Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease.

RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.

Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects.

BACKGROUND: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. OBJECTIVE: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. METHODS: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. RESULTS: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. CONCLUSIONS: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.

Potential Antigenic Cross-reactivity Between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Dengue Viruses.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross-reactivity. METHODS: We analyzed clinical data and serum samples from 55 individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To assess dengue serology status, we used dengue-specific antibodies by means of lateral-flow rapid test, as well as enzyme-linked immunosorbent assay (ELISA). Additionally, we tested SARS-CoV-2 serology status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS: Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P = 2.5E-5). This includes 9 cases of positive immunoglobulin M (IgM), 2 cases of positive immunoglobulin G (IgG), and 1 case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in 2 additional subjects using envelope protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (P = 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. CONCLUSIONS: Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.

Gene expression profiling of humans under exertional heat stress: Comparisons between persons with and without exertional heat stroke.

Exertional heat stroke (EHS) is a leading cause of preventable morbidity and mortality among both athletes and warfighters. Therefore, it is important to find blood biomarkers to predict susceptibility to EHS. We compared gene expression profiling from blood cells between two groups of participants - those with and those without a history EHS - by using genome-wide microarray analysis. Subjects with a history of EHS (n = 6) and non-EHS controls without a history of EHS (n = 18) underwent a heat tolerance test and a thermoneutral exercise challenge on separate days. The heat tolerance test comprised of 2-h of walking, at 5 km/h and 2% incline, with ambient conditions set at 40 °C, 40% relative humidity; the thermoneutral test was similar, but had ambient conditions set at 22 °C. Next, we examined gene expression profiles, quantified based on arithmetic differences (post minus pre) during the heat test minus changes during the thermoneutral test. Genes related to interleukins and cellular stress were significantly down-regulated in participants with a history of EHS compared to their non-EHS counterparts. Suppression of these genes may be associated with susceptibility to exertional heat injury. Prospective research is required to determine whether similar gene expression profiling can be potentially used as blood biomarkers to predict susceptibility to EHS.

[STRENUOUS AND PROLONGED EXERCISE AND UPPER RESPIRATORY TRACT INFECTION - TREATMENT OR THREAT?]

INTRODUCTION: Prolonged and strenuous exercise may lead to changes in the immune system function and to temporary suppression in defense against pathogens. These changes likely increase the risk of those engaging in prolonged and strenuous physical activity to develop upper respiratory tract infection and to reduce the level of performance. On the other hand, it appears that moderate physical activity reduces the risk of upper respiratory tract infection. Various populations, such as professional athletes and soldiers in combat units, who engage in daily strenuous exercise, may therefore be a high risk group. Integration of additional stress factors, such as sleep deprivation, emotional stress, nutritional deprivation, and dehydration also affect the immune system and may worsen the effect. On the other hand, there are those who claim that upper respiratory symptoms are due to non-infection inflammation causes such as allergy, asthma etc. Hence the effects of strenuous exercise on the immune system during training and competitions are not sufficiently clear. This review article will focus on the known effects of strenuous and prolonged exercise on the immune system, the possible mechanisms leading to these changes and their clinical impacts with applied emphasis to active populations such as athletes and soldiers.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.

Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders.

Background: Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care. Methods: We prospectively employed exome sequencing in children admitted to the general pediatric inpatient service at a large tertiary medical center in Israel. Genetic analysis was triggered by general and/or subspecialist pediatricians who were part of the primary inpatient team. We determined the diagnostic yield among children who were referred for exome sequencing and observed the effects of genetic diagnosis on medical care. Results: A total of fifty probands were evaluated and exome sequenced during the study period. The most common phenotypes included were neurodevelopmental (56%), gastrointestinal (34%), and congenital cardiac anomalies (24%). A molecular diagnosis was reached in 38% of patients. Among seven patients (37%), the molecular genetic diagnosis influenced subsequent clinical management already during admission or shortly following discharge. Conclusion: We identified a significant fraction of genetic etiologies among undiagnosed children admitted to the general pediatric ward. Our results support that early application of exome sequencing may be maximized by pediatric hospitalists' high index of suspicion for an underlying genetic etiology, prompting an in-house genetic evaluation. This framework should include a multidisciplinary co-management approach of the primary care team working alongside with subspecialties, geneticists and bioinformaticians.

Physiological Differences Between Heat Tolerant and Heat Intolerant Young Healthy Women.

Purpose: Heat intolerance (HI) is determined in the Israel Defense Force according to a heat tolerance test (HTT) before returning to duty after an exertional heat stroke (EHS) event. Recently, increased numbers of female combatants resulted in an increased number of EHS cases among women and a higher percentage of heat intolerance (HI) individuals. We aimed to evaluate the differences between tolerance to heat among women performing an HTT in relation to their menstrual cycle phase. Method: Thirty-three female participants were sorted into two groups: HI and heat tolerant (HT) according to two HTTs performed during both the luteal and follicular phases of the menstrual cycle or while consuming and during a break from consuming contraceptives. Results: HT women had an 18% higher maximal oxygen uptake (p < .005, 95% CI [2.6,9.8]) and 1.2% lower skin temperature in the HTT at the during and follicular phases (p < .01, 95% CI [0.12,0.77]) and 1.7% lower at the off and luteal phases (p < .001, 95% CI [0.34,0.92]). The mean sweat rate was 14% lower among the HI group only at the HTT at the during and follicular phases (p < .05, 95% CI (3,88)]). Conclusion: We found that HT can be predicted using aerobic capacity and core body temperature. Moreover, during the luteal phase, women presented altered thermoregulation that decreased the probability of being HT. This emphasizes the importance of considering the HT/HI criteria in the HTT for women, according to their aerobic ability and menstrual-cycle phase.

Rhabdomyolysis After Crawling Military Training.

INTRODUCTION: Rhabdomyolysis is a syndrome characterized by muscle necrosis followed by release of intracellular muscle contents into the circulation. Exertional rhabdomyolysis (ER) occurs in response to nonfamiliar and/or excessive, prolonged, or repetitive exercises, with eccentric characteristics. In military populations, due to the type of intense, all out physical loads, ER is a significant threat, particularly when training under heat stress. However, many other etiologies exist, and clinical presentations vary greatly. This heterogeneity may result in difficulty in prevention, diagnosis, and return-to-duty decision. The purpose of this report is to point to a new potential risk factor to an extreme muscle breakdown and ER. CASES DESCRIPTION: In this article, we describe three cases of ER in army recruits after strenuous acts of crawling over hard surfaces during an intense military selection process. The soldiers' creatine phosphokinase levels were markedly raised (44,000, 123,500, and 176,599 IU/L), but none of them developed any significant medical complication. DISCUSSION: There are two major mechanisms leading to ER: the mechanical pathway which is associated with muscle tension, and the metabolic pathway which is associated with cellular energy depletion. During this military selection process, the intensity of the exercises, and cycles of work and rest are highly controlled, and so are the timings of meals and fluids consumption. Moreover, the soldiers were all at least moderately fit and had participated in strenuous exercise events before. According to years of experience with this military selection process, under similar conditions (exercise volumes and loads) we have experienced along the years minimal medical events. At the same time, and this was the unique part in these case, all patients suffered significantly from mechanical injuries caused by crawling on hard surface which were not a part of the planned selection program. Thus, we suggest that the significant muscle breakdown in the presented cases occurred mostly due to crush injury and was not solely a result of the metabolic strain. CONCLUSION: Thus, we suggest that the extreme creatine phosphokinase levels may be attributed to a synergistic interaction between low-energy trauma, caused by crawling on hard soil and stones, and exertion. We also emphasize the fact that proper physiological support such as proper hydration may assist in prevention of ER complication such as acute renal failure.