Challenging diagnoses of tetraploidy/diploidy and trisomy 12: utility of first-tier prenatal testing methods

Introduction: Chromosome mosaicism and low-grade mosaicism present a challenge for diagnosis in the era of SNP array and NGS. Tetraploidy is a rare numerical chromosomal abnormality characterized by the presence of four copies of each chromosome. The prevalence of tetraploidy/diploidy mosaicism cases is extremely rare in the human population. Accurate estimates of the frequency of this chromosomal anomaly are lacking due to its classification as an extremely rare and difficult-to-detect condition.Methods: In this report, we describe two cases involving challenging diagnoses of tetraploidy/diploidy and trisomy 12. We utilized advanced genetic testing techniques, including SNP array, to examine the chromosomal abnormalities in these cases. We compared the results from SNP array to conventional G band karyotyping to assess the utility of first-tier prenatal testing methods.Results:Our analysis revealed two cases of tetraploidy/diploidy and trisomy 12 with atypical presentations. SNP array analysis provided higher resolution and more precise information about the chromosomal anomalies in these cases compared to conventional G band karyotyping. Additionally, the prevalence of tetraploidy/diploidy mosaicism was confirmed to be extremely rare in the population.Discussion: Low-level mosaicism is difficult to diagnose, and in many cases, it has traditionally been identified through techniques such as G band karyotype or FISH. Microarray has become an invaluable diagnostic tool for detecting chromosomal abnormalities, offering high-resolution insights. However, it may not always be able to detect rare occurrences of tetraploidy or tetraploidy/diploidy mosaicism. As a result, it is recommended to perform a G band karyotype analysis after obtaining a negative microarray result before considering other diagnostic methods with a potentially higher yield of diagnosis. For the detection of low-level mosaicism, combined diagnostic methods should be considered. The diagnosis of mosaicism is a multistep process that can be time-consuming, often requiring the application of more than one diagnostic technique. This approach is crucial for accurate diagnosis and comprehensive patient care. Further research is warranted to better understand the underlying mechanisms of these rare chromosomal anomalies and to develop more effective diagnostic strategies for challenging cases

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Cystathionine β-synthase 844ins68 Genetic Polymorphism in Spontaneous Abortion Susceptibility

Aim: Genetic polymorphisms in homocysteine-related genes are subject of a large body of research in pregnancy and newborn associated pathologies. The enzyme cystationine β-synthase (CBS) is involved in the transsulfuration pathway of homocysteine to cysteine. Our objective was to analyze the association of a common polymorphism exhibited by the CBS gene, 844ins68, with idiopathic spontaneous abortions (SA). Material and Methods: 131 patients with a history of at least one unexplained SA and 135 healthy women with at least one successful pregnancy and no SA were included in a case-control study. Simplex PCR was used to genotype the cases and control volunteers for the CBS 844ins68 polymorphism. Fisher’s exact test was performed to obtain the odds-based parameters describing the relationship between the two variables. Results: The variant allele was encountered with a frequency of 0.08 in the SA group and 0.048 in controls. The dominant model analysis of risk revealed the OR 1.957, 95%CI [0.920, 4.162], Fisher’s p = 0.09. Conclusion: The findings suggest possible effects of this polymorphism in SA risk that did not reach the significance level in this study. Future studies might validate or clarify the association between CBS 844ins68 and idiopathic SA

The C677T Variant in the Methylenetetrahydrofolate Reductase Gene and Idiopathic Spontaneous Abortion in a Romanian Population Group

Spontaneous abortions (SA) are a major public health problem and a frequent pregnancy associated disorder. Hereditary thrombophilia and hyperhomocysteinemia are considered to be important factors altering the placental circulation, the in utero development and the evolution of pregnancy. The MTHFR gene (methylenetetrahydrofolate reductase) exhibits an intensely studied polymorphism, C677T, that was repeatedly associated with hyperhomocysteinemia, increased thrombotic risk and was studied in relation with SA susceptibility. This study was aim to assessing the correlation of this polymorphism with idiopathic sporadic or recurrent SA in a Romanian population. In the case-control study, 131 patients with a history of SA and 135 women with no SA and at least one uneventful term delivery were included. The PCR-RFLP technique (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) was used to genotype the cases and controls and the results were analysed using the ?2 test. The present analysis indicates that the MTHFR 677TT homozygous genotype is positively associated with recurrent idiopathic SA (OR 2.493, 95%CI 0.974, 6.379, p-value 0.06). This association was no longer observed in sporadic SA patients (OR 1.214, 95%CI 0.488, 3.017, p-value 0.814). In conclusion, the present study is consistent with previous reports which state that the presence of MTHFR 677T variant in homozygous status could represent a genetic susceptibility factor for recurrent idiopathic SA. Moreover, this is the first attempt to investigate this correlation in a Romanian group and to offer epidemiological support in estimating the frequencies of some common genetic variants in the Romanian population

Novel Mutation in GALT Gene in Galactosemia Patient with Group B Streptococcus Meningitis and Acute Liver Failure

Classic galactosemia is an autosomal recessive disorder caused by the deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) involved in galactose metabolism. Bacterial infections are a known cause of early morbidity and mortality in children with classic galactosemia. The most common agent is Escherichia coli, but in rare situations, other bacteria are incriminated. We report a case of a three-week-old female patient with galactosemia, who presented with Group B Streptococcus (GBS) meningitis/sepsis. She received treatment with antibiotics, supportive therapy, and erythrocyte transfusion, but after a short period of improvement, she presented acute liver failure with suspicion of an inborn error of metabolism. Rapid nuclear magnetic resonance (NMR) spectroscopy from urine showed highly elevated values of galactose and galactitol. Under intensive treatment for acute liver failure and with a lactose-free diet, her clinical features and laboratory parameters improved considerably. Genetic testing confirmed compound heterozygous status for GALT mutations: c.563 A>G [p.Q188R] and c. 910 C>T, the last mutation being a novel mutation in GALT gene. In countries without an extensive newborn screening program, a high index of suspicion is necessary for early diagnosis and treatment of galactosemia

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

Objective Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries. Methods We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine,and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also in-terrogated forDMDgene modifiers. Results We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations. Conclusions Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility