Chromosomal Aberrations Research Articles

B-110 Descriptive Analysis of Multiple Myeloma Participants in the NIH All of Us Research Program Cohort: Insights into Demographics Disparities

Abstract Background Multiple Myeloma (MM) is a complex hematological malignancy characterized by significant heterogeneity in participant characteristics and treatment responses. The All of Us Research Program seeks to enroll 1 million diverse participants who share multiple sources of data, providing unique opportunities for research. A comprehensive descriptive analysis of MM participants within Electronic Health Records (EHR) databases can provide valuable insights into the disease's epidemiology, participant demographics, comorbidities, and treatment outcomes. Objective Using AI/ML predictive analytics, this study conducted a detailed descriptive analysis of MM participants’ EHR data in the All of Us Research Program cohort, which is enrolling 1 million diverse participants who share multiple sources of data. Methods We extracted data for participants diagnosed with MM from an extensive EHR database. The analysis included participant demographics (age, gender, race, ethnicity), diagnostic laboratory tests (SPEP, UPEP, CBC, renal function), comorbidities (renal impairment, bone disease, anemia, cardiovascular diseases), treatment details (chemotherapy, stem cell transplantation), and genetic markers (cytogenetic abnormalities). Results The analysis revealed diverse demographic patterns and a wide range of comorbidities associated with MM (Table 1). Conclusions The analysis demonstrated marked disparities in MM prevalence among African Americans and “More than one race,” revealing social and medical disparities. Implications: By understanding the diverse profiles of MM participants, stakeholders can more effectively address disparities in healthcare outcomes (1). Reference: 1. Zeng, C., Schlueter, D. J., Tran, T. C., Babbar, A., Cassini, T., Bastarache, L. A., & Denny, J. C. (2024). Comparison of phenomic profiles in the All of Us Research Program against the US general population and the UK Biobank. Journal of the American Medical Informatics Association. Retrieved from, https://doi.org/10.1093/jamia/ocad260

Comprehensive analysis of chromosomal breakpoints and candidate genes associated with male infertility: insights from cytogenetic studies and expression analyses.

The study aimed to investigate prevalent chromosomal breakpoints identified in balanced structural chromosomal anomalies and to pinpoint potential candidate genes linked with male infertility. This was acchieved through a comprehensive approach combining RNA-seq and microarray data analysis, enabling precise identification of candidate genes. The Cytogenetics data from 2,500 infertile males referred to Royan Research Institute between 2009 and 2022 were analyzed, with 391 cases meeting the inclusion criteria of balanced chromosomal rearrangement. Of these, 193 cases exhibited normal variations and were excluded from the analysis. By examining the breakpoints, potential candidate genes were suggested. Among the remaining 198 cases, reciprocal translocations were the most frequent anomaly (129 cases), followed by Robertsonian translocations (43 cases), inversions (34 cases), and insertions (3 cases).Some patients had more than one chromosomal abnormality. Chromosomal anomalies were most frequently observed in chromosomes 13 (21.1%), 14 (20.1%), and 1 (16.3%) with 13q12, 14q12, and 1p36.3 being the most prevalent breakpoints, respectively. Chromosome 1 contributed the most to reciprocal translocations (20.2%) and inversions (17.6%), while chromosome 14 was the most involved in the Robertsonian translocations (82.2%). The findings suggested that breakpoints at 1p36.3 and 14q12 might be associated with pregestational infertility, whereas breakpoints at 13q12 could be linked to both gestational and pregestational infertility. Several candidate genes located on common breakpoints were proposed as potentially involved in male infertility. Bioinformatics analyses utilizing three databases were conducted to examine the expression patterns of 78 candidate genes implicated in various causes of infertility.‏ In azoospermic individuals, significant differential expression was observed in 19 genes: 15 were downregulated (TSSK2, SPINK2, TSSK4, CDY1, CFAP70, BPY2, BTG4, FKBP6, PPP2R1B, SPECC1L, CENPJ, ‏SKA3, FGF9, NODAL, CLOCK), while four genes were upregulated ‏(‏HSPB1, MIF, PRF1, ENTPD6). In the case of Asthenozoospermia, seven genes showed significant upregulation (PRF1, DDX21, KIT, SRD5A3, MTCH1, DDX50, NODAL). Though RNA-seq data for Teratozoospermia were unavailable, microarray data revealed differential expression insix genes: three downregulated (BUB1, KLK4, PIWIL2) and three upregulated (AURKC, NPM2, RANBP2). These findings enhance our understanding of the molecular basis of male infertility and could provide valuable insights for future diagnostic and therapeutic strategies.

B-232 One Year Post-Implementation Experience Using a Custom Designed DNA Contamination Detection Module for a Clinical Myeloid Neoplasm Next Generation Sequencing Assay

Abstract Background In complex automated clinical laboratory Next Generation Sequencing (NGS) workflows, numerous opportunities exist for contamination events to occur. For oncology testing applications, detection of these events is crucial for accurate results reporting. A contamination detection module (MICon) using microhaplotype (MH) regions and an in-house designed analysis model was developed for use in a NGS assay for myeloid neoplasms (NGSHM) [1]. Variant detection for NGSHM has a validated analytical sensitivity of 2% variant allele frequency (VAF). Gross contamination events can potentially cause erroneous false positive variant detection whereas true low VAF mutations may be masked and evade detection. The following study was performed to evaluate MICon module performance on samples processed over the course of a year. Methods MH regions contain highly conserved tandem single nucleotide polymorphisms (SNPs) with high global heterogeneity occurring within a 300-nucleotide span. From the work of Kidd et al [2], 27 MH regions covering 92 SNPs and spanning 16 chromosomes were selected for inclusion in the 47 gene NGSHM target-capture panel. Sequencing was performed on a NovaSeq 6000 and analyzed through an internal bioinformatics pipeline, which incorporates the MICon module. MICon uses a binary classification model incorporating VAFs from MH regions, number of MH genotypes, and the contamination estimation score from verifyBamID to compute a single value on a 0-100 scale. Scores <50 are classified as non-contaminated and scores ≥50 require further investigation. Results The dataset was comprised of 10,990 samples. A total of 10,232 patient cases (93.1%) had non-contaminated MICon scores <50. Control replicates accounted for 261 samples (2.4%). There were 497 patient cases (4.5%) with MICon scores ≥50. Of the 497 patient cases, 137 (27.6%) had undergone hematopoietic stem cell transplantation (HSCT) and 114 (22.9%) contained gross chromosomal abnormalities, representing iatrogenic or tumor biological factors. An additional 135 (27.2%) of cases were contaminated from laboratory processing errors, 45 (9.1%) occurred due to chemistry failures during run processing, and 66 (13.2%) had an undetermined cause for a high score, representing laboratory-related and unknown factors. Overall, the 135 laboratory processing errors detected accounted for 1.3% of patient cases analyzed by the laboratory. These cases were repeated, and the non-contaminated results were accurately reported. Conclusions Herein it was shown the implementation of MICon has improved patient safety over the course of a year. The 1.3% of patient cases identified as arising from laboratory processing errors were successfully reprocessed. While the overall rate of laboratory processing errors appears low, the absolute number can be significant in a high-volume test setting, despite reliance on highly automated processes. Value is added by MICon through identifying errors that could result in the release of inaccurate patient results. By detecting previously unrealized errors, MICon has become an invaluable asset to the NGSHM assay by enhancing patient laboratory testing safety.

Chromosomal Abnormalities Detected by Chromosomal Microarray Analysis and Karyotype in Fetuses with Ultrasound Abnormalities.

Chromosomal microarray analysis (CMA) is a first-line test to assess the genetic etiology of fetal ultrasound abnormalities. The aim of this study was to evaluate the effectiveness of CMA in detecting chromosomal abnormalities in fetuses with ultrasound abnormalities, including structural abnormalities and non-structural abnormalities. A retrospective study was conducted on 368 fetuses with abnormal ultrasound who received interventional prenatal diagnosis at Meizhou People's Hospital from October 2022 to December 2023. Samples of villi, amniotic fluid, and umbilical cord blood were collected according to different gestational weeks, and karyotype and CMA analyses were performed. The detection rate of chromosomal abnormalities in different ultrasonic abnormalities was analyzed. There were 368 fetuses with abnormal ultrasound, including 114 (31.0%) with structural abnormalities, 225 (61.1%) with non-structural abnormalities, and 29 (7.9%) with structural combined with non-structural abnormalities. The detection rate of aneuploidy and pathogenic (P)/likely pathogenic (LP) copy number variations (CNVs) of CMA in fetuses with structural abnormalities was 5.26% (6/114), the detection rate of karyotype was 2.63% (3/114), and the additional diagnosis rate of CMA was 2.63%. In the fetuses with ultrasonic non-structural abnormalities, the detection rate of karyotype was 6.22% (14/225), the detection rate of aneuploidy and P/LP CNVs in fetuses with ultrasonic structural abnormalities was 9.33% (21/225), and the additional diagnosis rate of CMA was 3.11%. There was no significant difference in chromosome abnormality detection rate of CMA among structural abnormality, non-structural abnormality, and structural abnormality combined with non-structural abnormality groups (5.3%, 9.3%, and 13.8%, p = 0.241), also among multiple ultrasonic abnormality and single ultrasonic abnormality groups (14.8%, and 7.3%, p = 0.105). CMA can significantly improve the detection rate of genetic abnormalities in prenatal diagnosis of ultrasonic abnormal fetuses compared with karyotype analysis. CMA is a more effective tool than karyotyping alone in detecting chromosomal abnormalities in fetuses with ultrasound abnormalities.

A Nomogram Predicting Testicular Sperm Extraction Success in Men With Non-obstructive Azoospermia: A Multi-center Study

ObjectivesTo develop an efficient and easy-to-use nomogram which can predict testicular sperm extraction(TESE) success in men with non‐obstructive azoospermia(NOA) by using pre-operative parameters. Materials and MetodsData of 3093 men who underwent TESE for NOA were included in this study. Demographic data, testis volumes, presence of varicocele, length of infertility, history of previous surgeries, history of genitourinary infections, smoking status, chromosome abnormalities, presence of Y-chromosome microdeletion, family history of infertility, testis biopsy, surgical data, sperm retrieval rate, final pathology obtained at testicular sperm extraction, follicle stimulating hormone, luteinizing hormone, testosterone levels were recorded. The primary outcome was to develop an efficient nomogram which can predict the TESE success in men with NOA. The secondary outcomes were identifying the significant pre-operative parameters which are associated with success in TESE. ResultsSperm retrieval rate was 50.2%(1553/3093). Testis volume, history of varicocelectomy, chromosome abnormalities, presence of Y-chromosome microdeletion were shown to affect sperm retrieval rate significantly(p<0.05). Sperm retrieval success was higher in men with older age, higher testis volume(>10mL), lower follicle stimulating hormone level(≤ 12.92mIU/mL), lower luteinizing hormone level, and higher testosterone level(p<0.05). Only testis volume and patient’s age were associated with succesful sperm retrieval in multivariate logistic regression analysis. ConclusionIn men with NOA, high testis volume, old age, low follicle stimulating hormone level, low luteinizing hormone level, and high testosterone level are advantageous for successful sperm retrieval in TESE. Herein we present a nomogram which can predict the outcome of TESE in men with NOA with adequate success.

Chromosomal abnormalities in oocyte donor candidates: a French survey of over 8200 karyotypes

To study karyotypes of more than 8,200 oocyte donor candidates in nulliparous or multiparous women compared to a reference population. A retrospective observational multicentric study. The study included two cohorts of oocyte donor candidates recruited between January 2005 and October 2021: multiparous women with at least one child at the time of recruitment, and nulliparous women. Both were compared to a reference population composed of female newborns from literature. Not applicable. Blood lymphocyte karyotype. A total of 8229 oocyte donor candidates from 22 fertility centers were included in this study. Nulliparous women (n=1890) and multiparous ones (n=6339) were compared to 8102 female newborns. Overall, 65 candidates were carriers of chromosomal abnormalities and were therefore excluded from the donation process (0.79%, 95% CI: 0.60-0.98). The occurrence of balanced structural chromosomal rearrangements was globally increased in the study population (0.49%, 95% CI: 0.34-0.64) compared to female newborns (0.24%, 95% CI: 0.34-0.64, p=0.0086). The number of reciprocal translocations was increased 5-fold in nulliparous oocyte donor candidates (0.37%, 95% CI: 0.10-0.64, p=0.013). The incidence of sex chromosome mosaicism was notably increased in multiparous oocyte donor candidates, with 17 cases (0.27%, 95% CI: 0.14-0.40, p=0.0052). Among chromosomal aberration carriers only two nulliparous women (one reciprocal translocation and one sex chromosome mosaicism) had fertility issues with a diagnosis of premature ovarian failure. In this comprehensive 16-years French experience of karyotyping in oocyte donor candidates, we confirmed an increased incidence of balanced structural chromosomal rearrangements, especially among those without children at the time of recruitment. Karyotyping could be considered to identify any chromosomal abnormalities that may not be easily detectable through medical questioning. These abnormalities pose an inherent genetic risk for gamete recipients if left undetected.

Characteristics of Acute Myeloid Leukemia Patients with TP53 Alterations

Abstract Background TP53 is the most intensively studied gene in cancer. The vast majority of de novo AML patients have unaltered TP53 alleles; data from The Cancer Gene Atlas including adult patients with AML documented that ∼ 8% of cases harbor TP53 alterations. Objectives The objective of this study is to identify the features of TP53 alterations in acute myeloid leukemia (AML) patients, investigate its association with clinical findings, standard laboratory tests, morphological, cytogenetic and molecular profiles, and assess its influence on the overall outcome of patients on day 28 after induction therapy. Subjects and Methods The present study is an analytical observational study that was conducted on 60 de novo adult AML patients who presented to the Hematology/Oncology unit of Ain Shams University Hospitals. All patients’ samples were analyzed for TP53 deletion using LSI 17p13 FISH probe for detection of p53 deletion and they were further subjected to testing for TP53 Pro72Arg alterations by real time polymerase chain reaction. All patients were subjected to therapy and then followed up at day 28 to asses the outcome. Results Male gender and lower TLC were significantly associated with good outcome with (P-value ≤ 0.05). Patients with cytogenetic structural abnormalities showing 17q rearrangement showed significant association with bad outcome with (P-value ≤ 0.05) and t(8;21) was found to be highly significant in association with good outcome with (P-value&amp;lt; 0.01). FLT3ITD mutation was found to be highly significant in association with bad outcome with (P-value&amp;lt; 0.01). NPM mutation was significant in association with good outcome with (P-value ≤ 0.05). TP53 mutation was detected in 11.7 % of studied patients where 8.3% out of them were heterozygous mutation and 3.4% were homozygous. P53 mutation wassignificantly associated with advanced age, male gender and higher TLC with (P- value ≤ 0.05). Cytogenetic structural abnormalities including 11q23 rearrangement showed significant association with P53 mutation with (P-value ≤ 0.05) and t(8;21)+del 17p, del 17p&amp; -7 and del 17p only was found to be highly significant in association with p53 mutation with (P-value&amp;lt; 0.01). Normal karyotyping showed negative relation with P53 mutation with (P-value ≤ 0.05) where all patients who yielded normal karyotyping (35%) were negative for P53 alterations; that doesn't necessarily denote causation, but it's an observable pattern, and del 17p that was found to be highly significant in association with p53 mutation with (P-value&amp;lt; 0.01). P53 mutation was found to be highly significant in association with bad outcome with (P-value &amp;lt; 0.01). Unfavorable and Favorable risk stratification of ELN 2022 were found to be highly significant in association with p53 mutation with (P-value&amp;lt; 0.01). ELN 2022 risk stratification categories were found to be highly significant in association with patients’ outcomes with (P- value &amp;lt; 0.01). Conclusion TP53 alterations strongly identify high-risk AML patients with poor outcome in this study yet, this needs further investigation on larger sample size with longer follow up. Investigations of TP53 mutation especially in Adult AML may help with the selection of patients in need of intensive therapeutic strategy or may help with designation of new innovative targeted therapies. Key words Tp53, Mutation, Adult Acute Myeloid Leukemia.

Dimethyl Sulfoxide Attenuates Ionizing Radiation-induced Centrosome Overduplication and Multipolar Cell Division in Human Induced Pluripotent Stem Cells.

Centrosomes are important organelles for cell division and genome stability. Ionizing radiation exposure efficiently induces centrosome overduplication via the disconnection of the cell and centrosome duplication cycles. Over duplicated centrosomes cause mitotic catastrophe or chromosome aberrations, leading to cell death or tumorigenesis. Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), can differentiate into all organs. To maintain pluripotency, PSCs show specific cellular dynamics, such as a short G1 phase and silenced cell-cycle checkpoints for high cellular proliferation. However, how exogenous DNA damage affects cell cycle-dependent centrosome number regulation in PSCs remains unknown. This study used human iPSCs (hiPSCs) derived from primary skin fibroblasts as a PSC model to address this question. hiPSCs derived from somatic cells could be a useful tool for addressing the radiation response in cell lineage differentiation. After radiation exposure, the hiPSCs showed a higher frequency of centrosome overduplication and multipolar cell division than the differentiated cells. To suppress the indirect effect of radiation exposure, we used the radical scavenger dimethyl sulfoxide (DMSO). Combined treatment with radiation and DMSO efficiently suppressed DNA damage and centrosome overduplication in hiPSCs. Our results will contribute to the understanding of the dynamics of stem cells and the assessment of the risk of genome instability for regenerative medicine.

Predictors of Local Control With Palliative Radiotherapy for Multiple Myeloma

IntroductionWe performed a retrospective analysis of patients with multiple myeloma (MM) receiving palliative radiotherapy (RT) and assessed factors associated with local control, with a focus on dose/fractionation and cytogenetics. Materials and MethodsWe included patients who received palliative RT for MM at our institution. Cytogenetics were collected via fluorescence in situ hybridization. Follow-up imaging was used to assess local control. ResultsA total of 239 patients with 362 treated lesions were included. Eighty-six (36.0%) patients had high-risk cytogenetics. Most lesions received 20 Gray (Gy) in 5 fractions (131, 36.2%), 8 Gy in 1 fraction (93, 25.7%), or 30 Gy in 10 fractions (48, 13.3%). At a median follow-up of 4.3 years, 4-year local progression was 13.4% (95% confidence interval [CI]: 10.3-17.5). No cytogenetic abnormalities were correlated with local progression, nor were double- and triple-hit status. There was a nonsignificant trend toward association between number of treated lesions and local progression (HR for >3 vs. 1: 2.43 [95% CI: 0.88-6.74], P = .059). Among patients with >3 treated lesions, equivalent dose in 2 Gy fractions ≥20 Gy reduced progression (HR: 0.05 [95% CI: 0.01-0.23], P = .0001). ConclusionIn this large study of patients with MM, modern palliative RT achieved excellent rates of long-term local control. Although there was no dose-response observed in the overall cohort, patients with high volume symptomatic disease may benefit from EQD2 ≥20 Gy. High-risk cytogenetics did not appear to influence radioresponsiveness, and standard radiation doses appear to be effective for all MM patients regardless of cytogenetics.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Firsttrimester Diagnosis and Therapy @11 - 13 +6 Weeks of Gestation - Part 2 : Guideline of the DEGUM, ÖGUM, SGUMGG, DGGG, ÖGG, Gynecologie Suisse, DGPM, DGPGM, BVF, ACHSE (AWMF S2e LL 085-002 1.1.2024) (https://register.awmf.org/de/leitlinien/detail/085-002).

This extensive AWMF 085-002 S2e-guideline "First Trimester Diagnosis and Therapy @11 - 13 +6 Weeks of Gestation" has systematically analyzed high-quality studies and publications and the existing evidence (evidence tables) and produced recommendations (level of recommendation, level of evidence, strength of consensus). This guideline deals with the following topics in the context of the 11 - 13 +6 weeks scan: the legal basis, screening for anatomical malformations, screening for chromosomal defects, quality assessment and audit, screening for preeclampsia and FGR, screening for preterm birth, screening for abnormally invasive placenta (AIP) and placenta accreta spectrum (PAS), screening for velamentous cord insertion and vasa praevia, screening for diabetes mellitus and LGA. Screening for complications of pregnancy can best be carried out @11 - 13 +6 weeks of gestation. The issues of how to identify malformations, chromosomal abnormalities and certain disorders of placentation (high blood pressure and proteinuria, intrauterine growth retardation) have been solved. The problem of how to identify placenta percreta and vasa previa has been partially solved. What is still unsolved is how to identify disorders of glucose metabolism and preterm birth. In the first trimester, solutions to some of these problems are available: parents can be given extensive counselling and the risk that a pregnancy complication will manifest at a later stage can be delayed and reduced. This means that screening is critically important as it helps in decision-making about the best way to manage pregnancy complications (prevention and intervals between follow-up examinations). If no treatment is available and if a termination of pregnancy is considered, the intervention can be carried out with far lower complications compared to the second trimester of pregnancy. In most cases, further examinations are not required and the parents can be reassured. A repeat examination at around week 20 of gestation to complete the screening for malformations is recommended. Note: The guideline will be published simultaneously in the official journals of both professional societies (i.e. Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM and Geburtshilfe und Frauenheilkunde for the DGGG).

Firsttrimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation - Part 1.

This extensive AWMF 085-002 S2e-guideline "First Trimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation" has systematically analyzed high-quality studies and publications and the existing evidence (evidence tables) and produced recommendations (level of recommendation, level of evidence, strength of consensus).This guideline deals with the following topics in the context of the 11-13+6 weeks scan: the legal basis, screening for anatomical malformations, screening for chromosomal defects, quality assessment and audit, screening for preeclampsia and FGR, screening for preterm birth, screening for abnormally invasive placenta (AIP) and placenta accreta spectrum (PAS), screening for velamentous cord insertion and vasa praevia, screening for diabetes mellitus and LGA.Screening for complications of pregnancy can best be carried out @ 11-13+6 weeks of gestation. The issues of how to identify malformations, chromosomal abnormalities and certain disorders of placentation (high blood pressure and proteinuria, intrauterine growth retardation) have been solved. The problem of how to identify placenta percreta and vasa previa has been partially solved. What is still unsolved is how to identify disorders of glucose metabolism and preterm birth.In the first trimester, solutions to some of these problems are available: parents can be given extensive counselling and the risk that a pregnancy complication will manifest at a later stage can be delayed and reduced. This means that screening is critically important as it helps in decision-making about the best way to manage pregnancy complications (prevention and intervals between follow-up examinations).If no treatment is available and if a termination of pregnancy is considered, the intervention can be carried out with far lower complications compared to the second trimester of pregnancy. In most cases, further examinations are not required and the parents can be reassured. A repeat examination at around week 20 of gestation to complete the screening for malformations is recommended. NOTE:: The guideline will be published simultaneously in the official journals of both professional societies (i.e. Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM and Geburtshilfe und Frauenheilkunde for the DGGG).

