Chromosomal Abnormalities In Patients Research Articles

Primary amenorrhoea - cytogenetic study in 40 Indian women

Background Primary amenorrhoea (PA) refers to an ailment when adolescent girls do not attain menarche naturally. It is one of the most common gynaecological disorders specified. Chromosomal abnormalities play a pivotal role in PA. Cytogenetic analysis is an indispensable diagnostic tool to determine the abnormality of the chromosome. In an emerging country like India, cytogenetic analysis is at a nascent stage. There are very few studies on Cytogenetics present in eastern India, including West Bengal. In rural and suburban areas PA sufferers often experience late diagnosis and struggle to access suitable curative management. The aim of the study is to evaluate the various types of chromosomal abnormalities in patients suffering from PA for accurate, better management of the same and further counselling. Methods A total of 40 PA cases were referred by obstetricians and gynaecologists to the Department of Genetics of Nirnayan Health Care, Kolkata. To screen the chromosomal abnormalities, human leukocyte culture was accomplished with their peripheral venous blood followed by G-banding and then karyotyping was executed according to ISCN-2020. Result Out of 40 patients, 29 were normal among which 46,XX was found in 70% cases (n = 28) and 46,XX,9qh + in 2.5% (n = 1). The remaining 11 showed different types of abnormalities. 45,X was found in 10% (n = 4), 46,X,i(X)(q10) in 2.5% (n = 1), 46,X,del(X)(p11.2) in 2.5% (n = 1), 46,X,del(X)(p22.1) in 2.5% (n = 1), 46,X,del(X)(q24) in 2.5% (n = 1), 46,XY in 2.5% (n = 1), mos 45,X[22]/46,Xi(X)(q.10)[8] in 2.5% (n = 1) and mos 45,X[16]/46,XY[14] (2.5%) in 2.5% (n = 1). Conclusion This study indicates the importance of chromosomal study which must be included in early diagnosis of PA. Karyotyping at the appropriate phase of life will not only help in the judicial management of this disorder but will also give young girls a better lifestyle.

Prevalence and patterns of chromosomal abnormalities in patients suspected of genetic disorders: insights from a study in Ouagadougou, Burkina Faso.

Chromosomal abnormalities contribute significantly to human morbidity and mortality, leading to various pathologies. This study aimed to assess the prevalence of chromosomal abnormalities among patients suspected of genetic disorders in Ouagadougou, Burkina Faso. A descriptive cross-sectional study was conducted from January 1, 2018, to July 16, 2021, involving patients from different university hospitals in Ouagadougou. Blood samples were collected at Hôpital Saint Camille de Ouagadougou (HOSCO) and sent to the Cerba laboratory in France for cytogenetic analysis. A total of 61 cases with suspected genetic disorders were referred for cytogenetic examination. The average age of the patients was 26.81 years ± 18.92, ranging from 1 month to 68 years. Among the cases, 37 (60.65%) exhibited chromosomal abnormalities. Structural abnormalities were the most prevalent (78.38%), while number anomalies accounted for 21.62% of the cases. Chronic myeloid leukemia was detected in 59.45% of cases, followed by free and homogeneous trisomy 21 (18.91%) and sexual inversion (8.10%). Additionally, one case each of Turner syndrome and Klinefelter syndrome were identified. This this study revealed a high frequency of chromosomal abnormalities, with a predominance of structural abnormalities, among patients suspected of genetic disorders in Ouagadougou. The findings emphasize the significance of genetic evaluation and counseling services in the region, particularly for autosomal abnormalities.

The prenatal diagnosis and prognosis of fetal right aortic arch and double aortic arch malformation: A single-center study.

This study aimed to characterize the pathological types, diagnosis, chromosomal abnormalities, and postnatal clinical manifestations of right and double aortic arch malformations in fetuses. In this retrospective study, all fetuses diagnosed with right or double aortic arch anomalies for whom conventional two-dimensional echocardiography combined with spatio-temporal image correlation was performed at our tertiary referral center between December 2012 and December 2021 were included. In total, 234 fetuses with aortic arch abnormalities were identified. Forty-one cases lost to follow-up. One hundred ninety-three cases were included in this study. One hundred eighty-seven cases with right aortic arch. Six cases with double aortic arch. Most cases of right aortic arch with aberrant left subclavian artery (77/101, 76.2%) were isolated lesions, whereas most of those with mirror-image branching (45/75, 60%) were associated with intracardiac or extracardiac anomalies. Chromosomal abnormalities were screened prenatally in 113 fetuses with right aortic arch, among whom three with aberrant left subclavian artery (3/63, 4.8%) and eight with mirror-image branching (8/50, 16%) had chromosome anomalies (p < 0.05). Furthermore, three cases had microdeletion 22q11.2 and these were significantly associated with intracardiac malformations. Most cases of isolated right aortic arch do not present with clinical symptoms except isolated left subclavian artery and isolated left brachiocephalic trunk. In addition, the risk of chromosomal abnormalities in patients with isolated right aortic arch is very low. We recommend that pregnant women should be informed of the risks and benefits of undergoing invasive prenatal chromosomal detection.

The Precise Breakpoint Mapping in Paracentric Inversion 10q22.2q23.3 by Comprehensive Cytogenomic Analysis, Multicolor Banding, and Single-Copy Chromosome Sequencing.

Detection and precise genomic mapping of balanced chromosomal abnormalities in patients with impaired fertility or a clinical phenotype represent a challenge for current cytogenomics owing to difficulties with precise breakpoint localization in the regions enriched for DNA repeats and high genomic variation in such regions. Here, we present a comprehensive cytogenomic approach to breakpoint mapping in a rare paracentric inversion on 10q (in a patient with oligoasthenoteratozoospermia and necrozoospermia) that does not affect other phenotype traits. Multicolor banding, chromosomal microarray analysis, chromosome microdissection with reverse painting, and single-copy sequencing of the rearranged chromosome were performed to determine the length and position of the inverted region as well as to rule out a genetic imbalance at the breakpoints. As a result, a paracentric 19.251 Mbp inversion at 10q22.2q23.3 was described. The most probable location of the breakpoints was predicted using the hg38 assembly. The problems of genetic counseling associated with enrichment for repeats and high DNA variability of usual breakpoint regions were discussed. Possible approaches for cytogenomic assessment of couples with balanced chromosome rearrangements and problems like reproductive failures were considered and suggested as useful part of effective genetic counseling.

Chromosome Aberration on Growth and Developmental Disorder

Growth and development in humans begin at conception, which shows progress and interdependence. Normal children show the characteristic of growth and development. In children with growth and development disorder, chromosomal abnormality may be found. This study aimed to determine chromosomal abnormality in patients with growth and development disorder. The samples were taken from karyotype results of patients in the Medical Genetics Laboratory, Faculty of Medicine, Universitas Wijaya Kusuma Surabaya, from 2010-2020. The inclusion criteria were infants to adolescents aged 24 years and unmarried who experienced impaired growth and development, including sexual development. Chromosomal abnormalities were obtained from cytogenetic analysis using the G-banding method. From 75 samples with growth and development disorders, there were abnormalities in the number of autosomal chromosomes and sex chromosomes found in patients with Down syndrome, Turner syndrome, Klinefelter syndrome, and Edwards syndrome. Chromosomal structural abnormalities found were deletion, translocation, inversion, duplication, marker chromosome, and heteromorphism. This study showed the importance of karyotyping in children and adolescents with growth and developmental disorders.

Investigation of the Frequency and Type of Chromosomal Abnormalities in Women Patients with Amenorrhea.

Amenorrhea is defined as the absence of menstruation at the reproductive age of women. Amenorrhea caused by various etiological factors including genetic factors, intrauterine malformations, endocrine dysfunction, and environmental factors. Genetic factors particularly chromosomal abnormalities are the main cause of Amenorrhea. This study was performed to estimate the frequency and types of chromosomal abnormalities in patients with amenorrhea in the northeast of Iran. A total of 381 women with the history of amenorrhea participated in this study. Peripheral blood lymphocyte cultures were performed according to the standard GTG banding method. 296 (77%) of a total of all cases had a normal karyotype (46, XX) while 85 patients (23%) had abnormal karyotype. The numerical and structural abnormalities of X chromosome were observed in 52 (61%), the abnormalities of Y chromosome were observed in 23 (27.2%) and rearrangements between autosomal and/or sex chromosomes were observed in 10 (11.8%). The present study revealed that cytogenetic study is essential for early diagnosis and treatments of Amenorrhea.

CLINICAL AND CYTOGENETICS ANALYSIS OF WOMEN THAT WERE SUSPECTED FOR TURNER SYNDROME IDENTIFIED AS 19.8% CHROMOSOMAL ABNORMALITY IN NORTH INDIAN POPULATION

Purpose: The objective of present study was to know the contribution of different types chromosomal anomalies in manifestation of Turner syndrome. Turner syndrome is a chromosomal disorder mainly due to growth retardation and primary amenorrhoea. Cytogenetic analysis of cases referred for Turner syndrome is necessary for an early diagnosis which helps in genetic counselling to manage it in a better way. Total 23 Methods: 7 cases suspected for Turner syndrome, were included in this study for duration of 7 years (2007-2014). We implemented the standard protocol for peripheral whole blood lymphocyte culture, chromosome preparation followed by G-banding. Chromosomes were analysed according to the guidelines of International System for Human Cytogenetic Nomenclature (2005). Afte Results: r analysing 237 registered cases, chromosomal anomalies were seen only in 47 cases (19.8%). Careful clinical examination of patients with abnormal karyotype (n=47) revealed four major phenotypes i.e. growth retardation (n=19, 40.4%), primary amenorrhoea (n=19, 40.4%), primary amenorrhoea with growth retardation (n=6, 12.8%), and oligoamenorrhoea (n=3, 6.4%). Seven different types of chromosomal abnormalities were observed viz. Monosomy X (n=22, 46.8%), triple X syndrome (n=2, 4.2%), turner mosaic (n=3, 6.4%), ring chromosome (n=5, 10.6%), structural abnormalities with X chromosome (n=6, 12.8%), mosaic structural X abnormality (n=1, 2.1%), XY gonadal dysgenesis (n=8, 17%). This st Conclusion: udy revealed the frequency of most common clinical phenotype and different chromosomal abnormalities in patients suspected for turner syndrome. We observed growth retardation and primary amenorrhoea as most common clinical feature and monosomy of X chromosome as most frequent chromosomal abnormality in this cohort of study.

Chromosomal abnormalities related to fever of unknown origin in a Chinese pediatric cohort and literature review

BackgroundFever of unknown origin (FUO) has been difficult to diagnose in pediatric clinical practice. With the gradual change in the disease spectrum, genetic factors have received increasing attention. Limited studies have shown an association between FUO and chromosomal abnormalities. In this study, we investigated the clinical and genetic characteristics of patients with FUO presenting with chromosomal abnormalities in a Chinese pediatric cohort.ResultsChromosomal abnormalities were detected in 5.5% (8/145) of the patients with FUO. Six patients with inflammatory fever presented with pharyngitis/amygdalitis (4/6), oral aphthous ulcer (2/6), digestive symptoms (3/6), developmental delay (4/6) and elevated C-reactive protein levels (6/6) during fever. These patients were often considered to have systemic inflammatory diseases, such as Behcet’s disease or systemic juvenile idiopathic arthritis. Trisomy 8, 7q11.23 dup, 3p26.3-p26.1 del/17q12 dup, 22q11.21 del, and 6q23.3-q24.1 del were identified in patients with inflammatory fever. The TNFAIP3 gene was included in the 6q23.3-q24.1 deletion fragment. Two patients with central fever were characterized by facial anomalies, developmental delay, seizures and no response to antipyretic drugs and were identified as carrying the de novo 18q22.3-q23 del. By performing a literature review, an additional 19 patients who had FUO and chromosomal abnormalities were identified. Trisomy 8, 6q23.2-q24.3 del and 18q22.3-q23 del were reported to present as fever, similar to the findings of our study.ConclusionsWe emphasized the important role of detecting chromosomal abnormalities in patients with FUO, especially in patients with systemic inflammatory manifestations or developmental delay. Identifying chromosomal abnormalities may change the diagnosis and management of patients with FUO.

Evaluation of Associated Structural and Chromosomal Abnormalities in Patients with Fetal Cerebral Ventriculomegaly Detected in Ultrasonographic Imaging

OBJECTIVE: Fetal cerebral ventriculomegaly is defined as enlarged cerebral lateral ventricles. The etiology of fetal cerebral ventriculomegaly is multifactorial. Aneuploidy in ventriculomegaly is detected especially in moderate and severe ventriculomegaly accompanied by structural anomalies. This study aims to evaluate patients with fetal cerebral ventriculomegaly for associated structural and genetic abnormalities and their obstetric and neonatal outcomes. STUDY DESIGN: This retrospective cohort study was conducted at Dokuz Eylul University Faculty of Medicine, Obstetrics and Gynecology Department between January 2009 and December 2019. Eighty-seven cases were included in the study and were evaluated for associated structural abnormalities. The results of genetic diagnostic tests were evaluated retrospectively. Postpartum information of the cases was obtained from the hospital records and neurodevelopmental development of the newborns was recorded. RESULTS: Patients were classified as mild, moderate, and severe ventriculomegaly. Concomitant structural abnormalities were observed in 64% of the patients. Corpus callosum agenesis was the most common abnormality. The incidence of accompanying anomalies in severe ventriculomegaly was found to be significantly higher. Invasive prenatal tests were performed on 27 patients and one of them had a chromosomal abnormality. No significant correlation was observed between the incidence of postpartum neurodevelopmental disorders and the degrees of ventriculomegaly. CONCLUSIONS: Fetal cerebral ventriculomegaly is a dynamic process. The etiology is multifactorial and abnormalities can be detected during follow-up. All patients should be evaluated carefully for associated abnormalities. The cases should also be evaluated for neurodevelopmental outcomes after birth. All diagnosis, follow-up, and treatment options should be handled with a multidisciplinary approach.

Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype.

Chromosomal abnormality is one of the important causes of dysplasia in children. However, due to regional and ethnic differences, the reported rates of chromosomal abnormalities in patients with dysplasia vary greatly. Moreover, the clinical manifestations in children with rare chromosomal diseases were heterogeneous. So, we retrospectively analyzed the karyotype results of 436 children with dysplasia and conducted a detailed analysis of rare chromosomal diseases. The results showed that chromosomal abnormalities were present in 181 of 436 cases. Intellectual disability, dysmorphology, congenital malformations, the disorder of sexual development, and short stature were the main five clinical symptoms in children with chromosomal abnormalities. Moreover, 136 cases of Trisomy 21 (Tri21) were detected, of which 130 were standard Tri21, 5 were robertsonian Tri21, and 1 was chimera type. In addition, 16 cases of rare abnormal karyotype, including complex Tri21, complex Turner syndrome, 4p-syndrome, 18q-syndrome, and 5p-syndrome, were also detected. In summary, chromosome abnormality is one of the important causes of dysplasia in children. Furthermore, prenatal screening and diagnosis could play a great significance in preventing dysplasia in children. In addition, the retrospective analysis of rare cases is valuable for clinical diagnosis and risk assessment of recurrence.

Identification of a Novel Unbalanced t(4;8) (q12;q24) in Paediatric Acute Myeloid Leukemia M2 with AML-ETO Negative Patient by Fluorescence in Situ Hybridization Technique

Identification of chromosomal abnormalities in patients with Acute Myeloid Leukemia (AML) has contributed substantially to our current understanding of the molecular pathogenesis underlying leukemogenesis, and risk-stratification. Based on molecular abnormalities both influences treatment strategies and aids in determining prognosis. While over 300 established mutations have been documented in AML, the enhanced availability of genetic analysis and the increase in awareness of uncommon chromosomal translocations have made it possible for rare, apparently unique translocations to become recognized and to ultimately gain prognostic significance. Hence, we present a case of AML with a novel, t(4;8) involving breakpoints previously undescribed. Although the patient required second induction, first remission was ultimately achieved. While the prognostic significance of this translocation is not fully elucidated, it is our hope that documentation of this patient’s presentation will help to characterize the significance of a yet undefined cytogenetic abnormality in AML.

Evaluation of Chromosomal Abnormalities in Acute Myeloid Leukemia (AML) and Acute Lymphoid Leukemia (ALL)

Background: The present study evaluated the chromosomal and molecular variations in patients of acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Methods and Materials: A cross-sectional study was conducted at the Department of Oncology at a tertiary care center between April 2018 and June 2021. A total of 314 cases of acute myeloid and lymphoid leukemias were evaluated. Molecular and cytogenetic tests were conducted on these patients. Peripheral and bone marrow smears of all the subjects were sent to the laboratory for molecular and cytogenetic studies. The diagnosis was confirmed with morphology and specific staining, such as Gimsa, myeloperoxidase, molecular, and cytogenetic findings. The results of BM karyotype were classified as normal diploid, hypo and hyper diploid, complex karyotype, and pseudo-diploid. Data was explored using Statistical Package for the Social Sciences (SPSS) version 26. Results: A total of 314 patients were included in the study. Around 40 percent were diagnosed with AML while the 60% had ALL. The mean age of patients was 31.5 +/- 5.6 years. The karyotype revealed that 55.4% were normal diploid, 5.2% were hypo-diploid, 8.4% were hyper-diploid, 18.54% were pseudo-diploid, and the remainder had complex karyotype. A significant difference was observed between the acute leukemia and mean age (P &lt; 0.001). The mean age of acute myeloid leukemia (AML) patients was significantly higher than acute lymphoid leukemia (ALL). The pseudodiploid pattern was meaningfully more frequent in the AML patients compared with that in the MDS and ALL patients (P &lt; 0.001). Chromosomal abnormalities including monosomy of chromosome 14 and trisomy of chromosome 3 were the most prevalent. Conclusion: The current study revealed the variations in the chromosomal abnormalities in patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). The specific patterns associated with particular leukemia can help establish early diagnosis. Keywords: acute myeloid leukemia, acute lymphoid leukemia, chromosome, hematology, malignancy

