Publications by authors named "Keita Nakanishi"

41 Publications

Robotic open-thoracotomy-view approach using vertical port placement and confronting monitor setting.

Interact Cardiovasc Thorac Surg 2021 May 11. Epub 2021 May 11.

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

Objectives: Robotic lung resections (RLRs) are conventionally performed using look-up views of the thorax from the caudal side. To conduct RLR with views similar to those in open thoracotomy, we adopted a vertical port placement and confronting upside-down monitor setting, which we called robotic 'open-thoracotomy-view approach'. We herein present our experience of this procedure.

Methods: We retrospectively reviewed 58 patients who underwent RLR (43 with lobectomy; 15 with segmentectomy) with 3-arm open-thoracotomy-view approach using the da Vinci Surgical System between February 2019 and October 2020. The patient cart was rolled in from the left cranial side of the patient regardless of the side to be operated on. Robotic ports were vertically placed along the axillary line, and 2 confronting monitors and 2 assistants were positioned on each side of the patient. The right-side monitor, which was set up for the left-side assistant to view, projected the upside-down image of the console surgeon's view.

Results: All procedures were safely performed. The median duration of surgery and console operation was 215 and 164 min, respectively. Emergency conversion into thoracotomy and severe morbidities did not occur, and the median postoperative hospitalization duration was 3 days. In all procedures, the console surgeon and 2 assistants had direct 'bird-eye' views of the cranially located intrathoracic structures and instrument tips, which are sometimes undetectable with the conventional look-up view.

Conclusions: The open-thoracotomy-view approach setting is a possible option for RLR. It offers natural thoracotomy views and can circumvent some of the known limitations of the conventional procedure.
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http://dx.doi.org/10.1093/icvts/ivab033DOI Listing
May 2021

Differential impacts of postoperative complications on patients' survival in completely resected non-small-cell lung cancer.

Gen Thorac Cardiovasc Surg 2021 Mar 9. Epub 2021 Mar 9.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: The aim of this study was to investigate the effects of inflammatory respiratory complications on long-term survival in patients with resected non-small cell lung cancer. We defined inflammatory respiratory complications to include the following six conditions: pneumonia, empyema, bronchial fistula, respiratory dysfunction, acute interstitial pneumonia, and atelectasis.

Methods: Part of the National Clinical Database was linked to our prospective database from 2014 to 2017. Linkage was achieved for 866 patients. The Kaplan-Meier method was used to evaluate the overall, relapse-free, and cancer-related survival. The Cox proportional hazard model was used to analyze the impact of each complication.

Results: Of the 736 patients included in the study, 149 had complications. The 5-year overall and cancer-specific survival rates were significantly lower in patients with inflammatory respiratory complications. The Cox proportional hazard model showed that the inflammatory respiratory complications had a significant impact on overall survival (hazard ratio 2.48, 95% confidence interval 1.41-4.38) but not air leak (hazard ratio 1.38, 95% confidence interval 0.70-2.70).

Conclusions: Our study shows the differential impact of each complication on the survival of patients with non-small cell lung cancer. The presence of inflammatory respiratory complications was the only predictor of poor overall survival.
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http://dx.doi.org/10.1007/s11748-021-01619-zDOI Listing
March 2021

Left brachiocephalic vein aneurysm: a case report.

Surg Case Rep 2021 Mar 9;7(1):66. Epub 2021 Mar 9.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Aneurysm of the left brachiocephalic vein is a very rare clinical disease and only 40 cases have been reported so far.

Case Presentation: The patient was a 61-year-old woman with no related medical history. She underwent CT to investigate the cause of a cough and a mass was noted in the anterior mediastinum. Dynamic computed tomography with contrast medium injected into the left basilic vein demonstrated the venous aneurysm with blood flow to the left brachiocephalic vein. The patient had no symptoms, but because of the risk of pulmonary infarction and aneurysm rupture, the aneurysm was surgically resected. A median sternotomy was a reasonable approach because of the fragility of the venous aneurysm wall with little working space in the anterior mediastinum.

Conclusions: We diagnosed an aneurysm of the left brachiocephalic vein on preoperative imaging and excised it through a median sternotomy. The venous wall was thin and fragile in some areas and so this approach was appropriate in view of the possibility of intraoperative injury.
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http://dx.doi.org/10.1186/s40792-021-01148-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943670PMC
March 2021

Commentary: To know yourself is to know your neighbor.

J Thorac Cardiovasc Surg 2021 Jan 20. Epub 2021 Jan 20.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.030DOI Listing
January 2021

Comparison of surgical outcomes between thoracoscopic anatomical sublobar resection including and excluding subsegmentectomy.

Gen Thorac Cardiovasc Surg 2021 May 2;69(5):850-858. Epub 2021 Jan 2.

