Efficient test for deviation from Hardy-Weinberg equilibrium with known or ambiguous typing in highly polymorphic loci.

The Hardy-Weinberg equilibrium (HWE) assumption is essential to many population genetics models. Multiple tests were developed to test its applicability in observed genotypes. Current methods are divided into exact tests applicable to small populations and a small number of alleles, and approximate goodness-of-fit tests.

Graph-Based Imputation Methods and Their Applications to Single Donors and Families.

The outcome of Hematopoietic Stem Cell (HSCT) and organ transplant is strongly affected by the matching of the HLA alleles of the donor and the recipient. However, donors and sometimes recipients are often typed at low resolution, with some alleles either missing or ambiguous. Thus, imputation methods are required to detect the most probably high-resolution HLA haplotypes consistent with a typing.

Single-residue linear and conformational B cell epitopes prediction using random and ESM-2 based projections.

B cell epitope prediction methods are separated into linear sequence-based predictors and conformational epitope predictions that typically use the measured or predicted protein structure. Most linear predictions rely on the translation of the sequence to biologically based representations and the applications of machine learning on these representations. We here present CALIBER 'Conformational And LInear B cell Epitopes pRediction', and show that a bidirectional long short-term memory with random projection produces a more accurate prediction (test set AUC=0.

Combined imputation of HLA genotype and self-identified race leads to better donor-recipient matching.

Allogeneic Hematopoietic Cell Transplantation (HCT) is a curative therapy for hematologic disorders and often requires human leukocyte antigen (HLA)-matched donors. Donor registries have recruited donors utilizing evolving technologies of HLA genotyping methods. This necessitates in-silico ambiguity resolution and statistical imputation based on haplotype frequencies estimated from donor data stratified by self-identified race and ethnicity (SIRE).

Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa.

Background: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date.

Methods: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds.

From biorepositories to data repositories: Open-access resources accelerate early R&D and validation of equitable diagnostic tools.

Diagnostics are critical tools that guide clinical decision-making for patient care and support disease surveillance. Despite its importance, developers and manufacturers often note that access to specimen panels and essential reagents is one of the key challenges in developing quality diagnostics, particularly in low-resource settings. A recent example, as the COVID-19 pandemic unfolded there was a need for clinical samples across the globe to support the rapid development of diagnostics.

Trans-population graph-based coverage optimization of allogeneic cellular therapy.

Background: Pre-clinical development and in-human trials of 'off-the-shelf' immune effector cell therapy (IECT) are burgeoning. IECT offers many potential advantages over autologous products. The relevant HLA matching criteria vary from product to product and depend on the strategies employed to reduce the risk of GvHD or to improve allo-IEC persistence, as warranted by different clinical indications, disease kinetics, on-target/off-tumor effects, and therapeutic cell type (T cell subtype, NK, etc.

GRAMM: A new method for analysis of HLA in families.

Recently, haplo-identical transplantation with multiple HLA mismatches has become a viable option for stem cell transplants. Haplotype sharing detection requires the imputation of donor and recipient. We show that even in high-resolution typing when all alleles are known, there is a 15% error rate in haplotype phasing, and even more in low-resolution typings.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

Background And Objectives: To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes.

Limited Contribution of Donor Characteristics to One-Year Survival After Hematopoietic Stem Cell Transplantation.

A large number of association studies have related donor characteristics to survival after bone marrow transplantation, for leukemia in general and specifically for acute myeloid leukemia (AML) patients. However, population-based differences often do not hold at the single transplant level. We test whether transplantation outcomes can be predicted at the single-patient level and whether such predictions can be used to better choose donors.

HLA homozygosity is associated with Non-Hodgkin lymphoma.

The "heterozygote advantage" hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.

A Novel Point-of-Care Rapid Diagnostic Test for Screening Individuals for Antibody Deficiencies.

Purpose: No rapid diagnostic test exists to screen individuals for primary antibody deficiencies (PAD) at or near the point of care. In settings at risk for polio where live oral polio vaccine is utilized, undiagnosed PAD patients and cases with delayed diagnosis constitute a potential reservoir for neurovirulent polioviruses, undermining polio eradication. This research aimed to develop a rapid screening test suited for use in resource-limited settings to identify individuals with low immunoglobulin G (IgG) levels, enabling early diagnosis and appropriate treatment.

HLA haplotype frequency estimation for heterogeneous populations using a graph-based imputation algorithm.

HLA haplotype frequencies are estimated from ambiguous unphased HLA genotyping data using Expectation-Maximization (EM) algorithms. Current population genetics methods require independent EM frequency estimates for each population, and assume that each population is in Hardy-Weinberg Equilibrium (HWE). The HWE assumption of EM has thus far resulted in the exclusion of individuals from mixed or unknown ethnic backgrounds from reference datasets.

MHC Haplotyping of SARS-CoV-2 Patients: HLA Subtypes Are Not Associated with the Presence and Severity of COVID-19 in the Israeli Population.

HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with COVID-19 severity. Studies have proposed associations, based on a very small sample and a large number of tested HLA alleles, but no clear association between HLA and COVID-19 incidence or severity has been reported.

Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds.

SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia.

Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the gene () have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in cells.

Artificial stone dust-induced functional and inflammatory abnormalities in exposed workers monitored quantitatively by biometrics.

The manufacture of kitchen and bath countertops in Israel is based mainly on artificial stone that contains 93% silica as natural quartz, and ∼3500 workers are involved in cutting and processing it. Artificial stone produces high concentrations of silica dust. Exposure to crystalline silica may cause silicosis, an irreversible lung disease.

Molecular analysis of a series of Israeli families with Comèl-Netherton syndrome.

Background: Comèl-Netherton syndrome is a rare congenital autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities and atopic diathesis. It is caused by mutations in SPINK5, which encodes the serine protease inhibitor LEKTI.

Objectives: To delineate the spectrum of mutations carried by a series of Israeli patients in an attempt to establish an effective diagnostic strategy for this disease in Israel.

A novel splice-site mutation in the AAGAB gene segregates with hereditary punctate palmoplantar keratoderma and congenital dysplasia of the hip in a large family.

Background: Palmoplantar keratoderma punctata (PPKP) is a heterogeneous group of disorders characterized by hyperkeratotic papules occurring over the palms and soles during adolescence. PPKP type 1, also known as PPKP Buschke-Fischer-Brauer type, was recently found to result from mutations in the AAGAB gene, encoding the p34 protein. PPKP type 1 is usually not associated with extracutaneous features.

Met-induced membrane blebbing leads to amoeboid cell motility and invasion.

Met tyrosine kinase has been implicated in tumorigenesis and metastasis; its overexpression and deregulation is often observed in cancer. Although Met's functions in cell motility has been studied extensively, its involvement in bleb-based, amoeboid motility is yet to be determined. The aim of this work is to study the role of Met in amoeboid cell motility and invasion.

Non-syndromic autosomal recessive congenital ichthyosis in the Israeli population.

Background: Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses.