Genotype–Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review

PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR.

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A framework for integrated clinical risk assessment using population sequencing data

10.1101/2021.08.12.21261563 ◽

2021 ◽

Author(s):

James D. Fife ◽

Tho Tran ◽

Jackson R. Bernatchez ◽

Kiethen E. Shepard ◽

Christopher Koch ◽

...

Keyword(s):

Risk Ratio ◽

Disease Risk ◽

Population Level ◽

Disease Genes ◽

Sequencing Data ◽

Individual Level ◽

Clinical Risk ◽

Pathogenic Variants ◽

Significant Difference ◽

Cad Risk

Clinical risk prediction for genetic variants remains challenging even in established disease genes, as many are so rare that epidemiological assessment is not possible. Using data from 200,625 individuals, we integrate individual-level, variant-level, and protein region risk factors to estimate personalized clinical risk for individuals with rare missense variants. These estimates are highly concordant with clinical outcomes in breast cancer (BC) and familial hypercholesterolemia (FH) genes, where we distinguish between those with elevated versus population-level disease risk (logrank p<10-5, Risk Ratio=3.71 [3.53, 3.90] BC, Risk Ratio=4.71 [4.50, 4.92] FH), validated in an independent cohort (χ2 p=9.9x10-4 BC, χ2 p=3.72x10-16 FH). Notably in FH genes, we predict that 64% of biobank patients with laboratory-classified pathogenic variants are not at increased coronary artery disease (CAD) risk when considering all patient and variant characteristics. These patients have no significant difference in CAD risk from individuals without a monogenic variant (logrank p=0.68). Such assessments may be useful for optimizing clinical surveillance, genetic counseling, and intervention, and demonstrate the need for more nuanced approaches in population screening.

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Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽

10.1136/bmj.n214 ◽

2021 ◽

pp. n214

Author(s):

Weedon MN ◽

Jackson L ◽

Harrison JW ◽

Ruth KS ◽

Tyrrell J ◽

...

Keyword(s):

Positive Predictive Value ◽

Predictive Value ◽

Population Based ◽

Genome Project ◽

Personal Genome ◽

Uk Biobank ◽

Sequencing Data ◽

Snp Chip ◽

Pathogenic Variants ◽

The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

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Transcriptomic Analysis of Rice Plants Overexpressing PsGAPDH in Response to Salinity Stress

Genes ◽

10.3390/genes12050641 ◽

2021 ◽

Vol 12 (5) ◽

pp. 641

Author(s):

Hyemin Lim ◽

Hyunju Hwang ◽

Taelim Kim ◽

Soyoung Kim ◽

Hoyong Chung ◽

...

Keyword(s):

Salt Stress ◽

Abiotic Stress ◽

Salinity Stress ◽

Functional Enrichment ◽

Differentially Expressed ◽

Pathway Enrichment Analysis ◽

Sequencing Data ◽

Illumina Hiseq ◽

Rice Plants ◽

Significant Difference

In plants, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a main enzyme in the glycolytic pathway. It plays an essential role in glycerolipid metabolism and response to various stresses. To examine the function of PsGAPDH (Pleurotus sajor-caju GAPDH) in response to abiotic stress, we generated transgenic rice plants with single-copy/intergenic/homozygous overexpression PsGAPDH (PsGAPDH-OX) and investigated their responses to salinity stress. Seedling growth and germination rates of PsGAPDH-OX were significantly increased under salt stress conditions compared to those of the wild type. To elucidate the role of PsGAPDH-OX in salt stress tolerance of rice, an Illumina HiSeq 2000 platform was used to analyze transcriptome profiles of leaves under salt stress. Analysis results of sequencing data showed that 1124 transcripts were differentially expressed. Using the list of differentially expressed genes (DEGs), functional enrichment analyses of DEGs such as Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed. KEGG pathway enrichment analysis revealed that unigenes exhibiting differential expression were involved in starch and sucrose metabolism. Interestingly, trehalose-6-phosphate synthase (TPS) genes, of which expression was enhanced by abiotic stress, showed a significant difference in PsGAPDH-OX. Findings of this study suggest that PsGAPDH plays a role in the adaptation of rice plants to salt stress.