Department of Thoracic Surgery, Aichi Cancer Center, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681, Japan.

Objectives: Despite the ubiquitous utilization of anatomical sublobar resection for malignant lung tumors, the effectiveness and feasibility of subsegmentectomy remains unclear. This study therefore compared the perioperative outcomes between anatomical sublobar resection including (IS) and excluding (ES) subsegmentectomy.

Methods: Patients who had undergone anatomical sublobar resection at our institution from January 2013 to March 2019 were retrospectively reviewed. Clinicopathologic characteristics and perioperative outcomes of the IS group (n = 58) were then analyzed the compared to those of the ES group (n = 203).

Results: No statistically significant differences in age, sex, comorbidities, tumor location, preoperative pulmonary function, or tumor size on imaging were found between both groups. The IS group had significantly higher preoperative computed tomography-guided marking rates (40% vs. 18%; p < 0.01) and used significantly more staplers for intersegmental dissection than the ES group [4, interquartile range (IQR): 3-4 vs. 3, IQR: 3-4; p = 0.03]. Both groups had comparable 30-day mortality (0% vs. 0%; p > 0.99), intraoperative complications (7% vs. 10%; p = 0.61), and postoperative complications (5% vs. 8%; p = 0.58). After propensity score matching, the IS group experienced significantly lesser blood loss than the ES group (5 mL, IQR: 1-10 vs. 5 mL, IQR: 5-20; p = 0.03). Both groups experienced no local recurrence and demonstrated similar postoperative pulmonary functions after surgery.

Conclusions: IS may be a feasible and acceptable therapeutic option for malignant lung tumors. Nonetheless, future investigations are required to further validate the current findings.
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http://dx.doi.org/10.1007/s11748-020-01556-3DOI Listing
May 2021

Comparison of Surgical Outcomes Between Invasive Mucinous and Non-Mucinous Lung Adenocarcinoma.

Ann Thorac Surg 2020 Nov 23. Epub 2020 Nov 23.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear.

Methods: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography.

Results: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs. 8 ng/mL; p < .01), fewer lymph node metastasis (4% vs. 24%; p < .01), and more KRAS mutations (56% vs. 7%; p < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs. 27%; p = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs. 17%; p < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs. 35%; p < .01), more KRAS mutations (56% vs. 9%; p < .01), and higher intrapulmonary recurrence rate (84% vs. 31%; p < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs. 81%; p = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs. 77%; p < .01).

Conclusions: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.042DOI Listing
November 2020

Prognostic factors of stage I thymic epithelial tumors.

Gen Thorac Cardiovasc Surg 2021 Jan 3;69(1):59-66. Epub 2020 Jul 3.

Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Objective: According to the tumor-node-metastasis classification for thymic malignancies, the proportion of patients diagnosed with stage I is expected to increase significantly. However, whether those patients have homogenous clinicopathological features and survival has not been fully evaluated.

Methods: We reviewed 153 consecutive patients with stage I thymic epithelial tumors (133 thymomas, 15 thymic carcinomas, and 5 neuroendocrine tumors) who underwent complete resection at our institution between 2001 and 2016 and evaluated the prognostic significance of their clinicopathological factors.

Results: The stage I patients accounted for 78% of all thymic epithelial tumors. The 5-year overall survival and recurrence-free survival rates of the 153 patients were 94% and 80%, respectively. The patients with the histology of thymic carcinoma or neuroendocrine tumor and with a tumor larger than 5.0 cm showed significantly worse recurrence-free survival in multivariate analysis (p = 0.027 and 0.038, respectively). Only the tumor size was revealed as a significant prognostic factor for recurrence-free survival when limited in the 133 cases of thymoma (p = 0.048).

Conclusions: Patients with large tumors showed significantly worse recurrence-free survival than those with small tumors both in stage I thymic epithelial tumors and thymomas.
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http://dx.doi.org/10.1007/s11748-020-01427-xDOI Listing
January 2021

Clinicopathological Features, Surgical Outcomes, Oncogenic Status and PD-L1 Expression of Pulmonary Pleomorphic Carcinoma.

Anticancer Res 2019 Oct;39(10):5789-5795

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

Background/aim: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC.

Patients And Methods: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017.

Results: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%).

Conclusion: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.
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http://dx.doi.org/10.21873/anticanres.13782DOI Listing
October 2019

Favorable clinical application for segmental bronchial closure based on experiment results.

J Thorac Dis 2019 Jun;11(6):2267-2273

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Japan.

Background: We previously reported the clinical application of powered vascular staple (PVS) for closure of subsegmental or segmental bronchus (SSB). This study aimed to measure breakdown pressure in experiment and to investigate bronchopleural fistula (BPF) after thoracoscopic segmentectomy (TS).

Methods: Part 1: a total of 30 cadaveric pigs were used, and bronchi were categorized into the following four groups: small [S, bronchial outer diameter (BOD) of 4-8 mm, n=8], medium (M, 9-10 mm, n=9), and large (L, >10 mm, n=13). We additionally added a single additional suture to compensate for weak sites with large BOD (group R, n=6). The pressure was slowly increased, and stump breakdown was observed. Part 2: we investigated the morbidity of BPF formation at follow-up of at least 6 months in a total of 217 patients.

Results: Part 1: the mean leak pressure was the highest in M, followed by groups S, R and L'. However, the significant difference was not found between S and R. Part 2: no BPF was observed, clinically.

Conclusions: Based on experimental results and clinical experience, the proper selection of PVS should contribute to the safety, feasibility, and success as SSB closure.
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http://dx.doi.org/10.21037/jtd.2019.06.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626799PMC
June 2019

Thoracoscopic lobectomy using indocyanine green fluorescence to detect the interlobar fissure in a patient with displaced B3 and absence of fissure: A case report.

Thorac Cancer 2019 07 19;10(7):1654-1656. Epub 2019 Jun 19.

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

A 90-year-old woman was admitted to our hospital with suspected lung adenocarcinoma. Preoperative three-dimensional reconstructed computed tomography revealed displacement of the anterior segmental bronchus (B3) arising from the right middle lobe bronchus with absence of the fissure between the right upper and middle lobes. A complete thoracoscopic right upper lobectomy was successfully performed. It is crucial to identify such anomalies prior to lung resection to avoid intraoperative complications during thoracoscopic lobectomy or segmentectomy. Additionally, intravenous indocyanine green with a fluorescence system was useful to identify the proper interlobar fissure boundary intraoperatively. To the best of our knowledge, this is the first reported case of thoracoscopic lobectomy for lung cancer with displaced B3 and absence of the interlobar fissure to be performed by applying the intravenous indocyanine green method.
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http://dx.doi.org/10.1111/1759-7714.13104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610257PMC
July 2019

Successful postoperative recovery management after thoracoscopic lobectomy and segmentectomy using an ERAS-based protocol of immediate ice cream intake and early ambulation: a 3-year study.

Cancer Manag Res 2019 7;11:4201-4207. Epub 2019 May 7.

Department of Thoracic Surgery.

Enhanced recovery after surgery (ERAS) protocols are well known for reducing post-operative complications, facilitating early recovery and reducing hospitalization. In this study, we developed ERAS protocols involving immediate ice cream intake for checking postoperative chylothorax and subsequent early ambulation in order to investigate whether these methods have postoperative benefits. We retrospectively evaluated 500 patients who underwent thoracoscopic segmentectomy and/or lobectomy (TSL) between January 2014 and September 2017. The patients were divided into two groups: 271 patients for Phase I and 229 for Phase II. Ice cream intake commenced during Phase I. Phase I patients were made to walk on the following day, whereas Phase II ambulate within 4 hrs after immediate ice-cream intake. The mean ice cream intake was significantly higher in Phase II than in Phase I (81.6% vs 56.1%). In Phase II, 91.2% and 94.0% were able to ambulate within 4 and 6 hrs, respectively. Minor postoperative complications (Clavien-Dindo I-II classification) were lower in Phase II (3.1%) than in Phase I (10.4%); however, we found no statistical significance (=0.08). Multivariate analysis showed that ice cream intake and removal of chest drainage tube within 4-6 hrs significantly contributed to the reduction of hospitalization to ≤3 postoperative days (=0.03 and <0.01). The results of this study suggested that our ERAS protocol represented by immediate ice cream intake, and early ambulation is feasible and can help in reducing postoperative complications, chest drainage duration, and hospitalization after TSL.
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http://dx.doi.org/10.2147/CMAR.S195219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511617PMC
May 2019

Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome.

J Hum Genet 2019 Jul 23;64(7):673-679. Epub 2019 Apr 23.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Advances in molecular genetics have revealed that approximately 30% of cases with steroid-resistant nephrotic syndrome (SRNS) are caused by single-gene mutations. More than 50 genes are responsible for SRNS. One such gene is the nucleoporin, 93-KD (NUP93). Thus far, few studies have reported mutations of NUP93 in SRNS. Here, we describe an NUP93 biallelic mutation in a 9-year-old boy with focal segmental glomerular sclerosis (FSGS). Notably, one mutation comprised an intronic variant; we conducted in vivo and in vitro analysis to characterize this variant. We found two heterozygous mutations in NUP93: c.2137-18G>A in intron 19 and a novel nonsense mutation c.727A>T (p.Lys243*) in exon 8. We conducted RNA sequencing and in vitro splicing assays by using minigene construction, combined with protein expression analysis to determine the pathogenicity of the intronic variant. Both RNA sequencing and in vitro splicing assay showed exon 20-skipping by the intronic variant. In protein expression analysis, aberrant subcellular localization with small punctate vesicles in the cytoplasm was observed for the intronic variant. Taken together, we concluded that c.2137-18G>A was linked to pathogenicity due to aberrant splicing. NUP93 variants are quite rare; however, we have shown that even intronic variants in NUP93 can cause SRNS. This study provides a fundamental approach to validate the intronic variant, as well as new insights regarding the clinical spectrum of SRNS caused by rare gene variants.
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http://dx.doi.org/10.1038/s10038-019-0606-4DOI Listing
July 2019

Is Calcification in the Regional Lymph Nodes a Benign Feature in Patients with Lung Cancer?

World J Surg 2019 07;43(7):1850-1856

Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Calcified lymph nodes (LNs) on computed tomography (CT) in patients with lung cancer are generally considered to be a benign feature. However, few studies have evaluated the pathological status of such calcified LNs. We investigated the clinicopathological findings of patients with calcified LNs on preoperative CT who underwent operation for lung cancer and assessed the frequency of metastasis to calcified LNs as well as the risk factors associated with such metastases.

Methods: This was a retrospective study of 72 consecutive patients with calcified LNs detected on preoperative CT who underwent pulmonary resection for primary lung cancer between 2011 and 2013. A total of 354 LN stations including 101 LN stations with calcified LNs were evaluated.

Results: The frequency of metastasis to calcified LNs was 19.4% (14 of 72 patients) on a per-person basis and 18.8% (19 of 101 stations) on a per-nodal station basis. When the size of calcification was major (>5 mm), the frequency of metastasis to such calcified LNs was significantly lower than when it was minor (≦5 mm) on a per-nodal station basis (11.1% vs 27.7%, P = 0.043). Furthermore, when the size of calcification was major and the status of LN stations with calcified LNs was single, there was no metastasis to such LN stations (0 of 26 stations).

Conclusions: The frequency of metastasis to calcified LNs was about 20% on both a per-person and a per-nodal station basis. Although calcified LNs as well as non-calcified LNs should be dissected during operation, dissection of a single LN station with calcification, particularly major calcification, can be omitted.
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http://dx.doi.org/10.1007/s00268-019-04937-9DOI Listing
July 2019

Efficacy of preserving the residual stomach in esophageal cancer patients with previous gastrectomy.

Gen Thorac Cardiovasc Surg 2019 May 18;67(5):470-478. Epub 2019 Feb 18.

Department of Esophageal Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Objective: There is no consensus concerning whether the residual stomach should be preserved after esophagectomy for thoracic esophageal cancer patients with previous distal or segmental gastrectomy. The purpose of this retrospective study was to assess the efficacy of preserving the residual stomach after esophagectomy in patients with previous gastrectomy.

Methods: Between 2000 and 2015, 45 consecutive thoracic esophageal cancer patients with previous distal or segmental gastrectomy underwent esophagectomy followed by colon reconstruction. Patients were assigned to two groups according to how the residual stomach was treated (preservation group, n = 11; resection group, n = 34). We compared surgical outcomes and alterations of nutrition status, including the skeletal muscle area, between the two groups. In addition, we investigated the distribution of abdominal lymph node metastases in the resection group.

Results: Operative time and blood loss tended to be lower in the preservation group compared to the resection group. However, the difference did not reach statistical significance. The rate of patients decreasing skeletal muscle area after surgery was significantly higher in the resection group (88% vs 50%, P = 0.03). There were no patients with metastatic abdominal lymph nodes when the previous gastrectomy had been performed for gastric cancer and the esophageal cancer was located at the upper or middle esophagus in the resection group.

Conclusions: Preservation of the residual stomach after esophagectomy in esophageal cancer patients with previous gastrectomy may influence the postoperative nutrition status and can be selectively approved.
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http://dx.doi.org/10.1007/s11748-019-01070-1DOI Listing
May 2019

Salvage surgery for small cell lung cancer after chemoradiotherapy.

Jpn J Clin Oncol 2019 Apr;49(4):389-392

Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.

There are few reports on the use of salvage surgery for small cell lung cancer (SCLC). Five patients who underwent resection of post-chemoradiotherapy residual lesion/local reprogression of SCLC between 2005 and 2017 were included in the study. We retrospectively reviewed their surgical outcomes and prognosis to assess the feasibility and potential efficacy of salvage surgery. Indications for salvage surgery were local reprogression (four patients) and residual lesion (one patient) with ycN0 disease. Complete pathological resection was achieved in four patients; however, malignant pleural effusion was diagnosed in one patient after the surgery. Morbidity and mortality rates were 0%. Estimated 5-year survival rate was 67%. Recurrence and death after surgery occurred only in the patient with malignant pleural effusion. We demonstrate the feasibility of salvage surgery in SCLC. In carefully-selected patients, especially those without lymph node involvement, salvage surgery may provide effective local control and favorable survival outcomes.
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http://dx.doi.org/10.1093/jjco/hyz010DOI Listing
April 2019

Clinical and Genetic Characteristics in Patients With Gitelman Syndrome.

Kidney Int Rep 2019 Jan 28;4(1):119-125. Epub 2018 Sep 28.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Introduction: Gitelman syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most often diagnosed by chance blood test. Aside from that, some cases are also diagnosed from tetanic symptoms associated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroid dysfunction and short stature are known, but the incidence rates for these complications have not yet been elucidated. In addition, no genotype-phenotype correlation has been identified in GS.

Methods: We examined the clinical characteristics and genotype-phenotype correlation in genetically proven GS cases with homozygous or compound heterozygous variants in ( = 185).

Results: In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), or short stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrile convulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT prolongation was detected. Among 29 cases with short stature, 10 were diagnosed with growth hormone (GH) deficiency and GH replacement therapy started. Interestingly, there was a strong correlation in serum magnesium levels between cases with p.Arg642Cys and/or p.Leu858His and cases without these variants, which are mutational hotspots in the Japanese population (1.76 mg/dl vs. 1.43 mg/dl,  < 0.001).

Conclusion: This study has revealed, for the first time, clinical characteristics in genetically proven GS cases in the Japanese population, including prevalence of complications. Patients with hypokalemia detected by chance blood test should have gene tests performed. Patients with GS need attention for developing extrarenal complications, such as short stature, febrile convulsion, thyroid dysfunction, epilepsy, or QT prolongation. It was also revealed for the first time that hypomagnesemia was not severe in some variants in .
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http://dx.doi.org/10.1016/j.ekir.2018.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308995PMC
January 2019

Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene.

Clin Exp Nephrol 2019 May 24;23(5):669-675. Epub 2018 Dec 24.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Background: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS.

Methods: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case.

Results: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1-2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission.

Conclusions: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.
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http://dx.doi.org/10.1007/s10157-018-1682-zDOI Listing
May 2019

The utility of urinary CD80 as a diagnostic marker in patients with renal diseases.

Sci Rep 2018 11 23;8(1):17322. Epub 2018 Nov 23.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

CD80, which regulates T cell activation, may provide a differential diagnostic marker between minimal change disease (MCD) and other renal diseases, including focal segmental glomerular sclerosis (FSGS). However, recent reports show contrasting results. Therefore, we evaluated the utility of urinary CD80 as a diagnostic biomarker. We collected 65 urine samples from 55 patients with MCD (n = 31), FSGS (n = 4), inherited nephrotic syndrome (n = 4), Alport syndrome (n = 5) and other glomerular diseases (n = 11), and control samples (n = 30). We measured urinary CD80 levels by ELISA. Urinary CD80 (ng/gCr) (median, interquartile range) levels were significantly higher in patients with MCD in relapse (91.5, 31.1-356.0), FSGS (376.2, 62.7-1916.0), and inherited nephrotic syndrome (220.1, 62.9-865.3), than in patients with MCD in remission (29.5, 21.7-52.8) (p < 0.05). Elevation of urinary CD80 was observed, even in patients with inherited nephrotic syndrome unrelated to T cell activation. Additionally, urinary CD80 was positively correlated with urinary protein levels. Our results suggest that urinary CD80 is unreliable as a differential diagnostic marker between MCD in relapse and FSGS or inherited kidney diseases. Increased urinary CD80 excretion was present in all patients with active kidney disease.
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http://dx.doi.org/10.1038/s41598-018-35798-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251900PMC
November 2018

Three Severe Cases of Viral Infections with Post-Kidney Transplantation Successfully Confirmed by Polymerase Chain Reaction and Flow Cytometry.

Case Rep Nephrol Dial 2018 Sep-Dec;8(3):198-206. Epub 2018 Sep 25.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Viral infections in patients with post-kidney transplantation are often difficult to diagnose as well as treat. We herein report three cases with severe viral infections after kidney transplantation. All their causative pathogens could be detected promptly by polymerase chain reaction and flow cytometry during the early stages of infection. These examinations would also be of great use to monitor therapeutic responses and disease activity. It is indeed true that no specific treatment is available for most of the viral infections, but we should be aware that some infections, such as Epstein-Barr virus infection, can be treatable with prompt and specific treatment, such as rituximab.
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http://dx.doi.org/10.1159/000493092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206958PMC
September 2018

Lateral thermal spread and recurrent laryngeal nerve paralysis after minimally invasive esophagectomy in bipolar vessel sealing and ultrasonic energy devices: a comparative study.

Esophagus 2018 10 31;15(4):249-255. Epub 2018 May 31.

Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: This study aimed to compare the extent of lateral thermal spread of surrounding tissues after the use of advanced bipolar and ultrasonic coagulation and shearing devices. Association between recurrent laryngeal nerve paralysis (RLNP) and such devices was assessed in patients who underwent minimally invasive esophagectomy (MIE).

Methods: LigaSure (LS) and Sonicision (SONIC) were used. In ex vivo experiments using the porcine muscle, blade temperature and tissue temperature were measured using a thermometer after the activation of both devices. For the clinical assessment, 46 consecutive patients who received MIE were retrospectively assessed.

Results: The temperature generated at the blade of both devices increased with the activation time. The blade temperature of LS was significantly lower than that of SONIC (P < 0.001). The blade temperature of SONIC exceeded 100 °C after 3-s activation. The temperature of surrounding tissues after a single activation of the devices decreased with the tissue distance from activation blade. The temperatures of tissues at 1 and 2 mm away from the blade side of LS were significantly lower than those of SONIC (P = 0.001 and P < 0.001, respectively). The temperature of tissue 2 mm away from the blade side of LS increased 6.4 °C from the baseline temperature. Furthermore, the incidence of RLNP in the LS group was lower than that in the SONIC group (P = 0.044).

Conclusion: This study highlights the necessity of spatial and temporal recognition of the thermal spread of coagulation and shearing devices to reduce the thermal injuries following MIE.
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http://dx.doi.org/10.1007/s10388-018-0621-0DOI Listing
October 2018

Development of a Minimal Photosystem for Hydrogen Production in Inorganic Chemical Cells.

Angew Chem Int Ed Engl 2018 10 4;57(40):13066-13070. Epub 2018 Sep 4.

WestCHEM School of Chemistry, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.

Inorganic chemical cells (iCHELLs) are compartment structures consisting of polyoxometalates (POMs) and cations, offering structured and confined reaction spaces bounded by membranes. We have constructed a system capable of efficient anisotropic and hierarchical photo-induced electron transfer across the iCHELL membrane. Mimicking photosynthesis, our system uses proton gradients between the compartment and the bulk to drive efficient conversion of light into chemical energy, producing hydrogen upon irradiation. This illustrates the power of the iCHELL approach for catalysis, where the structure, compartmentalisation and variation in possible components could be utilised to approach a wide range of reactions.
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http://dx.doi.org/10.1002/anie.201805584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348376PMC
October 2018

TGFBI-associated corneal dystrophy and nephropathy: a novel syndrome?

CEN Case Rep 2019 02 7;8(1):14-17. Epub 2018 Aug 7.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Transforming growth factor beta-induced (TGFBI)-associated corneal dystrophies are a group of inherited progressive corneal diseases. One of these TGFBI-associated corneal dystrophies is Avellino corneal dystrophy, an autosomal dominant corneal dystrophy characterized by multiple asymmetric stromal opacities that potentially impair vision. Recently, a case with corneal dystrophy complicated by nephropathy possessing a pathogenic variant of the TGFBI gene was reported for the first time. Here, we report the second case with the same condition and the same mutation in the TGFBI gene. The patient was an 18-year-old male. He and his father had already been diagnosed with corneal dystrophy. Proteinuria was revealed in the patient during urine screening at school. Since his serum creatinine level was raised, a percutaneous renal biopsy was performed. Light microscopy demonstrated oligomeganephronia. Electron microscopy demonstrated an irregular basement membrane. TGFBI was analyzed by direct sequencing. A heterozygous mutation c.371G > A in exon 4, which caused an amino acid substitution from arginine to histidine at codon 124, was identified in the patient and his father. Although only one case of TGFBI-associated corneal dystrophy and nephropathy has been reported, our case's clinical and pathological findings were almost identical to those in that reported case. Further investigations of this new disease entity should be reported to all nephrologists and ophthalmologists.
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http://dx.doi.org/10.1007/s13730-018-0356-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361082PMC
February 2019

Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome.

J Am Soc Nephrol 2018 08 29;29(8):2244-2254. Epub 2018 Jun 29.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS.

Methods: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (=21, from 14 families) and nontruncating (=25, from 15 families) mutations at the transcript level.

Results: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (=0.001).

Conclusions: We report unpredictable atypical splicing in the gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.
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http://dx.doi.org/10.1681/ASN.2018030228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065097PMC
August 2018

Congenital chloride diarrhea needs to be distinguished from Bartter and Gitelman syndrome.

J Hum Genet 2018 Jul 30;63(8):887-892. Epub 2018 May 30.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Pseudo-Bartter/Gitelman syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter syndrome (BS) or Gitelman syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.
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http://dx.doi.org/10.1038/s10038-018-0470-7DOI Listing
July 2018

Clinical features predicting group A streptococcal pharyngitis in a Japanese paediatric primary emergency medical centre.

