters were interchangeable with acceptable percentage errors (EX-test MCF: 7.3%, IN-test MCF: 8.3%), but FIB-test MCF (27.0%) and CT results were not (EX-test CT: 44.7%, IN-test CT: 31.4%). The correlations of PT/INR or peak TG with EX-test CTs were higher than with EXTEM CTs (PT/INR: r = 0.80 and 0.41, peak TG: 0.43 and 0.18, respectively). FIB-test MCF has strong correlation with plasma fibrinogen and factor XIII level (r = 0.84 and 0.66, respectively). ROC analyses showed that ClotPro was capable of emulating well-established ROTEM thresholds (area under curves: 0.83-1.00). ClotPro demonstrated strong correlations in MCF parameters of ROTEM in CPB patients. It may be reasonable to modify ROTEM-based transfusion algorithm pertaining to MCF parameters to establish cut-off values for ClotPro device.

A pediatric case of primary ciliary dyskinesia caused by novel copy number variation in PIH1D3.

An 11-month-old boy with productive cough was referred to our hospital. He had nasal obstruction immediately after birth, and wheezing, wet cough, and rhinorrhea were observed daily after the neonatal period. Clinical and imaging findings revealed secretory otitis media, chronic sinusitis, and bronchiectasis. Primary ciliary dyskinesia was suspected. Transmission electron microscopy of nasal cilia showed defects of the outer and inner dynein arms. Genetic examinations of the family revealed copy number variation in PIH1 domain-containing 3 (PIH1D3) in the proband and mother. This is the first report of a Japanese patient with primary ciliary dyskinesia caused by copy number variation in PIH1D3.

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare hereditary disease. Most reports of PCD in Japan are case reports, and clinical analysis has not been performed. Differences in the causative genes might affect the clinical features in different ethnic groups. The purpose of this study was to clarify the clinical features of Japanese patients with PCD. METHODS: We performed a retrospective chart review of PCD patients seen at Mie University Hospital and patients whose blood samples were sent to us for genetic analysis from 2011 to 2020. Data on the following items were collected and analyzed: age at first visit to the hospital, age at diagnosis of PCD, process of referral to our facility, chief complaint, situs status, PrImary CiliARy DyskinesiA Rule (PICADAR) score, nasal nitric oxide concentration, otoscopic findings, rhinoscopic findings, and paranasal computed tomography scan findings. RESULTS: Sixty-seven patients (24 male, 43 female) were diagnosed with PCD during the study period. Age at diagnosis ranged from 2 months to 69 years (median, 17 years). Respiratory symptoms (77%) were the most common complaint, followed by nasal (15%) and aural (8%) symptoms. Situs inversus was present in 17 (25%) cases. Only 2 cases had congenital cardiac anomalies. The mean PICADAR score was 7.3 (range, 3-14) points. Approximately 50% of tympanic membranes showed retraction, suggesting otitis media with effusion. The mean Lund-Mackay score was 12.8 (range, 7-17) points, suggesting that the radiographic findings were not always severe. There was no significant difference in the total Lund-Mackay score between patients with and without situs inversus (12.7 vs. 12.6, respectively). CONCLUSION: Situs inversus was present in 25% of Japanese PCD patients, which is much lower than observed in other countries. This is a result of differences in the major disease-causing genes. The general rule that "situs inversus is observed in approximately 50% of PCD patients" cannot be applied, at least, in Japanese PCD patients.

Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15.

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.

A pediatric case of productive cough caused by novel variants in DNAH9.

We report the first Japanese case of primary ciliary dyskinesia caused by DNAH9 variations. The patient, a 5-year-old girl, had repeated episodes of productive cough after contracting the common cold at the age of 1 year and 6 months. She did not have a situs abnormality or congenital heart defect. We identified two novel DNAH9 variants, NM_001372.3: c. [1298C>G];[5547_5550delTGAC], (p.[Ser433Cys];[Asp1850fs]).

Extensive Lumbar Sympathetic Ganglion Block Combined With Epidural Block for Primary Erythromelalgia: A Case Report.

A 19-year-old-woman experienced severe burning pain in the lower extremities with erythema and swelling. She was diagnosed with primary erythromelalgia (PE). The pain was unresponsive to medications but relieved by immersing her feet in cold water. We performed a multilevel lumbar sympathetic ganglion block (LSGB) with 5% phenol at second lumbar vertebra (L2) and third lumbar vertebra (L3), and additional fourth lumbar vertebra (L4) levels. An epidural block was intermittently combined. The pain and skin lesions dramatically improved after the procedures, and she no longer needed medications or to soak her feet in cold water. This case demonstrated that extensive LSGB may be a therapeutic option for intractable PE.

