Complex Inheritance of Rare Missense Variants in PAK2, TAP2, and PLCL1 Genes in a Consanguineous Arab Family With Multiple Autoimmune Diseases Including Celiac Disease.

Background: Autoimmune diseases (AIDs) share a common molecular etiology and often present overlapping clinical presentations. Thus, this study aims to explore the complex molecular basis of AID by whole exome sequencing and computational biology analysis. Methods: Molecular screening of the consanguineous AID family and the computational biology characterization of the potential variants were performed. The potential variants were searched against the exome data of 100 healthy individuals and 30 celiac disease patients. Result: A complex inheritance pattern of PAK2 (V43A), TAP2 (F468Y), and PLCL1 (V473I) genetic variants was observed in the three probands of the AID family. The PAK2 variant (V43A) is a novel one, but TAP2 (F468Y) and PLCL1 (V473I) variants are extremely rare in local Arab (SGHP and GME) and global (gnomAD) databases. All these variants were localized in functional domains, except for the PAK2 variant (V43A) and were predicted to alter the structural (secondary structure elements, folding, active site confirmation, stability, and solvent accessibility) and functional (gene expression) features. Therefore, it is reasonable to postulate that the dysregulation of PAK2, TAP2, and PLCL1 genes is likely to elicit autoimmune reactions by altering antigen processing and presentation, T cell receptor signaling, and immunodeficiency pathways. Conclusion: Our findings highlight the importance of exploring the alternate inheritance patterns in families presenting complex autoimmune diseases, where classical genetic models often fail to explain their molecular basis. These findings may have potential implications for developing personalized therapies for complex disease patients.

Saudi Familial Hypercholesterolemia Patients With Rare LDLR Stop Gain Variant Showed Variable Clinical Phenotype and Resistance to Multiple Drug Regimen.

Familial hypercholesterolemia (FH), a well-known lipid disease caused by inherited genetic defects in cholesterol uptake and metabolism is underdiagnosed in many countries including Saudi Arabia. The present study aims to identify the molecular basis of severe clinical manifestations of FH patients from unrelated Saudi consanguineous families. Two Saudi families with multiple FH patients fulfilling the combined FH diagnostic criteria of Simon Broome Register, and the Dutch Lipid Clinic Network (DLCN) were recruited. LipidSeq, a targeted resequencing panel for monogenic dyslipidemias, was used to identify causative pathogenic mutation in these two families and in 92 unrelated FH cases. Twelve FH patients from two unrelated families were sharing a very rare, pathogenic and founder LDLR stop gain mutation i.e., c.2027delG (p.Gly676Alafs*33) in both the homozygous or heterozygous states, but not in unrelated patients. Based on the variant zygosity, a marked phenotypic heterogeneity in terms of LDL-C levels, clinical presentations and resistance to anti-lipid treatment regimen (ACE inhibitors, ß-blockers, ezetimibe, statins) of the FH patients was observed. This loss-of-function mutation is predicted to alter the free energy dynamics of the transcribed RNA, leading to its instability. Protein structural mapping has predicted that this non-sense mutation eliminates key functional domains in LDLR, which are essential for the receptor recycling and LDL particle binding. In conclusion, by combining genetics and structural bioinformatics approaches, this study identified and characterized a very rare FH causative LDLR pathogenic variant determining both clinical presentation and resistance to anti-lipid drug treatment.

Exome Analysis Identifies a Novel Compound Heterozygous Alteration in TGM1 Gene Leading to Lamellar Ichthyosis in a Child From Saudi Arabia: Case Presentation.

Background: Lamellar ichthyosis is an autosomal recessive type of rare skin disorders characterized with defective epidermis leading hyperkeratosis with brownish-gray scales over the body. These patients are born as collodion babies and may also exhibit additional features like erythema, ectropion, and eclabium. This disease is mainly caused by homozygous and compound heterozygous alterations in transglutaminase 1 encoding gene (TGM1), which is located on 14q12. Case presentation: This study reports the genetic analysis of a 4-year Saudi girl presenting lamellar ichthyosis. She was the first child of unrelated parents. The family had no previous history of the disease phenotype. She was born as a collodion baby without any prenatal complications. At the time of this study she had developed rough scaly skin on her legs, arms and trunk regions with thick palms and soles. Whole exome sequencing (WES) followed by Sanger sequence validation identified a novel compound heterozygous variant in TGM1 gene. The paternal variant was a missense transition (c.1141G>A; p.Ala381Thr) present at exon 7, while maternal variant (c.758-1G>C) was present at the intron4-exon5 boundary. To the best of our knowledge these variants had not been reported before in TGM1 gene. Conclusion: In isolated and inbred populations, homozygous variants are identified more frequently; however, our results suggest that compound heterozygous variants should also be considered especially when the marriages are not consanguineous.