J Int Med Res 2018 May 8;46(5):1791-1800. Epub 2018 Mar 8.

1 Department of Paediatrics, 236610 Kobe University Graduate School of Medicine , Kobe, Japan.

Objectives To identify clinical features that predict Group A streptococcal (GAS) pharyngitis in a Japanese paediatric primary emergency medical centre. Methods The prevalence of GAS pharyngitis according to age and body temperature (BT) was calculated among 3098 paediatric patients with pharyngitis. The numbers of GAS-positive and -negative patients for each clinical parameter, and each point increase in the McIsaac score were compared and likelihood ratios (LRs) were calculated. Results The prevalence of GAS pharyngitis was extremely low in patients aged < 1 (1.2%) and 1 year (3.9%). The GAS-positive rate was significantly higher in patients with a BT < 38.0°C compared with ≥ 38.0°C (30.0% vs. 19.8%). A BT ≥ 38.0°C was not a predictive finding for GAS pharyngitis (positive LR: 0.82). Rash was the most useful individual predictor, and a McIsaac score of 4 or 5 increased the probability; however, the positive LRs were 1.74 and 1.30, respectively. Conclusions The prevalence of GAS pharyngitis is extremely low in patients aged < 1 and 1 year, and a BT ≥ 38.0°C is not a predictive symptom. Although a rash and McIsaac score of 4 or 5 are associated with an increased probability, they cannot be used to confirm GAS infection.
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http://dx.doi.org/10.1177/0300060517752954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991234PMC
May 2018

Development of ultra-deep targeted RNA sequencing for analyzing X-chromosome inactivation in female Dent disease.

J Hum Genet 2018 May 19;63(5):589-595. Epub 2018 Feb 19.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

The pattern of X-chromosome inactivation (XCI) can affect the clinical severity of X-linked disorders in females. XCI pattern analysis has been conducted mainly by HUMARA assay, a polymerase chain reaction-based assay using a methylation-sensitive restriction enzyme. However, this assay examines the XCI ratio of the androgen receptor gene at the genomic DNA level and does not reflect the ratio of either targeted gene directly or at the mRNA level. Here, we report four females with Dent disease, and we clarified the correlation between XCI and female cases of Dent disease using not only HUMARA assay but also a novel analytical method by RNA sequencing. We constructed genetic analysis for 4 female cases showing high level of urinary low-molecular-weight proteinuria and their parents. Their XCI pattern was analyzed by both HUMARA assay and an ultra-deep targeted RNA sequencing of the CLCN5 gene using genomic DNA and mRNA extracted from both leukocytes and urine sediment. All four cases possessed pathogenic variants of the CLCN5 gene. XCI analysis revealed skewed XCI in only two cases, while the other two showed random XCI. All assay results of HUMARA and targeted RNA sequencing in both leukocytes and urinary sediment were clearly identical in all four cases. We developed a novel XCI analytical assay of ultra-deep targeted RNA sequencing and revealed that skewed XCI explains the mechanism of onset of female Dent disease in only half of such cases.
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http://dx.doi.org/10.1038/s10038-018-0415-1DOI Listing
May 2018

Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases.

Clin Exp Nephrol 2018 Aug 25;22(4):881-888. Epub 2018 Jan 25.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Background: Comprehensive genetic approaches for diagnosing inherited kidney diseases using next-generation sequencing (NGS) have recently been established. However, even with these approaches, we are still failing to detect gene defects in some patients who appear to suffer from genetic diseases. One of the reasons for this is the difficulty of detecting copy number variations (CNVs) using our current approaches. For such cases, we can apply methods of array-based comparative genomic hybridization (aCGH) or multiplex ligation and probe amplification (MLPA); however, these are expensive and laborious and also often fail to identify CNVs. Here, we report seven cases with CNVs in various inherited kidney diseases screened by NGS pair analysis.

Methods: Targeted sequencing analysis for causative genes was conducted for cases with suspected inherited kidney diseases, for some of which a definitive genetic diagnosis had not been achieved. We conducted pair analysis using NGS data for those cases. When CNVs were detected by pair analysis, they were confirmed by aCGH and/or MLPA.

Results: In seven cases, CNVs in various causative genes of inherited kidney diseases were detected by pair analysis. With aCGH and/or MLPA, pathogenic CNV variants were confirmed: COL4A5 or HNF1B in two cases each, and EYA1, CLCNKB, or PAX2 in one each.

Conclusion: We presented seven cases with CNVs in various genes that were screened by pair analysis. The NGS-based CNV detection method is useful for comprehensive screening of CNVs, and our results revealed that, for a certain proportion of cases, CNV analysis is necessary for accurate genetic diagnosis.
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http://dx.doi.org/10.1007/s10157-018-1534-xDOI Listing
August 2018

An in vitro splicing assay reveals the pathogenicity of a novel intronic variant in ATP6V0A4 for autosomal recessive distal renal tubular acidosis.

BMC Nephrol 2017 Dec 4;18(1):353. Epub 2017 Dec 4.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuo, Kobe, Hyogo, 6500017, Japan.

Background: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare hereditary disease caused by pathogenic variants in the ATP6V0A4 gene or ATP6V1B1 gene, and characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia and nephrocalcinosis. Although several intronic nucleotide variants in these genes have been detected, all of them fell in the apparent splice consensus sequence. In general, transcriptional analysis is necessary to determine the effect on function of the novel intronic variants located out of splicing consensus sequences. In recent years, functional splicing analysis using minigene construction was used to assess the pathogenicity of novel intoronic variant in various field.

Methods: We investigated a sporadic case of dRTA with a compound heterozygous mutation in the ATP6V0A4 gene, revealed by next generation sequencing. One variant was already reported as pathogenic; however, the other was a novel variant in intron 11 (c.1029 + 5G > A) falling outside of the apparent splicing consensus sequence. Expression of ATP6V0A4 was not detected in peripheral leukocytes by RT-PCR analysis. Therefore, an in vitro functional splicing study using minigene construction was conducted to analyze the splicing pattern of the novel variant.

Results: A minigene assay revealed that the novel intronic variant leads to a 104 bp insertion immediately following exon 11. In addition, this result was confirmed using RNA extracted from the patient's cultured leukocytes.

Conclusion: These results proved the pathogenicity of a novel intronic variant in our patient. We concluded that the minigene assay is a useful, non-invasive method for functional splicing analysis of inherited kidney disease, even if standard transcriptional analysis could not detect abnormal mRNA.
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http://dx.doi.org/10.1186/s12882-017-0774-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716019PMC
December 2017

Detection of a Splice Site Variant in a Patient with Glomerulopathy and Fibronectin Deposits.

Nephron 2018 3;138(2):166-171. Epub 2017 Nov 3.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Background/aims: Glomerulopathy with fibronectin deposits (GFND; OMIM: 601894) is a very rare inherited kidney disease caused by pathogenic variants in the FN1 gene. Only 9 exonic pathogenic variants in FN1, 9 at the heparin-binding site, and 1 at the integrin-binding site have been reported. No intronic variants in FN1 have been detected.

Methods: We found a pathogenic intronic variant in intron 36 (c.5888-2A>G) located at the heparin-binding site. To determine whether this mutation influences splicing processes, we conducted RT-PCR analysis and an in vitro splicing assay using minigene construction.

Results: RT-PCR using RNA extracted from leukocytes of the proband failed because of the low expression of FN1 mRNA in leukocytes. We conducted in vitro functional splicing analysis using minigenes and found that c.5888-2A>G caused a 12 bp deletion at exon 37 by the activation of a novel splicing acceptor site within exon 37. We were able to detect the same abnormal transcript in mRNA extracted from the patient's urinary sediment and confirmed the pathogenicity of c.5888-2A>G by both RT-PCR using the patient sample and an in vitro splicing assay.

Conclusion: Intronic variants can cause GFND. Minigene analysis is useful for determining the pathogenicity of the intronic variants and could be used for all inherited kidney diseases.
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http://dx.doi.org/10.1159/000484209DOI Listing
September 2019

A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome.

Eur J Med Genet 2017 Dec 9;60(12):631-634. Epub 2017 Aug 9.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Lowe syndrome is an X-linked inherited disorder diagnosed by congenital cataracts, intellectual impairment, and renal tubular dysfunction. It is caused by pathogenic variants of the oculocerebrorenal syndrome of Lowe gene (OCRL), of which more than 250 have been reported so far. Around 30 of these variants are intronic nucleotide changes; however, to show the pathogenicity of these variants is usually laborious. In this report, we conducted genetic testing of a patient clinically diagnosed with Lowe syndrome to detect the presence of OCRL variants. We analyzed variant transcript expression in peripheral blood leukocytes and using a minigene construct in addition to in silico analysis. We detected a 9 base pair intronic insertion between OCRL exon 10 and exon 11 derived from the alteration of the splicing acceptor site in intron 10 caused by the intronic splicing variant NM_000276.3: c.940-11G>A (p.Lys313_Val314insAsnSer*). The findings obtained from transcript analysis of peripheral blood leukocytes and the minigene construct assay were identical to those of in silico analysis. All assays detected the same transcript abnormality and were reliable in revealing the pathogenicity of the intronic variant. The in vitro assay can also be used to clarify the complicated splicing mechanisms in inherited kidney diseases.
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http://dx.doi.org/10.1016/j.ejmg.2017.08.001DOI Listing
December 2017