👤 Shahid Mansoor

Inborn errors of metabolism (IEM) are frequently underdiagnosed in low-resource settings due to limited diagnostic infrastructure. We hypothesized that an integrated clinical-genomic approach could improve diagnosis and management of these conditions. Nineteen Pakistani families with clinically suspected IEM underwent systematic clinical assessment, available biochemical testing, and whole-exome sequencing (WES). Variants were classified according to ACMG/AMP guidelines using evidence from population databases, in silico prediction tools, segregation analysis, and genotype-phenotype correlation. Clinical diagnoses and management strategies were reassessed based on molecular findings. WES provided a molecular diagnosis in 90% (17/19) of families and enabled targeted therapeutic interventions in 70% (13/19). However, clinical outcomes were variable due to advanced disease in some cases and limited follow-up. Seven novel variants were identified in CYP27B1, DYM, MTTP, ALDH3A2, USP53, BRAF, and JAG1, while twelve recurrent mutations were detected in PIGN, GCDH, CLCN7, RNASEH2C, ABCB11, MPV17, IDUA, SMPD1, FBP1, SLC37A4, ACADM, and UGT1A1. Integrating genomic findings with clinical reassessment improved diagnostic precision. An integrated clinical-genomic approach enabled accurate diagnosis of pediatric IEM in resource-limited settings, with particular utility in children with metabolic disorders in a consanguineous population. Identification of both novel and recurrent variants expanded the genotypic and phenotypic spectrum of these disorders and highlighted the clinical utility of genomic diagnostics in optimizing patient care. Show less

Hypertriglyceridemia has been proposed as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Triglycerides (TG) are viewed as a marker for remnant cholesterol in triglyceride-rich lipoproteins, as this remnant cholesterol has been identified as a causal risk factor for ASCVD. The limited number of effective treatments for elevated TG has fueled the search for novel pharmacotherapy options, and multiple medication classes are being explored. Apolipoprotein C3 (APOC3) and angiopoietin-like protein 3 (ANGPTL3) are among the most promising targets. Several novel agents utilizing these pathways, including olezarsen, plozasiran, and zodasiran, are currently under development for the management of elevated TG, with olezarsen approved in 2024 for the management of familial chylomicronemia syndrome. This comprehensive review provides updated insights into the development of novel hypertriglyceridemia treatments. Show less

This study aimed to investigate alterations in the expression of four key cytokines (IL-7, IL-11, IL-15, and IL-27) and assess differential FAM26F expression in response to Hepatitis C virus (HCV) infection. Additionally, it sought to analyze changes in these cytokines after treatment in 244 chronic HCV patients and 28 controls undergoing various treatments, including standard interferon, pegylated interferon, and Direct Acting Antivirals (DAAs). The objective was to compare immune system regulation between treatment groups. The expression levels of FAM26F and the cytokines (IL-7, IL-11, IL-15, and IL-27) were evaluated using Real-time qPCR in PBMCs of treatment groups. Results revealed significant downregulation of IL-7 and IL-27 in infected individuals compared to healthy controls, persisting even after treatment. This suggests the crucial roles of these immune modulators in facilitating the necessary T-cell response for viral clearance. IL-11 expression also remained suppressed post-treatment, supporting viral clearance by restoring the Th1 response. The decrease in IL-11 levels during treatment indicates the restoration of the Th1 response, vital for viral clearance. IL-15, the key cytokine regulating cytotoxic cells (NKT and NK cells), displayed consistent expression across all sample groups, indicating maintained IL-15-induced cytotoxicity in both control and infected individuals. Additionally, FAM26F expression was reduced in the HCV-infected group compared to controls, but higher in HCV-recovered cases, potentially due to reduced infection and enhanced immunity. In conclusion, this research unveils the relationship between FAM26F and HCV infection, highlighting the virus's tendency to suppress cytokine and FAM26F expression. An effective treatment strategy for establishing an ideal host immune response may involve restoring FAM26F and cytokine expression to their normal levels. Show less

Cytokines play an important role in SARS-CoV-2 infection progression and severity. A number of inflammatory cytokines have been directly associated with disease severity including IL-6 (interleukin-6), IL-10, TNF-α (tumor necrosis factor alpha), IFN-γ (interferon-gamma). Here, in this study, the aim was to better understand the interplay between host immune response mediated by cytokines and severity of SARS-CoV-2 infection by assessing cytokine expression. Therefore, we measured expression levels of a total of 12 genes (IFNA-1, IFN-γ, IL-1α, IL-1β, IL-4, IL-6, IL-7, IL-10, IL-11, IL-13, IL-15, and IL-27) encoding inflammatory, anti-inflammatory and regulatory cytokines using QRT-PCR in hospitalized patients with severe infection compared to mildly infected. IFN-γ was identified as a potent marker of disease severity as indicated previously. Moreover, levels of IL-7 were also found to be partially reduced in patients compared to the healthy controls and linked negatively to disease severity. Identification of these cytokines may be helpful in not only understanding disease pathogenesis but also in better management of the patients after covid infection. Show less

Despite periodic drops in popularity, Arctic sled dogs continue to play a vital role in northern societies, providing both freight transit and recreational race activities. In this study, we selected the Mackenzie River Husky, a freight dog of complex history, and the Chinook, an American Kennel Club recognized freight dog breed whose heritage reportedly overlaps that of the MKRH, for detailed population analysis. We tested each to determine their component breeds and used admixture analysis to ascertain their population structure. We utilized haplotype analysis to identify genomic regions shared between each population and their founding breeds. Our data show that the Alaskan Malamutes and modern Greenland sled dog contributed to both populations, but there are also unexpected contributions from the German Shepherd dog and Collie. We used haplotype analysis to identify genomic regions nearing fixation in population type and identify provocative genes in each region. Finally, in response to recent reports regarding the importance of dietary lipid genes in Arctic dogs, we analyzed 8 such genes in a targeted analysis observing signatures of selection in both populations at the MLXIPL gene loci. These data highlight the genetic routes that breeds of similar function have taken toward their occupation as successful sled dogs. Show less

Dipygus is a complete caudal duplication deformity in its severest form. The structures derived from the embryonic cloaca and notochords are duplicated to various extent. We report a male baby who presented to us with complete somatic and visceral duplication below the umbilical level associated with gastroschisis and imperforated anus. Staged surgical corrections were suggested and three out of the four stages were performed successfully. Show less