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Over-expression of IL-6 coding gene in the peripheral blood of migraine with aura patients

Human Antibodies ◽

10.3233/hab-210442 ◽

2021 ◽

pp. 1-5

Author(s):

Mahdi Ramezani ◽

Alireza Komaki ◽

Mohammad Mahdi Eftekharian ◽

Mehrdokht Mazdeh ◽

Soudeh Ghafouri-Fard

Keyword(s):

Migraine With Aura ◽

Peripheral Blood ◽

Healthy Subjects ◽

Migraine Without Aura ◽

P Value ◽

Healthy Controls ◽

Over Expression ◽

Significant Difference ◽

Male Patients ◽

Years Lived With Disability

Migraine is a common disorder which is placed among the top ten reasons of years lived with disability. Cytokines are among the molecules that contribute in the pathophysiology of migraine. In the current study, we evaluated expression levels of IL-6 coding gene in the peripheral blood of 120 migraine patients (54 migraine without aura and 66 migraine with aura patients) and 40 healthy subjects. No significant difference was detected in expression of IL-6 between total migraine patients and healthy controls (Posterior beta = 0.253, P value = 0.199). The interaction effect between gender and group was significant (Posterior beta =-1.274, P value = 0.011), therefore, we conducted subgroup analysis within gender group. Such analysis revealed that while expression of this gene is not different between male patients and male controls (Posterior beta =-0.371, P value > 0.999), it was significantly over-expressed in female patients compared with female controls (Posterior beta = 0.86, P= 0.002). Expression of IL-6 was significantly higher in patients with aura compared with controls (Posterior beta = 0.63, adjusted P value = 0.019). However, expression of this cytokine coding gene was not different between patients without aura and healthy subjects (Posterior beta = 0.193, adjusted P value = 0.281). Therefore, IL-6 might be involved in the pathophysiology of migraine among females and migraine with aura among both sexes.

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Comparative Evaluation of Orthostatic Hypotension in Patients with Diabetic Nephropathy

Kidney & Blood Pressure Research ◽

10.1159/000517316 ◽

2021 ◽

pp. 1-7

Author(s):

Gamze Aytaş ◽

Rümeyza Kazancıoğlu ◽

Ömer C. Elçioğlu ◽

Meltem Gürsu ◽

A. Serra Artan ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Orthostatic Hypotension ◽

Electronic Device ◽

Channel Blockers ◽

Factors Affecting ◽

Clinical Criteria ◽

Measure Blood Pressure ◽

Significant Difference ◽

Male Patients ◽

Very High

Introduction: Orthostatic hypotension (OH) affects 5–20% of the population. Our study investigates the presence of OH in diabetic nephropathy (DNP) patients and the factors affecting OH in comparison with nondiabetic chronic kidney disease (NDCKD) patients. Method: Patients presented to the nephrology clinic, and those who consented were included in the study. DNP was defined by kidney biopsy and/or clinical criteria. NDCKD patients of the same sex, age, and eGFR were matched to DNP patients. Demographic parameters and medications were obtained from the records. OH was determined by Mayo clinic criteria. The same researcher used an electronic device to measure blood pressure (BP). All samples were taken and analyzed the same day for biochemical and hematologic parameters and albuminuria. Results: 112 (51 F, 61 M, mean age: 62.56 ± 9.35 years) DNP and 94 (40 F, 54 M, mean age: 62.23 ± 10.08 years) NDCKD patients were included. There was no significant difference between DNP and NDCKD groups in terms of OH prevalence (70.5 vs. 61.7%, p = 0.181). Male patients had significantly higher OH prevalence than female patients (74.7 vs. 60.0%, p = 0.026). There was no significant difference in change in systolic BP between the groups (24.00 [10.00–32.00] mm Hg vs. 24.00 [13.75–30.25] mm Hg, p = 0.797), but the change in diastolic BP was significantly higher in the DNP group (8.00 [2.00–13.00] mm Hg vs. 6.00 [2.00–9.00] mm Hg, p = 0.025). In the DNP group, patients with OH had significantly higher uric acid levels than those without OH (7.18 ± 1.55 vs. 6.36 ± 1.65 mg/dL, p = 0.017). And, 73.7% of patients on calcium channel blockers developed OH (p = 0.015), and OH developed in 80.6% of 36 patients on alpha-blockers (p = 0.049). Conclusion: OH prevalence is very high in CKD, and etiology of CKD does not have a statistically significant effect on the frequency of OH, despite a difference that could be meaningful clinically. Therefore, patients with CKD are checked for OH, with or without concurrent diabetes mellitus. Evaluation of postural BP changes should be a part of nephrology practice.

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Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

European Journal of Human Genetics ◽

10.1038/s41431-020-00720-w ◽

2020 ◽

Vol 28 (12) ◽

pp. 1763-1768

Author(s):

Thomas Bourinaris ◽

◽

Damian Smedley ◽

Valentina Cipriani ◽

Isabella Sheikh ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

De Novo ◽

Age At Onset ◽

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Sequencing Data ◽

Juvenile Form ◽

Pathogenic Variants ◽

Degenerative Disorders ◽

Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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Primary or Redo Posterior Sagittal Anorectoplasty without a Stoma: To Feed or Not to Feed?

