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Half of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.
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Cirrose Hepática , Doenças Renais Policísticas , Criança , Doenças Genéticas Inatas , Homozigoto , Humanos , Cinesinas , Sequenciamento do ExomaRESUMO
BACKGROUND: Pulmonary hypertension (PH) poses a significant challenge in the selection of candidates for heart transplantation, impacting their eligibility and post-transplant outcomes. Mechanical circulatory support (MCS) devices, particularly left ventricular assist devices (LVADs), have emerged as a therapeutic option to manage PH in this patient population. This systematic review aims to evaluate the effectiveness of MCS devices in reversing fixed pulmonary hypertension in heart transplant candidates. METHODS: A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Web of Science, to identify studies that evaluated the effectiveness of MCS devices in reversing fixed pulmonary hypertension in heart transplant candidates. Data on pulmonary vascular resistance, PH reversal, heart transplant eligibility, and post-transplant outcomes were extracted and synthesized. RESULTS: The review included studies that demonstrated the potential of MCS devices, especially LVADs, to significantly reduce pulmonary vascular resistance and reverse fixed pulmonary hypertension in heart transplant candidates. These findings suggest that MCS devices can improve transplant eligibility and may positively impact post-transplant survival rates. However, the literature also indicates a need for further comparative studies to optimize MCS device selection and treatment protocols. CONCLUSION: MCS devices, particularly LVADs, play a crucial role in the management of fixed pulmonary hypertension in heart transplant candidates, improving their eligibility for transplantation and potentially enhancing post-transplant outcomes. Future research should focus on comparative effectiveness studies to guide clinical decision-making and optimize patient care in this challenging clinical scenario.
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Transplante de Coração , Coração Auxiliar , Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/terapia , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/complicações , Resultado do Tratamento , Resistência Vascular/fisiologiaRESUMO
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA), which has been treated successfully with eculizumab. The optimal duration of eculizumab in treating patients with aHUS remains poorly defined. METHODS: We conducted a multicenter retrospective study in the Arabian Gulf region for children of less than 18 years of age who were diagnosed with aHUS and who discontinued eculizumab between June 2013 and June 2021 to assess the rate and risk factors of aHUS recurrence. RESULTS: We analyzed 28 patients with a clinical diagnosis of aHUS who had discontinued eculizumab. The most common reason for the discontinuation of eculizumab was renal and hematological remission (71.4%), followed by negative genetic testing (28.6%). During a median follow-up period of 24 months after discontinuation, 8 patients (28.5%) experienced HUS relapse. The risk factors of recurrence were positive genetic mutations (p = 0.020). On the other hand, there was no significant relationship between the relapse and age of presentation, the need for acute dialysis, the duration of eculizumab therapy before discontinuation, or the timing of eculizumab after the presentation. Regarding the renal outcomes after discontinuation, 23 patients were in remission with normal renal function, while 4 patients had chronic kidney disease (CKD) (three of them had pre-existing chronic kidney disease (CKD) before discontinuation, and one case developed a new CKD after discontinuation) and one patient underwent transplantation. CONCLUSIONS: The discontinuation of eculizumab in patients with aHUS is not without risk; it can result in HUS recurrence. Eculizumab discontinuation can be performed with close monitoring of the patients. It is essential to assess risk the factors for relapse before eculizumab discontinuation, in particular in children with a positive complement variant and any degree of residual CKD, as HUS relapse may lead to additional loss of kidney function. Resuming eculizumab promptly after relapse is effective in most patients.
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Variants in the GLIS family zinc finger protein 2 (GLIS2) are a rare cause of nephronophthisis-related ciliopathies (NPHP-RC). A reduction in urinary concentration and a progressive chronic tubulointerstitial nephropathy with corticomedullary cysts are the major characteristic features of NPHP. NPHP demonstrates phenotypic and genetic heterogeneity with at least 25 different recessive genes associated with the disease. We report a female, from a consanguineous family, who presented age 9 years with echogenic kidneys with loss of cortico-medullary differentiation and progressive chronic kidney disease reaching kidney failure by 10 years of age. A novel homozygous in-frame deletion (NM_032,575.3: c.560_574delACCATGTCAACGATT, p.H188_Y192del) in GLIS2 was identified using whole exome sequencing (WES) that segregated from each parent. The five amino acid deletion disrupts the alpha-helix of GLIS2 zinc-finger motif with predicted misfolding of the protein leading to its predicted pathogenicity. This study broadens the variant spectrum of GLIS2 variants leading to NPHP-RC. WES is a suitable molecular tool for children with kidney failure suggestive of NPHP-RC and should be part of routine diagnostics in kidney failure of unknown cause, especially in consanguineous families.