Consanguinity and Occurrence of Monogenic Diseases in a Single Tertiary Centre in Riyadh, Saudi Arabia: A 2 Years Cross-Sectional Study.

Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population. Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022. The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%). In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.

Unexplained Recurrent Pregnancy Loss: Clinical Application of Immunophenotyping.

Recurrent pregnancy loss (RPL) is defined as the failure of two or more pregnancies and affects approximately 5% of couples, often without a clear cause. The etiologies of RPL include factors such as maternal age, endocrine dysfunction, uterine abnormalities, chromosomal abnormalities, thrombophilias, infections, and autoimmune disorders. However, these conditions account for only 50%-60% of RPL cases. Research has explored whether an altered immune system, compared to the physiological state, may be linked to RPL. This review aims to determine whether specific immunophenotypes are associated with unexplained Recurrent Pregnancy Loss (uRPL) and whether targeted therapies addressing specific immunophenotypic alterations can improve pregnancy outcomes. A literature review was conducted using Pubmed/Medline, Scopus, and Embase databases, analyzing data from 95 articles published between 2001 and 2023. The roles of various cells of the immune system (B lymphocytes, T lymphocytes, natural killer cells, macrophages) in different tissues (peripheral blood, menstrual blood) were specifically investigated in women with uRPL. Specific immunophenotypes have been demonstrated to be associated with this condition. However, there is a need to standardize immunophenotyping assays and conduct more trials to stratify RPL risk and improve potential therapeutic strategies.

Firsttrimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation- Part 2.

This extensive AWMF 085-002 S2e-guideline "First Trimester Diagnosis and Therapy @ 11-13+6 Weeks of Gestation" has systematically analyzed high-quality studies and publications and the existing evidence (evidence tables) and produced recommendations (level of recommendation, level of evidence, strength of consensus).This guideline deals with the following topics in the context of the 11-13+6 weeks scan: the legal basis, screening for anatomical malformations, screening for chromosomal defects, quality assessment and audit, screening for preeclampsia and FGR, screening for preterm birth, screening for abnormally invasive placenta (AIP) and placenta accreta spectrum (PAS), screening for velamentous cord insertion and vasa praevia, screening for diabetes mellitus and LGA.Screening for complications of pregnancy can best be carried out @ 11-13+6 weeks of gestation. The issues of how to identify malformations, chromosomal abnormalities and certain disorders of placentation (high blood pressure and proteinuria, intrauterine growth retardation) have been solved. The problem of how to identify placenta percreta and vasa previa has been partially solved. What is still unsolved is how to identify disorders of glucose metabolism and preterm birth.In the first trimester, solutions to some of these problems are available: parents can be given extensive counselling and the risk that a pregnancy complication will manifest at a later stage can be delayed and reduced. This means that screening is critically important as it helps in decision-making about the best way to manage pregnancy complications (prevention and intervals between follow-up examinations).If no treatment is available and if a termination of pregnancy is considered, the intervention can be carried out with far lower complications compared to the second trimester of pregnancy. In most cases, further examinations are not required and the parents can be reassured. A repeat examination at around week 20 of gestation to complete the screening for malformations is recommended. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i.e. Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM and Geburtshilfe und Frauenheilkunde for the DGGG).

Griscelli syndrome: a diagnostic challenge of a rare disease: a case report

Introduction: Griscelli syndrome (GS) is a rare autosomal recessive genetic disorder that primarily manifests as hair and skin hypopigmentation, with three types differentiated by their specific genetic defects as well as by their clinical features. Clinically, GS type 1 is characterized by early neurological alterations, while GS type 2 is characterized by immunodeficiency and could present with neurological symptoms, and type 3 is characterized by a chromosomal anomaly without a specific clinical profile besides hypopigmentation. This article details the challenges faced in the diagnosis of a patient with GS who presents with neurological symptoms followed by immunological deficits. Case presentation: A 7-month-old female presented with complaints of developmental delay following an otitis media infection. Upon examination, she exhibited signs of psychomotor developmental regression and had pale bronze skin and silvery-gray hair, as well as hepatosplenomegaly. The examination of her hair shaft revealed a pattern consistent with GS. During her hospitalization, the patient developed an intermittent fever and signs of hemophagocytic lymphohistiocytosis (HLH). She subsequently developed recurrent seizures treated with phenytoin and Aciclovir. Shortly she succumbed to respiratory distress syndrome and multisystem failure. Discussion: The presence of HLH confirms the type of GS. However, in some cases, the HLH criteria could not be fulfilled, presenting a diagnostic challenge. Conclusion: The genetic examination is the only way to differentiate GS type 1 from type 2. However, when it is not available, the presence of specific symptoms and features may assist in the classification. Furthermore, treatments should be administered when GS type 2 is suspected since they have the potential to improve life quality through treating HLH, delaying and altering the neurological symptoms.

Study of Estrogen Receptor Gene Thymine-Adenine Repeat Polymorphisms in Low Birth Weight and Premature Infants with Bone Disease

Abstract Introduction Metabolic Bone disease (MBD) of prematurity is a disorder of bone health with hypocalcemia, hypo or hyperphosphatemia and radiological findings of bone demineralization. MBD often presents in newborns &amp;lt;28wks of gestation in 16-40% of VLBW and ELBW (Rustico et al., 2014). Several pathophysiological conditions have been suggested as factors behind MBD including inadequate supply of calcium and phosphorus. as well as side effects of some drugs as corticosteroids (Lothe et al., 2011 &amp; Sharma and Sohi, 2012). Genetic predisposition to low bone mass content (BMC) in premature infants have been studied lately (Saraff et al., 2021). Estrogen Receptor (ER), a group of nuclear receptor superfamily members has been recently implicated in the development of osteoporosis suggesting the use of its gene as a possible candidate gene for bone mineral density (BMD) (Gennari et al. 2005). The targeted deletion of ER in mice has affected the periosteum (Clancy et al., 2017). Having several polymorphic sites for ER, the low number of Thymine adenine repeats (Ho-L) was found to relate with increased fracture risk or BMD in certain populations (Rooney et al., 2017). Aim of the Work Studying the relation between allelic polymorphism of Thymine Adenine repeats variant of ER gene and metabolic bone disease in low birth weight and premature infants. Patients and Methods A case-controlled study conducted at NICU Ain Shams University Hospitals starting from February 2022 till February 2023. Inclusion criteria: Cases (25): VLBW premature infants with bone disease evidenced by laboratory data (low calcium, low phosphorous and high alkaine phosphatase. (Hung et al., 2011) serving as group 1. Controls (25): VLBW premature infants without bone disease evidenced by normal laboratory data, serving as group 2. Exclusion criteria: Full term infants, or premature infants with syndromic features suggesting genetic diseases or chromosomal anomalies. Parents of patients signed an informed consent before being enrolled to this study and after approval of Ethical committee Ain Shams University. All patients and controls were subjected to the following: Full history taking and examination with special emphasis on length, weight and their SDS, gestational age. Laboratory sample for measurement of ALP, Calcium, phosphorous. Genomic DNA was extracted then amplified by PCR to study TA repeats of ER using gene jet purification mini kit (Kany et al., 2019). Results Group 1 had a percent of females and males of 58 and 48% respectively. their birth weight SD ranged from -6.8 to -3.86 while length SD ranged from -2.8 to -3.6. According to laboratory parameters; there was statistically significant decrease in the level of Ca (8.41 ± 0.86) and Phosphorus (1.96 ± 0.43)and increase in alkaline phosphatase (935.60 ± 50.83) among group 1 compared to group 2. Genotyping of TA repeats of ER, Ho-L(homo with low T-A repeated sequences &amp;lt;19), He-LH(hetero with low and high T-A repeated sequences &amp;lt;19 and&amp;gt;18) were statistically significantly higher in Group 1, while Ho-H(homo with high T-A repeated sequences &amp;gt;18) was significantly higher among group 2. There was a statistically significant increase of Ho-L in males more than females. Also gestational age, birth weight and birth length were less in Ho-L group. Percentage of infants on mechanical ventilation was higher among those with Ho-L group. Conclusion This study concluded that premature infants with less TA repeats of ER gene showed higher incidence of MBD, suggesting the possible link between TA repeats of ER gene with the development of MBD.

Recent progress in AML with recurrent genetic abnormalities.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by various molecular abnormalities that significantly impact its pathogenesis and prognosis. Currently, the prognosis of AML patients is stratified on the basis of co-existing chromosomal and genetic abnormalities. AML patients with NPM1 or CEBPA mutations, which are frequently identified in cytogenetically normal AML, are classified in the favorable-risk group, although approximately 40% of patients relapse. Similarly, a clinical high-risk group has been identified among patients with acute promyelocytic leukemia, but the underlying molecular abnormalities remain unclear. FLT3 mutations frequently overlap in these favorable-risk AMLs, including core binding factor AML, and their prognostic impact is still controversial. As such, further risk stratification and treatment optimization based on various molecular abnormalities are warranted to improve the prognosis of favorable-risk AMLs. These molecular abnormalities are also considered therapeutic targets, and targeted therapies have been developed over the years. In recent years, several targeted agents have been approved and demonstrated to improve the prognosis of AML. However, resistance to targeted therapies is also a challenge. This Progress in Hematology features current trends and challenges in favorable-risk AML and FLT3 mutations that are frequently identified in these patients.

Feasibility of preimplantation genetic testing for aneuploidy on frozen-thawed embryos following conventional IVF insemination.

Intracytoplasmic sperm injection (ICSI) is commonly employed in preimplantation genetic testing (PGT) to minimize the risk of foreign sperm DNA contamination. Cryopreserved embryos from patients with recurrent miscarriage or repeated implantation failure, who have undergone conventional in vitro fertilization (IVF), can be thawed and biopsied for PGT. Therefore, we aimed to assess the accuracy and effectiveness of preimplantation genetic testing for aneuploidy (PGT-A) on frozen embryos using conventional IVF (c-IVF) insemination methods. From January 2021 to November 2023, our center conducted 107 thawed cryopreserved embryo biopsy cycles to screen for PGT-A. Among them, 58 cycles used c-IVF insemination, and 49 used ICSI insemination. Basic patient clinical information, laboratory data, PGT test results, and clinical outcome data were collected. To minimize the confounding effects of patient characteristics and embryo quality on PGT-A outcomes, clinical outcomes, and contamination assessment, these variables were included in the analysis. We then evaluated the blastocyst euploidy rate, clinical outcomes, and accuracy of PGT-A results between the two groups and analyzed potential contamination in the c-IVF insemination group. A total of 320 blastocysts underwent PGT-A testing, with 179 blastocysts from c-IVF insemination and 141 from ICSI insemination. Considering participants' baseline characteristics and embryological outcomes, no significant differences were found between the two groups regarding infertility type, average age, body mass index, percentage of PGT-A indications, or quality of embryonic development. Regarding PGT-A results, all 320 biopsy samples were successfully analyzed, showing no statistical variance in chromosomal euploidy, abnormality, or mosaicism rates between the two insemination methods. No parental contamination was detected in the c-IVF insemination group. When assessing clinical outcomes, parameters such as biochemical pregnancy, clinical pregnancy, and miscarriage rates did not exhibit significant discrepancies between the two groups, and no misdiagnoses were reported during the study period. Embryo transfer and PGT-A results are not affected by potential parental contamination in frozen-thawed embryos conceived via c-IVF. PGT-A guided embryo transfer in thawed embryos conceived by c-IVF is a viable and clinically effective approach.

Prevalence of Congenital Anomalies in Iran.

Annually, 3-8 million infants are born with congenital anomalies worldwide, ranging from 3% to 7% of births in different countries. This study aimed to investigate the nationwide epidemiological features of birth defects in Iran. This cross-sectional study was conducted in six major regions across Iran. The data sources were the maternity facilities affiliated with regional universities of medical sciences. All children were examined by obstetricians, pediatricians, or midwives at birth, and newborns were followed until discharge from the facility for health status, maturity, and congenital defects. A total of 138,643 births were registered in the maternity facilities across the study regions. Among these newborns, 3,458 cases were diagnosed with congenital anomalies, representing an overall prevalence rate of 249.4 per 10000 births (95% CI: 241.2-257.8). Genital organ anomalies exhibited the highest rates of defects in the country with 92.7 per 10000 births (95% CI: 86.4-98.9), followed by limb anomalies at 83.3 per 10000 births (95% CI: 77.4-89.3). The prevalence of respiratory system, chromosomal, and urinary tract anomalies was less than 10 per 10000 births. Until a national registry for congenital anomalies is established, this study provides essential data on the magnitude of the health problems caused by congenital anomalies in Iran. The findings would be vital for planning and evaluating antenatal screening for birth defects, particularly for high-risk groups and regions in the country.