Deciphering metabolomics and lipidomics landscape in zebrafish hypertrophic cardiomyopathy model.

To elucidate the lipidomic and metabolomic alterations associated with hypertrophic cardiomyopathy (HCM) pathogenesis, we utilized cmybpc3-/- zebrafish model. Fatty acid profiling revealed variability of 10 fatty acids profiles, with heterozygous (HT) and homozygous (HM) groups exhibiting distinct patterns. Hierarchical cluster analysis and multivariate analyses demonstrated a clear separation of HM from HT and control (CO) groups related to cardiac remodeling.

The genetic cause of neurodevelopmental disorders in 30 consanguineous families.

Objective: This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs).

Methods: We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified.

Genetic background of primary and familial HLH in Qatar: registry data and population study.

Background: Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports.

Conserved genes regulating human sex differentiation, gametogenesis and fertilization.

The study of the functional genome in mice and humans has been instrumental for describing the conserved molecular mechanisms regulating human reproductive biology, and for defining the etiologies of monogenic fertility disorders. Infertility is a reproductive disorder that includes various conditions affecting a couple's ability to achieve a healthy pregnancy. Recent advances in next-generation sequencing and CRISPR/Cas-mediated genome editing technologies have facilitated the identification and characterization of genes and mechanisms that, if affected, lead to infertility.

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project.

Childhood glaucoma (CG) encompasses a heterogeneous group of genetic eye disorders that is responsible for approximately 5% of childhood blindness worldwide. Understanding the molecular aetiology is key to improving diagnosis, prognosis and unlocking the potential for optimising clinical management. In this study, we investigated 86 CG cases from 78 unrelated families of diverse ethnic backgrounds, recruited into the Genomics England 100,000 Genomes Project (GE100KGP) rare disease cohort, to improve the genetic diagnostic yield.

Deciphering the complex interplay of obesity, epithelial barrier dysfunction, and tight junction remodeling: Unraveling potential therapeutic avenues.

Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence.

A loss-of-function AGTR1 variant in a critically-ill infant with renal tubular dysgenesis: case presentation and literature review.

Background: Renal tubular dysgenesis (RTD) is a severe disorder with poor prognosis significantly impacting the proximal tubules of the kidney while maintaining an anatomically normal gross structure. The genetic origin of RTD, involving variants in the ACE, REN, AGT, and AGTR1 genes, affects various enzymes or receptors within the Renin angiotensin system (RAS). This condition manifests prenatally with oligohydramninos and postnatally with persistent anuria, severe refractory hypotension, and defects in skull ossification.

Burden of Mendelian disorders in a large Middle Eastern biobank.

Background: Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.

Methods: Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.

Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder.

Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy-Walker malformation, respiratory distress, and multiorgan dysfunctions.

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC.

Equity, diversity, and inclusion at the Global Alliance for Genomics and Health.

A lack of diversity in genomics for health continues to hinder equitable leadership and access to precision medicine approaches for underrepresented populations. To avoid perpetuating biases within the genomics workforce and genomic data collection practices, equity, diversity, and inclusion (EDI) must be addressed. This paper documents the journey taken by the Global Alliance for Genomics and Health (a genomics-based standard-setting and policy-framing organization) to create a more equitable, diverse, and inclusive environment for its standards and members.

A variant in sperm-specific glycolytic enzyme enolase 4 (ENO4) causes human male infertility.

Background: Although defects in sperm morphology and physiology lead to male infertility, in many instances, the exact disruption of molecular pathways in a given patient is often unknown. The glycolytic pathway is an essential process to supply energy in sperm cell motility. Enolase 4 (ENO4) is crucial for the glycolytic process, which provides the energy for sperm cells in motility.

An integrated tumor, immune and microbiome atlas of colon cancer.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications.

A Complex Intrachromosomal Rearrangement Disrupting in a Family with Popliteal Pterygium and Van der Woude Syndromes.

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers.

A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family.

Background: Isolated growth hormone deficiency (IGHD) is caused by a severe shortage or absence of growth hormone (GH), which results in aberrant growth and development. Patients with IGHD type IV (IGHD4) have a short stature, reduced serum GH levels, and delayed bone age.

Objectives: To identify the causative mutation of IGHD in a consanguineous family comprising four affected patients with IGHD4 (MIM#618157) and explore its functional impact .

The link between glycemic control measures and eye microvascular complications in a clinical cohort of type 2 diabetes with microRNA-223-3p signature.

Background: Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR).

Methods: In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and β cell function measurements.

Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease.

Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology.

The role of dietary antioxidants in type 2 diabetes and neurodegenerative disorders: An assessment of the benefit profile.

Healthy diet is vital to cellular health. The human body succumbs to numerous diseases which afflict severe economic and psychological burdens on the patient and family. Oxidative stress is a possible crucial regulator of various pathologies, including type 2 diabetes and neurodegenerative diseases.

Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank.

Background: The genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine.

Methods: We evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry.

A novel homozygous variant in homologous recombination repair gene ZSWIM7 causes azoospermia in males and primary ovarian insufficiency in females.

Infertility is a common, clinically heterogeneous reproductive disorder worldwide with a prevalence of about 15%. To date about eighty genes have been discovered to cause non-syndromic infertility, affecting males and females equally, though traditionally the genetic analysis of each group has been conducted separately. Here, we report the clinical and genetic characterization of a consanguineous family of Pakistani origin with multiple individuals, including male and female, affected with infertility.