European Journal of Pediatric Surgery ◽

10.1055/s-0037-1608805 ◽

2017 ◽

Vol 29 (02) ◽

pp. 150-152 ◽

Cited By ~ 1

Author(s):

Clare Skerrit ◽

Alexander Dingemans ◽

Victoria Lane ◽

Alejandra Sanchez ◽

Laura Weaver ◽

...

Keyword(s):

Breast Milk ◽

Wound Dehiscence ◽

Anorectal Malformations ◽

Wound Complication ◽

Wound Complications ◽

Age At Surgery ◽

Significant Difference ◽

Male Patients ◽

The Mean ◽

Picc Line

Introduction Repair of anorectal malformations (ARMs), primarily or with a reoperation, may be performed in certain circumstances without a diverting stoma. Postoperatively, the passage of bulky stool can cause wound dehiscence and anastomotic disruption. To avoid this, some surgeons keep patients NPO (nothing by mouth) for a prolonged period. Here, we report the results of a change to our routine from NPO for 7 days to clear fluids or breast milk. Materials and Methods After primary or redo ARM surgery, patients given clear liquids were compared to those who were kept strictly NPO. Age, indication for surgery, incision type, use of a peripherally inserted central catheter (PICC) line, and wound complications were recorded. Results There were 52 patients, including 15 primary and 37 redo cases. Group 1 comprised 11 female and 15 male patients. The mean age at surgery was 4.9 years (standard deviation [SD]: 2.3). There were 8 primary cases and 18 redo cases. Twelve (46.6%) received a PICC line. The average start of clear liquids was on day 5.3 (SD: 2.2) after examination of the wound, and the diet advanced as tolerated. The first stool passage was recorded on average on day 2.3 (SD: 1.3). Four minor wound complications and no major wound complications occurred.Group 2 comprised 14 females and 12 male patients. The mean age at surgery was 3.5 (SD: 2.4) years. There were 7 primary and 19 redo cases. One (3.8%) patient required a PICC line. A clear liquid diet was started within 24 hours after surgery. A regular diet was started on average on day 5.8 (SD: 1.3). The first stool passage was recorded on an average of day 1.6 (SD: 0.9). Three minor wound complications occurred; however, there was no significant difference between the two groups (SD: 0.71). One major wound complication occurred. However, there was no significant difference in major wound complications between the groups (SD: 0.33). Conclusion No increase in wound problems was noted in children receiving clear liquids or breast milk compared with the strict NPO group, and PICC line use was reduced. We believe this change in practice simplifies postoperative care without increasing the risk of wound complications.

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Low Level of Serum Sclerostin in Adult Patients with Tumor-induced Osteomalacia Comparing with X-linked Hypophosphatemia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab579 ◽

2021 ◽

Author(s):

Xiaolin Ni ◽

Qi Zhang ◽

Xiang Li ◽

Qianqian Pang ◽

Yiyi Gong ◽

...

Keyword(s):

Bone Mass ◽

Cross Sectional Study ◽

Healthy Controls ◽

Cross Sectional ◽

Significant Difference ◽

Healthy Control ◽

Premenopausal Patients ◽

Male Patients ◽

Sclerostin Level ◽

Sclerostin Antibody

Abstract Context Sclerostin is an inhibitor of Wnt-β-catenin signaling to regulate bone formation. Circulating sclerostin levels were reported to be elevated in patients with X-linked hypophosphatemia (XLH), and sclerostin antibody (Scl-Ab) has been shown to increase bone mass and normalize circulating phosphate levels in Hyp mice. However, circulating sclerostin level in acquired hypophosphatemic patients with tumor-induced osteomalacia (TIO) remains rare reported. Objectives This study was designed to evaluate serum sclerostin levels in TIO patients comparing them with age-, sex- matched healthy controls and XLH patients, and analyze correlation of circulating sclerostin with BMD and laboratory parameters. Design, Setting and Participants 190 individuals including 83 adult TIO patients, 83 adult healthy controls and 24 adult XLH patients were enrolled in this cross-sectional study. Main outcome measures Serum sclerostin levels were determined in TIO patients, healthy controls and XLH patients. Results TIO patients (43 male and 40 female) aged 44.3 ± 8.7 (mean ± SD) years had lower levels of circulating sclerostin than healthy controls (94.2 ± 45.8 vs 108.4 ± 42.3 pg/mL, p = 0.01) with adjustment for age, gender, BMI and diabetes rate. Sclerostin levels were positively associated with age (r = 0.238, p = 0.030). Male patients had higher sclerostin level than female patients (104.7 ± 47.3 vs 83.0 ± 41.8 pg/mL, p = 0.014) and postmenopausal patients had higher tendency of sclerostin level than premenopausal patients (98.4 ± 48.8 vs 71.6 ± 32.3 ng/ml, p = 0.05). Sclerostin levels were positively associated with BMD of L1-4 (r = 0.255, p = 0.028), femoral neck (r = 0.242, p = 0.039) and serum calcium (r = 0.231, p = 0.043). TIO subgroup patients (n=24, 35.9 ± 7.3 years old) comparing with age-, sex-matched adult XLH patients and healthy controls revealed significant difference of sclerostin levels (XLH, TIO and healthy control were 132.0 ± 68.8, 68.4 ± 31.3 and 98.6 ± 41.1 pg/mL, respectively, p < 0.001). Conclusions Circulating sclerostin levels were decreased in TIO patients but increased in XLH patients, which might be result of histological abnormality and bone mass.

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A quality of life assessment of military recruits after refractive surgery

International Eye Research ◽

10.18240/ier.2020.01.08 ◽

2020 ◽

Vol 1 (1) ◽

pp. 42-46

Author(s):

Jian-He Xiao ◽

◽

Shi-Yang Li ◽

Xing Xing ◽

Ai-Hong Zhao ◽

...

Keyword(s):

Quality Of Life ◽

Refractive Error ◽

High Myopia ◽

Refractive Surgery ◽

Laser In Situ Keratomileusis ◽

Significant Difference ◽

Lenticule Extraction ◽

Postoperative Interval

AIM: To evaluate the quality of life of recruits after refractive surgery. METHODS: Population-based, cross-sectional study. Using the Quality of Life Impact of Refractive Correction (QIRC) questionnaire, the quality of life in 615 recruits underwent refractive surgery was evaluated. The overall score and each question score of QIRC were compared between subgroups of different strength of preoperative refractive error, postoperative interval, type of surgical procedure and postoperative recovery. RESULTS: The mean overall QIRC score of recruits underwent refractive surgery was 49.15±7.89. Significant difference was found for strength of preoperative refractive error (F=4.16, P<0.05), with the low myopia group (50.67±7.59) had significantly better scores than those with high myopia (47.57±7.52, F=4.16, P<0.05). Recruits after a postoperative interval no more than 6mo (49.18±7.86) scored equally to those of more than 6mo (49.18±8.03). Recruits underwent surface ablation surgery scored lowest (46.68±6.09), but showed no significant difference when compared with all underwent refractive surgery (t=1.99, P>0.05). Scores of recruits underwent mechanical microkeratome laser in situ keratomileusis (MK-LASIK), Sub-Bowman’s keratomileusis (SBK), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK), femtosecond lenticule extraction (ReLEx flex) or small-incision lenticule extraction (ReLEx SMILE) procedure showed no significant difference too. Recruits had adverse complaints postoperatively (45.85±6.66) scored lower when compared with all underwent refractive surgery (t=5.28, P<0.01). CONCLUSION: The quality of life of recruits after refractive surgery was good except those with postoperative complications. Preoperative low myopia recruits had better quality of life than medium and high myopia ones.

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Are You Experienced? US Ambassadors and International Crises, 1946–2014

Foreign Policy Analysis ◽

10.1093/fpa/orab026 ◽

2021 ◽

Vol 17 (4) ◽

Author(s):

Paul K MacDonald

Keyword(s):

United States ◽

International Politics ◽

The United States ◽

International Crises ◽

Systematic Analysis ◽

Militarized Disputes ◽

Political Appointees ◽

Significant Difference ◽

The Military ◽

Sizable Number

Abstract How important are ambassadors in international politics? While a growing body of research stresses the importance of diplomacy in international politics, it remains unclear if individual ambassadors make a significant difference or what attributes make for an effective ambassador. This paper explores these questions through a systematic analysis of 2,730 US ambassadors between 1946 and 2014. The United States is distinctive in that it sends a sizable number of noncareer political appointees to serve as ambassadors. This provides a unique opportunity to examine how an ambassador's experience shapes where they are placed and how they perform. Using various techniques to address selection effects, including matching, I find that the United States is less likely to experience a militarized dispute with a host nation when it is represented by a political ambassador. Moreover, political ambassadors with professional experience in politics or the military, those who are close to the president, and those who are appointed in permissive congressional environments are less likely to experience militarized disputes during their tenure. Individual ambassadors matter, but diplomatic experience alone is not the only attribute that makes for an effective ambassador.

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