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Background: Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice. In the investigation of inherited cystic kidney disease and renal ciliopathy syndromes, WES has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. The yield of WES critically depends on the characteristics of the patient population. Methods: In this study, we selected 8 unrelated Omani children, presenting with renal ciliopathy syndromes with a positive family history and originating from consanguineous families. We performed WES in affected children to determine the genetic cause of disease and to test the yield of this approach, coupled with homozygosity mapping, in this highly selected population. DNA library construction and WES was carried out using SureSelect Human All Exon V6 Enrichment Kit and Illumina HiSeq platform. For variants filtering and annotation Qiagen Variant Ingenuity tool was used. Nexus copy number software from BioDiscovery was used for evaluation of copy number variants and whole gene deletions. Patient and parental DNA was used to confirm mutations and the segregation of alleles using Sanger sequencing. Results: Genetic analysis identified 4 potential causative homozygous variants each confirmed by Sanger sequencing in 4 clinically relevant ciliopathy syndrome genes, ( TMEM231, TMEM138, WDR19 and BBS9), leading to an overall diagnostic yield of 50%. Conclusions: WES coupled with homozygosity mapping provided a diagnostic yield of 50% in this selected population. This genetic approach needs to be embedded into clinical practise to allow confirmation of clinical diagnosis, to inform genetic screening as well as family planning decisions. Half of the patients remain without diagnosis highlighting the technical and interpretational hurdles that need to be overcome in the future.
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Ciliopatias , Exoma , Criança , Ciliopatias/diagnóstico , Ciliopatias/genética , Consanguinidade , Exoma/genética , Humanos , Síndrome , Sequenciamento do ExomaRESUMO
INTRODUCTION: Recently, prolonged intermittent renal replacement therapies (PIRRT) have emerged as cost-effective alternatives to conventional CRRT and their use in the pediatric population has started to become more prominent. However, there is a lack of consensus guidelines on the use of PIRRT in pediatric patients in an intensive care setting. METHODS: A literature search was performed on PubMed/Medline, Embase, and Google Scholar in conjunction with medical librarians from both India and the Cleveland Clinic hospital system to find relevant articles. The Pediatric Continuous Renal Replacement Therapy workgroup analyzed all articles for relevancy, proposed recommendations, and graded each recommendation for their strength of evidence. RESULTS: Of the 60 studies eligible for review, the workgroup considered data from 37 studies to formulate guidelines for the use of PIRRT in children. The guidelines focused on the definition, indications, machines, and prescription of PIRRT. CONCLUSION: Although the literature on the use of PIRRT in children is limited, the current studies give credence to their benefits and these expert recommendations are a valuable first step in the continued study of PIRRT in the pediatric population.
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Injúria Renal Aguda/terapia , Terapia de Substituição Renal Contínua/métodos , Estado Terminal/terapia , Terapia de Substituição Renal Intermitente/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: Cardiogenic shock (CS) is still the leading cause of in-hospital mortality in patients presenting with acute myocardial infarction (AMI). The aim of this study was to determine the in-hospital mortality and clinical outcome in AMI patients presenting with CS in a tertiary hospital in Oman. METHODS: This retrospective observational study included patients admitted to the cardiology department between January 2013 and December 2014. A purposive sampling technique was used, and 63 AMI patients with CS admitted to (36.5%) or transferred from a regional hospital (63.5%) were selected for the study. RESULTS: Of 63 patients, 73% (n = 46) were Omani and 27% (n = 17) were expatriates: 79% were male and 21% were female. The mean age of patients was 60±12 years. The highest incidence of CS (30%) was observed in the 51-60 year age group. Diabetes mellitus (43%) and hypertension (40%) were the predominant risk factors. Ninety-two percent of patients had ST-elevation MI, 58.7% patients were thrombolysed, and 8% had non-ST-elevation MI. Three-quarters (75%) of CS patients had severe left ventricular systolic dysfunction (defined as ejection fraction <30%). Coronary angiogram showed single vessel disease in 17%, double vessel disease in 40%, and triple vessel disease in 32% and left main disease in 11%. The majority of the patients (93.6%) underwent percutaneous coronary intervention (PCI), among them 23 (36.5%) underwent primary PCI. In-hospital mortality was 52.4% in this study. CONCLUSIONS: CS in AMI patients presenting to a tertiary hospital in Oman have high in-hospital mortality despite the majority undergoing PCI. Even though the in-hospital mortality is comparable to other studies and registries, there is an urgent need to determine the causes and find any remedies to provide better care for such patients, specifically concentrating on the early transfer of patients from regional hospitals for early PCI.