Cytogenetic analysis of 2959 couples with spontaneous abortion and detailed analysis of rare karyotypes

Chromosome abnormality is one of the important causes of spontaneous abortion. However, due to regional and ethnic differences, the reported rates of chromosomal abnormalities in patients with spontaneous abortion vary greatly. At present, there is no large sample statistics of chromosome abnormality in patients with spontaneous abortion in Yantai, Shandong province, China and hence 2959 couples (5918 individuals) with spontaneous abortion were recruited for this study. G banding was used to examine the karyotype of patients. The results showed that chromosomal abnormalities were present in 173 of 2959 couples with the rate of 5.85%. Female carriers were significantly higher than male. Chromosomal abnormality rate was positively correlated with the number of spontaneous abortions. Structural aberrations were significantly greater than numerical aberrations, with a prevalence of 92.49% and 7.51%, respectively. Balanced translocation, Robertson translocation and inversion were the most common types of chromosomal structural abnormalities. Among them, the proportion of balanced translocation was the highest (63.13%, 101/160). In addition, three cases of rare complex abnormal karyotype were detected. In summary, chromosome abnormality could be one of the important causes of spontaneous abortion in Yantai, Shandong province, China. The sex of patients with chromosomal abnormalities and the number of spontaneous abortions should be considered in genetic counselling. When one of the partners have chromosome abnormality, preimplantation genetic diagnosis and prenatal diagnosis could play a great significance for preventing the birth of children with chromosomal diseases and reducing birth defects.

Cytogenetic Studies in Primary Amenorrhoea Cases.

ABSTRACTBackground:Amenorrhoea is considered a kind of menstrual disorder in a woman of reproductive age. It is a symptom with many potential causes such as an abnormality in the hypothalamic–pituitary–ovarian axis, anatomical abnormalities of the genital tract or functional causes.Aims:In this study, we aimed to investigate chromosomal abnormalities in patients presenting with primary amenorrhoea.Study Setting and Design:This study was conducted in the medical genetic laboratory.Materials and Methods:Chromosomal analysis was carried out in 134 cases that were referred to the human genetic laboratory from 2010 to 2017, employing (GTG) Giemsa banding.Statistical Analysis:Statistical analyses were carried out by Microsoft Office Excel (2019).Results:The karyotype results revealed 77.6% (n = 104) with normal chromosome composition while 22.38% (n = 30) showed chromosomal abnormalities. Among the patients with abnormal chromosome constituents, 53.54% exhibited numerical aberration and 46.66% showed structural abnormalities.Conclusion:The present study has emphasised that karyotyping is one of the fundamental investigations in the evaluation of primary amenorrhoea.

Frequency of Chromosomal Translocations Are Significantly Higher in Therapy Related Myeloid Neoplasm As Compared to Primary MDS

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders with variable outcomes. Acquired chromosome abnormalities in patients with myelodysplastic syndromes (MDS) are among the most valuable determinants of prognosis. However, chromosomal translocations are rare in MDS, and their prognostic implication is not well known. To elucidate factors driving chromosomal translocations in MDS, we compared the frequency of MDS patients with and without prior exposure to DNA damaging cytotoxic therapies.Methods: We evaluated diagnostic bone marrow metaphase cytogenetic data of MDS patients enrolled in South Australian MDS/AML registry data. Appropriate Institutional Review Board approval was obtained. Diagnosis and subclassification of MDS were done according to World Health Organization (WHO) 2016 criteria and risk stratified according to the revised International Prognostic Scoring System (R-IPSS) (Greenberg et al., 2012). Standard G-banding method was used for cytogenetic analysis.To decipher changes induced by cytotoxic therapy (CT) from that of myeloid neoplasm in general, we compared cytogenetic profile of three carefully selected cohorts: (i) tMN, in which a myeloid neoplasm occurred in a cancer survivor following exposure to cytotoxic (n = 206, 15.5%); (ii) myeloid neoplasm developing in unrelated cancer survivors with NO prior exposure to CT (a diagnosis of primary MN and another cancer; pMN+Ca) (n =148, 12%). This would include myelodysplastic syndrome or acute myeloid leukemia diagnosed in patients managed with surgical resection of breast cancer and NO exposure to CT; (iii) primary MDS without preceding independent cancer and/or exposure to CT (pMDS) (n = 893,72.5%)Results: The median age of 1247 patients analyzed was 72.50 (IQR 64.9 to 79) and 64% patients were male. Majority of patients were diagnosed with pMDS (n=893; 72.5%), while 206 (15.5%) and 148 (12%) were classified as t-MN and pMN+Ca respectively.Ten percent (114/1247) patients harbored translocations at the time of diagnosis. The most frequent chromosomes involved in translocation are chromosome 1 (37/114, 34.5%), 3 (15/114, 13.8%), 5 (6/114= 5.3%) (Fig.1A). Most common chromosome partners for translocation with chromosome 1 were chromosome 3, 7 and 21.The frequency of chromosomal translocations in patients with monsomal (55/114, 48%) and complex (70/114, 61%) karyotype were higher than patients without. There is a clear relationship in incidence of chromosomal translocations with increasing IPSS-R scores. The frequency of translocations in the Very high risk IPSS-R risk category was significantly higher compared to patients with Very low risk category (27% vs.1.1%).Importantly, frequency of chromosomal translocations was significantly higher in t-MN as compared pMN+Ca and P-MN patients who were not exposed to DNA damaging cytotoxic therapies prior to their diagnosis (17% vs. 4% vs. 8%, P=0.0004; Fig 1B). Notably, the survival of patients with chromosomal translocation was significantly poorer as compared to patients without translocation (Fig.1C). Poor OS of patients with translocation is most probably due to association with complex karyotype (Fig.1D).Conclusion: This comprehensive analysis demonstrates that chromosomal translocations are observed in 10% of MDS patients. Chromosomal translocations are significantly higher in patients who had prior exposure to cytotoxic therapy as compared to patients without. [Display omitted] DisclosuresHiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities.

To identify the most prevalent chromosomal abnormalities in patients with non-obstructive azoospermia (NOA), consolidate their surgical sperm retrieval (SSR) rates and determine the significant predictors of positive SSR in this patient population. A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Fifty-three studies including 2965 patients were identified through searching the PubMed database. Klinefelter Syndrome (KS) was the most prevalent chromosomal abnormality reported in 2239 cases (75.5%). Azoospermia factor c (AZFc) microdeletions were the second most common (18.6%), but men with these deletions had higher SSR rates than patients with KS (41.95% with AZFc vs. 38.63% with KS). When examining predictors of SSR in KS patients, younger age was a significant predictor of positive SSR in patients undergoing microsurgical testicular sperm extraction (micro-TESE). Higher testosterone was a favourable predictor in those undergoing micro-TESE and conventional TESE. Lower luteinizing hormone (LH) and follicular stimulating hormone (FSH) values were significantly associated with positive SSR with testicular sperm aspiration (TESA). No parameter predicted SSR rates in patients with AZFc microdeletions. Overall, genetic abnormalities have significant implications on SSR success in patients with NOA.

Prevalence of Chromosomal Abnormalities in Patients with Consanguineous Marriages Referred to Sarem Women’s Hospital, Tehran, Iran

Prevalence of Chromosomal Abnormalities in Patients with Consanguineous Marriages Referred to Sarem Women’s Hospital, Tehran, Iran

Clonal Cytogenetic Abnormalities in Myeloid Neoplasms Arising from Fanconi Anemia — a Single Center Study from India

Fanconi anemia (FA) is a genomic instability disease caused by defective DNA repair which predisposes patients into developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Identification of clonal abnormalities in FA patients is vital to detect transformation before the onset of a high-grade MDS/leukemia.We analyzed bone marrow (BM) samples from a series of 50 patients with FA who were diagnosed at the Christian Medical College, Vellore, India from January 2005 - July 2017 by peripheral chromosome breakage analysis (CBA) or FANCD2 ubiquitination analysis of peripheral blood or dermal fibroblasts. Inclusion in the current study was based on the availability of karyotyping samples performed on the BM aspirate collected at diagnosis. Peripheral blood and dermal fibroblasts were collected at diagnosis for CBA and FANCD2 western blot.All 50 patients evaluated had phenotypic features suggestive of FA. There were 28 patients who had increased CBA scores alone while 21 had both increased CBA scores as well as defective FANCD2 ubiquitination. One patient with negative CBA score showing hematopoietic mosaicism with defective FANCD2 ubiquitination pattern in dermal fibroblasts alone was also included in the study.The median age at diagnosis was 16 years (range 1-35) and 35 (70%) were male. Abnormal karyotypes were obtained in 38 patients while the remaining (n=12) showed a normal karyotype. Examination of bone marrow aspirate and trephine was consistent with MDS in 29 (MDS-RS-MLD n= 3; MDS-EB n= 10; MDS-U n=12; h-MDS n=4), while the remaining had either AML (n=8) or a hypoplastic marrow (n=13). The 12 patients who had a normal karyotype were predominantly hypoplastic (n=8) or had either MDS (n=3) or AML (n=1). Abnormalities of chromosomes 1 and 7 were the most commonly reported chromosome aberration and was seen in 17 patients each (45%). A partial deletion 5q was present in 7 (18%) patients while gains of chromosomes 8 and 21 were seen in 5 and 6 patients respectively. Complex karyotypes involving abnormalities of 3 or more chromosomes were seen in 16 (42%) patients who had MDS/AML. FA gene mutation analysis of 8 patients showed FANCA gene mutations in 7 patients (4-abnormal KT, 3-normal KT) while 1 patient with abnormal karyotype had a mutation in the FANCJ gene.Post treatment karyotypes were available in 2 patients with AML and 1 patient with MDS which showed persistence of the leukemic clone identified at diagnosis (n=1) or clonal evolution (n=1, gain of chromosome 9) while the third patient showed a new clone after treatment which retained two of the three abnormalities documented at diagnosis.Using the Revised International Prognostic Scoring system for MDS majority of the patients (n=20) with MDS were classified in the poor or very poor risk groups while the remaining patients were in the good (n=6) or intermediate (n=3) risk group.Five of the 8 patients with AML were classified as poor risk according to the refined MRC cytogenetic classification while 3 were grouped in the intermediate risk group.Among the 13 patients showing a hypoplastic marrow, one patient had monosomy 7 which has been shown to have an increased risk of transformation to MDS/AML. One patient who had gain of 1q due to an unbalanced translocation transformed to AML in 9 months.We report a distinct pattern of chromosome abnormalities in patients with FA-MDS/AML consistent with previous reports, underscoring the need for inclusion of karyotype analysis in the laboratory evaluation strategy of FA patients for early detection of transformation to hematologic malignancies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Translocation (11;14) and Survival of Patients with AL Amyloidosis and Multiple Myeloma

Translocation (11;14) and survival of patients with AL amyloidosis and multiple myelomaTakao Yogo, Kanji Miyazaki, Kenshi SuzukiDepartment of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanBackgroundAmyloid light-chain (AL) amyloidosis is characterized by the deposition of immunoglobulin light chains as amyloid fibrils. Immunoglobulin heavy chain translocation (11;14) is one of the most prevalent chromosomal abnormality in patients with AL amyloidosis, although its clinical significance is still unknown. In this study, we investigated the clinical significance of t(11;14) with AL amyloidosis by comparing with patients having multiple myeloma bearing the same translocation.MethodsWe reviewed 62 patients with AL amyloidosis and 78 patients with multiple myeloma who were newly diagnosed and examined t(11;14) using fluorescence in situ hybridization (FISH). The study was conducted between May 2012 and December 2016 at the Japanese Red Cross Medical Center.Results FISH-based t(11;14) were detected in 15 (24.2%) patients with AL amyloidosis and 13 (16.7%) with multiple myeloma. In patients with AL amyloidosis, t(11;14) gave poor overall survival (P=0.039), whereas the positivity of t(11;14) gave no significant difference in patients with multiple myeloma (P=0.675). Among AL amyloidosis patients, the 24-month survival rate was 38.6% in the t(11;14)-positive group and 76.7% in the t(11;14)-negative group. Although the percentage of plasma cells in bone marrow is high in the t(11;14)-positive group (7.4% vs. 3.6%, p=0.005), there is no significant difference in the overall survival between patients with more than 10% plasma cells (n=12) and patients with less than 10% plasma cells (n=50). Overall survival was superior in autologous stem-cell transplantation (ASCT) group (n=15) compared with non-ASCT group (n=47) (p=0.029). However, even after taking these factors into consideration, t(11;14) had a negative prognostic impact on the overall survival of patients with AL amyloidosis.Conclusionst(11;14) is associated with adverse outcome in patients with AL amyloidosis. [Display omitted] DisclosuresSuzuki:Bristol-Myers K.K: Honoraria; Novarltis: Honoraria; Celgen: Honoraria; Ono: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria.

Innate Immune Signal Pathway Activation Induced By Combined Loss of Del(5q) MDS Genes, Tifab and Mir-146a, Accelerates Hematopoietic Stem Cell Exhaustion Driven By Chronic Exposure to a TLR Ligands

Deletion of the long arm of chromosome 5 (del(5q)) is the most frequently observed chromosomal abnormality in patients with myelodysplastic syndrome (MDS). We previously reported that deletion of TRAF-interacting protein with forkhead-associated domain B (TIFAB) and miR-146a, two haploinsufficient genes in del(5q) MDS, activates the Toll-like receptor (TLR) signaling cascade in hematopoietic stem/progenitor cells (HSPC) by increasing TRAF6 protein stability and mRNA translation, respectively (Varney et al., JEM 2015 and Varney et al., Leukemia 2017). To investigate the epistasis of TIFAB and miR-146a, we generated a mouse model in which Tifab and miR-146a were simultaneously deleted (Tifab-/-; miR-146a-/-, herein dKO). Consistent with increased TRAF6 expression, dKO mice exhibit phosphorylation of IRAK1 and IRAK4 kinases, indicating activation of the TLR/innate immune pathway in bone marrow (BM) HSPC of dKO mice. To determine whether combined deletion of Tifab and miR-146a exaggerates the hematopoietic-specific defects observed in either Tifab- or miR-146a-deficient mice in vivo, BM cells from WT, Tifab-/-, miR-146a-/-, and dKO mice were transplanted into lethally-irradiated syngeneic recipient mice. As previously reported, a minor subset of Tifab-/- and ~ 50% of miR-146a-/- mice succumbed to a bone marrow failure (BMF)-like disease. For dKO mice, 80% of mice developed a more rapid and penetrant BMF-like disease as compared to loss of Tifab or miR-146a alone. Moribund dKO mice presented with leukopenia, severe anemia, and thrombocytopenia. Since TLR activation is a common feature of MDS due to overexpression and secretion of damage-associated molecular patterns (DAMPs) within the BM microenvironment (Monlish et al., Front Immunol 2016), we explored the biological effect of systemic TLR activation on hematopoietic stem cell (HSC) function of dKO mice following exposure to chronic low dose lipopolysaccharide (LPS), a TLR4 agonist. After 4 weeks, the proportion of myeloid cells in peripheral blood (PB) of LPS-treated dKO mice was significantly increased as compared to WT mice exposed to LPS. BM cellularity of dKO mice was dramatically decreased by LPS exposure while that of WT mice was only slightly affected by LPS. The proportion of CD48-CD150+Lineage-Sca1+c-Kit+ (LSK) of dKO mice was significantly reduced by exposure to LPS as compared to WT mice, which correlated with loss of HSC quiescence. We next performed competitive repopulation assays using WT and dKO BM cells exposed to LPS. As expected, the chimerism of donor-derived PB cells from LPS-treated WT mice was significantly lower than that from WT control mice. Intriguingly, LPS-treated dKO mice showed significantly reduced chimerism of donor-derived PB and CD48-CD150+ LSK BM cells as compared to vehicle-treated dKO mice or WT mice exposed to LPS. Importantly, the impaired hematopoietic reconstitution was more pronounced following serial BM transplantation. These results indicate that deletion of Tifab and miR-146a diminishes the long-term repopulating potential of HSC driven by in vivo TLR stimulation. To uncover the molecular consequences that explain the functional HSC defect of dKO mice exposed to TLR activation, RNA-sequencing was performed on LSK from dKO and WT mice treated with LPS. Following TLR activation, we observed differential expression of distinct genes in dKO LSK as compared to WT LSK. Pathway network analyses revealed changes in chromatin organization, epigenetic regulations, and cellular senescence in WT LSK exposed to LPS as compared to control WT cells. In contrast, dKO LSK exposed to LPS exhibited enrichment in pathways associated with axon guidance, carbohydrate metabolism, and megakaryocyte development and platelet production as compared to control dKO cells. These results suggest the differential impact of TLR stimulation on hematopoiesis in Tifab;miR-146a-deficient mice. Collectively, our findings indicate that innate immune signal pathway activation induced by combined loss of Tifab and miR-146a accelerates HSC exhaustion driven by chronic exposure to TLR ligands via the activation of distinct signal pathways. These findings have important implications in the role of TLR stimulation in the cellular consequence of MDS HSC. DisclosuresNo relevant conflicts of interest to declare.