Characterization of Sll1558 in environmental stress tolerance of Synechocystis sp. PCC 6803.

So far, the molecular mechanisms underlying the acidic-stress responses of plants are complicated and only fragmentally understood. Here, we investigated the mechanisms responsible for acidic-stress acclimation. Previously, DNA microarray analysis identified the sll1558 gene in Synechocystis sp. PCC 6803 (hereafter called Synechocystis 6803) to be upregulated following short-term acid treatment (1 h at pH 3.0). The sll1558 gene encodes uridine diphosphate-glucose pyrophosphorylase (UDP-glucose pyrophosphorylase), which catalyzes the conversion of glucose-1-phosphate into UDP-glucose. We constructed mutant cells for this gene and analyzed their phenotype. The sll1558 gene did not completely segregate in sll1558 mutant cells; thus, Sll1558 is essential for the survival of Synechocystis 6803. Besides, the partially disrupted sll1558 mutant cells were highly sensitive to acidic stress (pH 6.0) as well as other stress conditions (high salt, high osmolality, high/low temperature, and ultraviolet-B stress); the number of sll1558 transcripts increased under these conditions. UDP-glucose is used for the synthesis of various materials, such as glycolipids. From the membrane lipid composition analysis, digalactosyldiacylglycerol decreased and phosphatidylglycerol increased in the partially disrupted sll1558 mutant cells under acidic stress. These results suggest that sll1558 is important not only for the survival of Synechocystis 6803, but also for tolerance under various stress conditions.

Clotting Time Results Are Not Interchangeable Between EXTEM and FIBTEM on Rotational Thromboelastometry.

OBJECTIVE: To explore how cytochalasin D (CyD) affects clot initiation and to compare clotting times (CTs) of EXTEM and FIBTEM on rotational thromboelastometry in cardiac surgical patients undergoing cardiopulmonary bypass (CPB). DESIGN: Retrospective cohort study with translational in vitro coagulation experiments. SETTING: Single-center, tertiary, academic medical center. PARTICIPANTS: Patients who underwent cardiac surgery with CPB between November 2015 and August 2017. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study's primary measurements were CTEXTEM and CTFIBTEM before and after CPB. Additionally, the authors performed translational in vitro coagulation experiments using commercial plasma. In these experiments, the impact of CyD on in vitro thrombin generation (TG) was assessed using 10 platelet-rich plasma (PRP) samples and calibrated automated thrombogram. The impact of CyD on ROTEM-CT also was evaluated in vitro using the same 10 PRP samples. One hundred fifty-three patients had clinical CTEXTEM and CTFIBTEM measurements. CTFIBTEM was shorter than CTEXTEM before and after CPB by 6.8% (95% confidence interval [CI], 5.5-8.1) and 8.9% (95% CI, 4.7-13.0), respectively. These results correlated with in vitro experiments, where TG lag time was shortened by CyD and CTFIBTEM was shorter than CTEXTEM. CONCLUSION: CyD shortens the onset of TG and clot formation, resulting in shorter CTFIBTEM than CTEXTEM. The authors' data suggest that CTEXTEM and CTFIBTEM are not interchangeable. Additional clinical studies are warranted to assess if CTFIBTEM can be used to optimize the indication for plasma transfusion.

Copy number variation in DRC1 is the major cause of primary ciliary dyskinesia in the Japanese population.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The involvement of copy number variation (CNV) in the development of PCD is largely unknown. METHODS: We examined 93 Japanese patients with clinically suspected PCD from 84 unrelated families. CNV was examined either by exome sequencing of a PCD gene panel or by whole-exome sequencing (WES). The identified alterations were validated by PCR and Sanger sequencing. Nasal ciliary ultrastructure was examined by electron microscopy. RESULTS: Analysis of CNV by the panel or WES revealed a biallelic deletion in the dynein regulatory complex subunit 1 (DRC1) gene in 21 patients, which accounted for 49% of the PCD patients in whom a disease-causing gene was found. Sanger sequencing of the PCR product revealed a 27,748-bp biallelic deletion including exons 1-4 of DRC1 with identical breakpoints in all 21 patients. The ciliary ultrastructure of the patients with this CNV showed axonemal disorganization and the loss or gain of central microtubules. CONCLUSION: The deletion of DRC1 is the major cause of PCD in Japan and this alteration can cause various ciliary ultrastructural abnormalities.