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Simple Summary: Patients suffering from multiple myeloma receive many lines of treatment including chimeric antigen receptor T cell (CART) therapy. Myeloma patients may develop devastating secondary malignancies such as myelodysplastic syndrome (MDS). The causative relationship between various anti-myeloma treatments and MDS is not fully understood. We report a study of five CART-treated patients myeloma patients who had MDS (four only after CART and one already prior to CART). We found that all these patients had all their MDS-related molecular changes (mutations) already prior to CART even if they did not have overt MDS in bone marrow evaluation before CART. No new mutations developed after CART, but the frequency of pre-existing mutations did increase. Our study presents evidence that anti-myeloma CART therapy may promote the expansion of pre-existing MDS clones rather than causing the development of new ones. Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones. [ABSTRACT FROM AUTHOR]

Background Preconception carrier screening for cystic fibrosis ( CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. Methods An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/ TG tracts. Results We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. Conclusions Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates. [ABSTRACT FROM AUTHOR]

Objective It has been hypothesized that carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism. In the present study, we assessed the risk for symptoms of androgen excess in carriers of CYP21 gene mutations and the effect of different mutations on phenotype. Design All subjects underwent clinical evaluation, ACTH stimulation testing, and molecular analysis of the CYP21 gene. Patients One hundred and eighty-seven subjects were included in the study. Five groups were defined according to genotype: A, 38 patients with classical-congenital adrenal hyperplasia (CAH); B, 16 patients with non classical CAH; C, 66 family member carriers; D, 24 children and adolescents with symptoms suggestive of hyperandrogenism who were found to be heterozygous and E, 43 subjects with androgen excess symptoms who had normal genotype. Measurements Cortisol and 17-hydroxyprogesterone (17OHP) were measured basally and 60 min after ACTH stimulation. Analysis of seven common mutations of the CYP21 gene, which collectively cover 95% of the mutations in the Israeli population, was performed. The hormonal results were correlated with the genotype. Results The symptomatic carriers had a significantly higher rate of the mild mutation V281L compared with the family members (58% vs. 22%) and significantly higher levels of ACTH-stimulated 17OHP (mean 37·2 and 21 nmol/l, respectively; P = 0·025). Higher values of peak 17OHP levels were found in the carriers of the V281L mutation compared with carriers of other mutations ( P = 0·025). Stimulated 17OHP levels were significantly higher in carriers compared with normal genotype subjects ( P < 0·0001). Conclusions Our findings are the first to show that there is increased risk of androgen excess in carriers of CYP21 mutations and that the risk is related to genotype. Carriers for the mild, V281L mutation, are at higher risk of symptoms of androgen excess than carriers of the severe mutations. It appears that the variable phenotypes can be at least partially attributed to the degree of impairment of enzyme activity in different mutations. The severe consequences of hyperandrogenism in some of the carrier subjects indicate the need for long-term follow-up in these patients. [ABSTRACT FROM AUTHOR]

Background Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. Methods A retrospective review of governmental databanks, the national CF registry and CF centers. Results CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004–2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0–98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. Conclusions PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening. [ABSTRACT FROM AUTHOR]