Percutaneous ultrasound-guided alcohol ablation of solitary parathyroid adenoma in a patient with primary hyperparathyroidism.

Parathyroidectomy is considered the definitive cure for primary hyperparathyroidism due to a single parathyroid adenoma, which represents the most common cause of chronic hypercalcemia. However, in few cases, surgery may be technically difficult or risky. We report the use of percutaneous ultrasound-guided alcohol ablation of a parathyroid adenoma as an alternative to surgery in an 88-year-old male patient with significant medical comorbidities.

Impact of admission serum glucose level on in-hospital outcomes following coronary artery bypass grafting surgery.

OBJECTIVE: The impact of admission serum glucose (SG) level on outcomes in coronary artery bypass grafting (CABG) surgery is unknown. The present study sought to determine whether elevated admission SG level is associated with adverse outcomes following CABG surgery. METHODS: Patients undergoing CABG surgery between January 2000 and December 2005 at a single centre were identified (n=2856). Admission SG levels of less than 9.2 mmol/L and 9.2 mmol/L or greater were chosen to divide patients into two groups based on the 75th percentile of SG distribution. A logistic regression model was generated to determine the impact of admission SG level on a composite outcome of any one or more of in-hospital mortality, stroke, perioperative myocardial infarction, sepsis, deep sternal wound infection, renal failure, requirement for postoperative inotropes and prolonged ventilation. RESULTS: In total, 76.3% of patients had an admission SG level of less than 9.2 mmol/L (group A) and 23.7% had an admission SG level of 9.2 mmol/L or greater (group B). Group B patients were more likely to be female, have diabetes, have preoperative renal failure, have an ejection fraction of less than 40%, experience myocardial infarction within 21 days before surgery, and have triple vessel or left main disease (P<0.05). Univariate analysis revealed no difference in in-hospital mortality between group A (2.2%) and group B (3.2%) (P=0.12); however, the composite outcome was more likely to occur in group B (40.8%) versus group A (27.9%) (P=0.0001). After multivariable adjustment, admission SG level of 9.2 mmol/L or greater remained an independent predictor of composite outcome (OR=1.3, 95% CI 1.0 to 1.7, P=0.02, receiver operating characteristic = 78%). CONCLUSION: Admission SG level of 9.2 mmol/L or greater is associated with significant morbidity in patients undergoing CABG surgery.

Yoga Practice for the Management of Type II Diabetes Mellitus in Adults: A systematic review.

The effect of practicing yoga for the management of type II Diabetes was assessed in this systematic review through searching related electronic databases and the grey literature to the end of May 2007 using Ovid. All randomized controlled clinical trials (RCTs) comparing yoga practice with other type of intervention or with regular practice or both, were included regardless of language or type of publication. Each study was assessed for quality by two independent reviewers. Mean difference was used for summarizing the effect of each study outcomes with 95% confidence intervals. Pooling of the studies did not take place due to the wide clinical variation between the studies. Publication bias was assessed by statistical methods. Five trials with 363 participants met the inclusion criteria with medium to high risk of bias and different intervention characteristics. The studies' results show improvement in outcomes among patients with diabetes type II. These improvements were mainly among short term or immediate diabetes outcomes and not all were statistically significant. The results were inconclusive and not significant for the long-term outcomes. No adverse effects were reported in any of the included studies. Short-term benefits for patients with diabetes may be achieved from practicing yoga. Further research is needed in this area. Factors like quality of the trials and other methodological issues should be improved by large randomized control trials with allocation concealment to assess the effectiveness of yoga on diabetes type II. A definitive recommendation for physicians to encourage their patients to practice yoga cannot be reached at present.