Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls. Prospective Egyptian patients (n = 514) and controls (n = 400) underwent clinical phenotyping and genetic testing. Rare variants in 13 validated HCM genes were classified according to standard clinical guidelines and compared with a prospective HCM cohort of majority European ancestry (n = 684). A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10⁻⁷), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (five-fold greater than European patients), highlighting the importance of recessive inheritance in consanguineous populations. Finally, rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10⁻⁵) due to the underrepresentation of Middle Eastern populations in current reference resources. This proportion increased to 53.3% after incorporating methods that leverage new ancestry-matched controls presented here. Studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM. The genetic architecture of hypertrophic cardiomyopathy (HCM) in the Egyptian population was assessed by comparing the frequency of rare variation in HCM genes with Egyptian controls as well as with a UK HCM cohort (left). HCM minor genes MYL2, MYL3 and CSRP3 were more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity (top right). Integrating methods that leverage Egyptian controls increased the yield of clinically actionable variants (pathogenic, likely pathogenic) from 19% (initial analysis) to 29.6% (cohort-informed analysis) (bottom right). HCM: Hypertrophic Cardiomyopathy; ACMG/AMP: American College of Medical Genetics and Genomics/Association of Molecular Pathology. Created with BioRender.com.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease, with a prevalence of at least 1 in 500 in the general population. The disease is pleiotropic and is characterized by an increased stiffness of the myocardium, partly due to changes in the extracellular matrix (ECM), with elevated levels of interstitial fibrosis. Myocardial fibrosis is linked to impaired diastolic function and possibly phenotypic heterogeneity of HCM. The ECM consists of a very large number of proteins, which actively interact with each other as well as with myocardial cells. The role of other multiple components of the ECM in HCM has not been defined. Fibulin-2 is a glycoprotein component of the ECM, which plays an important role during embryogenesis of the heart; however, its role in adult myocardium has not been adequately studied. We here describe, for the first time, abnormal expression of fibulin-2 in the myocardium in patients with HCM as compared to normal controls. This abnormal expression was localized in the cytoplasm of myocardial cells and in the interstitial fibroblasts. In addition, fibulin-2 levels, measured by ELISA, were significantly elevated in the serum of patients with HCM as compared to normal controls.

Comprehensive genomic databases offer unprecedented opportunities towards effective tailored strategies for the prevention and treatment of disease. The integration of genomic and phenotypic data from diverse ethnic populations is also key to advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases, however, are not representative of the global human population, making variant interpretation challenging and uncertain, especially in underrepresented populations such as the North African population. To address this, a study of 391 Egyptian healthy volunteers (EHVols) was initiated as a milestone towards establishing the 1000 Egyptian Genomes project.

In this paper a generalized formulation for the spectral domain Green's functions of unit current sources embedded within a multilayer stack is presented. The current source can be either electric or magnetic. It can be oriented either parallel to the layers or perpendicular to them. The electric and magnetic fields due to these generalized sources are calculated. The proposed technique utilizes inward and outward recurrence processes in order to solve for the desired quadruple-dyadic Green's functions. It requires the calculation of 6 spectral coefficients only, from which all types of spectral Green's functions can be calculated. The proposed formulation is written such that the electromagnetic fields are directly obtained in terms of the current sources rather than the vector and scalar potentials with no explicit analogy with transmission lines. The dependencies on the z-coordinates of the source and field points are expressed explicitly, which is important for Volume Integral Equation (VIE) formulation. The proposed generalized formulation is applied on a number of plasmonic layer structures such as Insulator/Metal/Insulator (IMI), Metal/Insulator/Metal (MIM), and five-layer plasmonic/dielectric layer structure. The poles of the spectral domain Green's functions are linked to the Surface Plasmon Polaritons (SPPs), i.e. surface wave modes, associated with the source-free layer structure. The spectral Green's functions calculated using the proposed generalized technique are also used by an in-house Method of Moments (MoM) solver. The results of this solver are compared with those obtained by a full-wave commercial software.

Cardiac valves exhibit highly complex structures and specialized functions that include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied. In this work we analyzed the differential methylation profiles of 12 non-diseased aortic and mitral valve tissue samples (in matched pairs). Analysis of methylation data (reduced representation bisulfite sequencing (RRBS)) of 1601 promoters genome-wide revealed 584 differentially methylated (DM) promoters, of which 13 were reported in endothelial mesenchymal trans-differentiation (EMT), 37 in aortic and mitral valve disease and 7 in ECM remodeling. Both functional classification as well as network analysis showed that the genes associated with the DM promoters were enriched for WNT-, Cadherin-, Endothelin-, PDGF- and VEGF-signaling implicated in valvular physiology and pathophysiology. Additional enrichment was detected for TGFB-, NOTCH- and Integrin-signaling involved in EMT as well as ECM remodeling. This data provides the first insight into differential regulation of human aortic and mitral valve tissue and identifies candidate genes linked to DM promoters. Our work will improve the understanding of valve biology, valve tissue engineering approaches and contributes to the identification of relevant drug targets.