Recommendation of premarital genetic screening in the Syrian Jewish community based on mutation carrier frequencies within Syrian Jewish cohorts.

BACKGROUND: There is a paucity of information available regarding the carrier frequency for autosomal recessive pathogenic variants among Syrian Jews. This report provides data to support carrier screening for a group of autosomal recessive conditions among Syrian Jews based on the population frequency of 40 different pathogenic variants in a cohort of over 3800 individuals with Syrian Jewish ancestry. METHODS: High throughput PCR amplicon sequencing was used to genotype 40 disease-causing variants in 3840 and 5279 individuals of Syrian and Iranian Jewish ancestry, respectively. These data were compared with Ashkenazi Jewish carrier frequencies for the same variants, based on roughly 370,000 Ashkenazi Jewish individuals in the Dor Yeshorim database. RESULTS: Carrier screening identified pathogenic variants shared among Syrian, Iranian, and Ashkenazi Jewish groups. In addition, alleles unique to each group were identified. Importantly, 8.2% of 3401 individuals of mixed Syrian Jewish ancestry were carriers for at least one pathogenic variant. CONCLUSION: The findings of this study support the clinical usefulness of premarital genetic screening for individuals with Syrian Jewish ancestry to reduce the incidence of autosomal recessive disease among persons with Syrian Jewish heritage.

A founder deletion in the TRPM1 gene associated with congenital stationary night blindness and myopia is highly prevalent in Ashkenazi Jews.

Congenital stationary night blindness (CSNB) is a disease affecting the night vision of individuals. Previous studies identified TRPM1 as a gene involved in reduced night vision. Homozygous deletion of TRPM1 was the cause of CSNB in several children in 6 Ashkenazi Jewish families, thereby prompting further investigation of the carrier status within the families as well as in large cohorts of unrelated Ashkenazi and Sephardi individuals. Affected children were tested with a CSNB next-generation (NextGen) sequencing panel. A deletion of TRPM1 exons 2 through 7 was detected and confirmed by PCR and sequence analysis. A TaqMan-based assay was used to assess the frequency of this deletion in 18266 individuals of Jewish descent. High-throughput amplicon sequencing was performed on 380 samples to determine the putative deletion-flanking founder haplotype. Heterozygous TRPM1 deletions were found in 2.75% (1/36) of Ashkenazi subjects and in 1.22% (1/82) individuals of mixed Ashkenazi/Sephardic origin. The homozygous deletion frequency in our data was 0.03% (1/4025) and was only found in Ashkenazi Jewish individuals. Homozygous deletion of exons 2-7 in TRPM1 is a common cause of CSNB and myopia in many Ashkenazi Jewish patients. This deletion is a founder Ashkenazi Jewish deletion.

Myc and AP-1 expression in T cells and T-cell activation in patients after hematopoietic stem cell transplantation.

Regeneration of the immune system after hematopoietic stem cell transplantation (HSCT) is a slow process. We attempted to identify problems in the recovery of the immune system by examining expressions of early event cell cycle proteins Myc, Jun, and Fos, as well as DNA binding of Myc, activating protein 1 (AP-1), and CD4 cell activation values, in phytohemagglutinin-activated T lymphocytes taken from patients after HSCT. HSCT patients showed lower protein expression levels of Myc and Jun, as well as Myc and AP-1 DNA-binding levels, as compared to healthy controls. C-Jun was lower in long-term survivors of HSCT than short-term survivors. Adenosine triphosphate (ATP) values in CD4 cells were also lower in HSCT patients than healthy controls, but showed a time-dependent increase post-transplant. Non-surviving patients showed lower levels of both Fos protein and ATP as compared to surviving patients and a negative correlation between Fos values and lymphocyte percentage that was not present in surviving patients. There was a strong positive correlation between Fos values and lymphocyte percentage and between AP-1 values and white blood count, in patients without graft-versus-host disease (GVHD), that did not exist in patients who suffered from GVHD. Patients 2 years post-HSCT showed a positive correlation between AP-1 and Myc DNA-binding protein values, similar to those values found in healthy controls. Our study identified significant factors that account for the delay in immune reconstitution after transplant; this knowledge may improve the management of post-HSCT patients.

Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model).

Bone marrow transplantation (BMT) to treat severe hematologic malignancies often leads to potentially fatal acute graft-versus-host disease (GVHD), despite attempts at better donor-recipient matching and/or use of immunosuppressive agents. We report that embryo-derived PreImplantation Factor (PIF) plays a determining role in developing maternal/host tolerance toward the semiallogeneic or total allogeneic embryo and in regulating systemic immune response. Synthetic PIF treatment has proven effective in preventing immune attacks in nonpregnant models of autoimmunity. In this study, we tested the capability of PIF to prevent the development of acute GVHD in semiallogeneic or totally allogeneic murine BMT models. We examined the regulatory effect of PIF both in vivo and in vitro to control deleterious GVHD while maintaining its ability to preserve the beneficial graft-versus-leukemia (GVL) effect. Bone marrow and spleen cells from C57BL/6 donors were transplanted in semiallogeneic (C57BL/6xBALB/c) F1 or allogeneic (BALB/c) mice, which were then treated with PIF 1 mg/kg/day for 2 weeks. Short-term PIF administration reduced acute GVHD in both models and increased survival for up to 4 months after semiallogeneic or totally allogeneic BMT. This effect was coupled with decreased skin inflammation (semiallogeneic model) and decreased liver inflammation (both models), as well as reduced colon ulceration (allogeneic model). GVHD-associated cytokine and chemokine gene expression were decreased in the liver. PIF further lowered circulating IL-17 levels, but not IFN-γ levels. Both in vivo and in vitro, PIF treatment was demonstrated to lead to decreased inducible nitric oxide synthase expression and decreased lipopolysaccharide-activated macrophages to lower nitric oxide secretion. Significantly, PIF did not diminish the beneficial GVL effect in the B cell leukemia model. PIF acts primarily by inducing the regulatory phenotype on monocytes/antigen-presenting cells, which controls T cell proliferation. Overall, our data demonstrate that PIF protects against semiallogeneic and allogeneic GVHD long term by reducing both target organ and systemic inflammation and by decreasing oxidative stress, while preserving the beneficial GVL effect.