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Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis.This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a subset of cases (n=4092). This subgroup was age and gender matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank.The ratio of males (31.08%; 27.01%) and the mean age (36.85±15.20; 33.89±14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p0.05). FVL prevalence, CT positivity rate, history of thrombosis, and Pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p0.05). Disease severity was mainly affected by Factor V Leiden and not related to genotypes at the Prothrombin mutations.Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients. This article is protected by copyright. All rights reserved.

The chronological age of a person is a key determinant of etiology and prognosis in the setting of ischemic stroke. Telomere length, an indicator of biological aging, progressively shortens with every cell cycle. Herein, we determined telomere length from peripheral blood leukocytes by Southern blot analyses in a prospective cohort of ischemic stroke patients (n = 163) and equal number of non-stroke controls and evaluated its association with various ischemic stroke features including etiology, severity, and outcome. A shorter telomere length (i.e. lowest quartile; ≤ 5.5 kb) was significantly associated with ischemic stroke (OR 2.95, 95% CI 1.70–5.13). This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. No significant association was present between admission lesion volume and telomere length; however, patients with shorter telomeres had higher admission National Institutes of Health Stroke Scale scores when adjusted for chronological age, risk factors, etiology, and infarct volume (p = 0.046). On the other hand, chronological age, but not telomere length, was associated with unfavorable outcome (modified Rankin scale > 2) and mortality at 90 days follow-up. The association between shorter telomere length and more severe clinical phenotype at the time of admission, might reflect reduced resilience of cerebral tissue to ischemia as part of biological aging.

Background Epidermolysis bullosa with pyloric atresia (EB-PA), also known as Carmi syndrome, is an uncommon, autosomal recessive genodermatosis that typically affects the skin and gastrointestinal tract. EB-PA is caused by homozygous or compound heterozygous mutations in the integrin alpha 6 (ITGA6) gene on chromosome 2q31.1 or in the integrin beta 4 (ITGB4) gene on 17q25.1. Case presentation A male premature infant was born with aplasia cutis, atresia of the pylorus, and bilateral hydronephrosis. His clinical and imaging findings were compatible with EB-PA. A novel, small deletion of the last two bases in exon 6 and the first two nucleotides of intron 6 (c.565_566+2del) in ITGB4 gene was identified. Conclusion EB-PA-aplasia cutis congenita is known to be a non-treatable condition with a poor prognosis as the reported case. The novel mutation reported in this patient may lead to the lethal form of this disease. Identification of underlying genetic abnormality is critical to give genetic counseling.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology. Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay. We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1. Segregation analysis in all available family members confirmed recessive inheritance of the mutation. The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice.

Background: Telomeres are specific nucleotide repeats that play a central role in control of DNA damage related to cell division and aging. The degree of telomere shortening that occurs as part of aging is associated with age-related non-cancer diseases like hypertension, diabetes mellitus and coronary artery disease. Although a number of studies have highlighted that a similar relationship might exist with ischemic stroke, contradictory reports are also present in the literature. In this study we investigated the association between telomere length and ischemic stroke, not only in terms of stroke risk in general, but also from the perspective of stroke etiology and severity. Methods: In a Caucasian cohort, telomere length was determined by Southern blot from peripheral blood leukocytes in 163 consecutive ischemic stroke patients, and 210 controls without any prior history of ischemic stroke. Univariate and multivariate analyses were performed to determine the contribution of telomere length to stroke risk, stroke etiology, admission NIHSS score and DWI lesion volume. Results: The median (interquartile range) telomere length was 7.0 (5.5-9.0) kb in the overall population. Expectedly, telomere length was negatively correlated with aging (r=-0.23; p Conclusion: Almost all etiologic subtypes of ischemic stroke are related to shortened telomere length, irrespective of the age of the subject. Furthermore, presence of short telomeres negatively influences the tolerance of brain to ischemia, thereby causing more severe clinical phenotypes in these patients in the setting of ischemic stroke.

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.

Glucocorticoids (GCs) are the key drugs for the treatment of pediatric acute lymphoblastic leukemia (ALL). Herein, investigation of the relationship between the N363S and BclI polymorphisms of the GC receptor gene (NR3C1) and the side effects of GCs during pediatric ALL therapy was aimed.N363S and BclI polymorphisms were analyzed in 49 patients with ALL treated between 2000 and 2012. The control group consisted of 46 patients with benign disorders. The side effects of GCs noted during the induction and reinduction periods were evaluated retrospectively according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.The BclI allele and genotype frequencies were found similar in the two groups. No N363S polymorphism was detected in either of the groups. During induction, dyspepsia was found more frequently in the CG than in the CC (wild-type) genotype (36.4% vs. 5.3%, p=0.018) and depression symptoms more frequent in patients with the G allele (CG+GG) than the CC genotype (39.3% vs. 10.5%, p=0.031). During reinduction, Cushingoid changes, dyspepsia, and depression symptoms were more frequent in patients with the G allele (CG+GG) than in patients with the CC genotype (48.1% vs. 17.6%, p=0.041; 29.6% vs. 0.0%, p=0.016; 40.7% vs. 11.8%, p=0.040, respectively).In our study, patients with the BclI polymorphism were found to have developed more frequent side effects. We think that the BclI polymorphism should be considered while designing individualized therapies in childhood ALL.Amaç: Çocukluk çağı akut lenfoblastik lösemisinde (ALL), glukokortikoidler (GC) tedavinin ana yapı taşını oluşturmaktadırlar. Bu çalışmada pediatrik ALL tedavisi sırasında GC’lerin yan etkileri ile GC reseptör geninin (NR3C1) N363S ve BclI polimorfizmleri arasındaki ilişkinin araştırılması amaçlandı. Gereç ve Yöntemler: N363S ve BclI polimorfizmleri 2000 ile 2012 yılları arasında tedavi edilmiş 49 ALL hastasında incelendi. Kontrol grubu benign hastalıkları olan 46 çocuktan oluşturuldu. İndüksiyon ve reindüksiyon sırasında görülen GC yan etkileri Ulusal Kanser Enstitüsü’nün “Advers Etkiler için Ortak Terminoloji Kriterleri” (CTCAE version 4,0), kullanılarak dosya ve hemşire gözlemlerinden geriye dönük olarak incelendi. Bulgular: BclI alel ve genotip sıklığı açısından iki grup arasında fark yoktu. N363S polimorfizmi her iki grupta da tespit edilmedi. İndüksiyon sırasında, dispeptik yakınmalar CG genotipinde CC (yaban tip) genotipine göre daha sık görüldü (%36,4-%5,3; p=0,018) ve depresyon semptomları G alelini taşıyanlarda (CG+GG), CC genotipine göre daha sık tespit edildi (%39,3-%10,5; p=0,031). Reindüksiyon sırasında, Cushingoid değişiklikler, dispeptik yakınmalar ve depresyon semptomları G aleli taşıyanlarda (CG+GG) CC genotipine göre daha fazla tespit edildi (sırasıyla %48,1-%17,6, p=0,041; %29,6-%0,0 p=0,016; %40,7-%11,8; p=0,040). Sonuç: Çalışmamızda, BclI polimorfizmine sahip bireyler daha sık yan etki gösterdiler. Çocukluk çağı ALL tedavisinde bireysel tedaviler geliştirilirken BclI polimorfizminin de göz önünde bulundurulmasının gerektiğini düşünüyoruz.

Background Etiology of developmental delay/intellectual disability is very heterogeneous. In recent years, genetic causes have been defined through the use of chromosomal microarray analysis as a first step genetic test. Results Samples from 30 patients with multiple congenital anomaly and/or mental retardation were analyzed with array comparative genomic hybridization in the context of this study. Before this analysis, karyotyping, subtelomeric fluorescence in situ hybridization and additionally fragment analysis for fragile X in males, had been routinely made all of which were reported to be normal. The purpose of our study was to determine the copy number variations as well as to investigate methods to increase diagnostic yield of array comparative genomic hybridization and forming a suitable flow chart decision pipeline for test indication especially for developing countries. Genomic changes were identified at a rate of about 27% in our series. Although this ratio is higher than the literature data, it could be due to the patient selection criteria. Conclusion Chromosomal microarray analysis is not easily utilized for all patients because of its high-cost. Thus, for increasing cost-effectiveness, it may be used step by step for defined targets. Along with discussing the patients with copy number variations relevant with the phenotype, we suggest a flow chart for selection of diagnostic test with the highest diagnostic rate and the lowest expenditure which is quite important for developing countries. Electronic supplementary material The online version of this article (10.1186/s13039-019-0436-2) contains supplementary material, which is available to authorized users.

The ETV6/RUNX1 fusion gene is a valuable prognostic marker that is frequently observed in B-cell precursor acute lymphoblastic leukemia (B-cell ALL). However, the clinical significance of copy number aberrations in these genes remains unclear. In this study, the effects of various aberrations inETV6 and RUNX1 gene copy number on disease prognosis were evaluated in 21 pediatric patients diagnosed with B-cell ALL with/without t(12;21). The prognostic significance of changes in gene copy number of ETV6 or RUNX1 in the presence or absence of hyperdiploidy, trisomy 21, and t(12;21) translocation were also evaluated. RUNX1 gene copy number amplifications were detected in 83 % of the patients who lacked t(12;21) and in all of the patients with hyperdiploidy. Trisomy 21 was detected in 78 % of the patients with hyperdiploidy. Changes in ETV6 gene copy number were detected in patients who lacked both the t(12;21) translocation and RUNX1 gene copy number amplifications. However, RUNX1 gene copy number amplification and ETV6 deletion were observed in all of the patients with t(12;21). RUNX1 gene copy number amplification was associated with hyperdiploidy, but not with t(12;21). Thus, the evaluation of distinct FISH and cytogenetic patterns in patients with B-cell ALL may strengthen the prognostic significance of changes in gene copy number.

We report on a 4.5-year-old boy with interstitial monosomy 9p in a unique and complex de novo rearrangement. The patient had been referred for craniofacial dysmorphism, delayed psychomotor development, and various congenital malformations. We combined cytogenetic studies and FISH analyses to delineate the deletion. The result of our cytogenetic studies was 46,XY,der(9)(p22pter). In order to confirm the deletion, we also performed FISH analysis, which showed that the 9p subtelomeric region was inserted into chromosome 13. Molecular karyotyping was performed to describe the exact genomic breakpoints of the rearrangement. In conclusion, this case is a complex insertion/deletion abnormality which has not been reported before.

Constitutional trisomy 8 mosaicism (CT8M) is a rare chromosomal abnormality. The phenotype varies from normal features to severe malformations. CT8M increases the risk of developing leukemia and myelodysplastic syndrome. As CT8M is very rare, its diagnosis can easily be overlooked, especially in cases with mild phenotypes. Here, we report the diagnostic process of a 40-year-old female patient with CT8M and discuss the importance of follow-up in monitoring for hematological malignancies.

To the Editor:‘‘Criduchatsyndrome’’(CDCS/[OMIM#123450])isone of the most common deletion syndromes,involving the short arm of chromosome 5, with anestimated incidence of 1 in 50,000 live births [Levyetal.,2002].Thesizesofthedeletionsrangefromtheentire short arm to only 5p15.3 [Overhauser et al.,1994; Gersh et al., 1995; Sreekantaiah et al., 1999].Although the latter is responsible for the character-istic cat-like cry, the typical cri du chat syndrome iscaused by deletion of the band 5p15.2 [Gersh et al.,1994; Church et al., 1995; Mainardi et al., 2001].Clinical manifestations of the syndrome include adiagnostic high pitched, monotonous cry similar tothemewingofacat,microcephaly,aroundfacewithhypertelorism, epicanthic folds, micrognathia, pro-minentnasalbridge,abnormaldermatoglyphics,anddelayed growth, and severe psychomotor andmental delay [Lejeune et al., 1963; Niebuhr, 1978].Approximately 85% of the cases are caused by denovodeletions(themajorityareofpaternalinorigin[Overhauser et al., 1990]), whereas 10–15% of casesare familial and result from unbalanced segregationof parental translocation chromosomes. Further-more,onlyabout5%ofthefamilialcasesarecausedby meiotic recombination aneusomy [Niebuhr,1978], which occurs when a parental inversion ofchromosome5recombinestoproduceagametewithpartial monosomy of the short arm and partialtrisomy of the long arm [Beemer et al., 1984;Schroeder et al., 1986; Kumar et al., 1987; Dobbsetal.,1988;Sonodaetal.,1989;Chernosetal.,1992;Onoetal.,1993;Goodartetal.,1996;Levyetal.,2002;Bocian et al., 2005].In this report, we describe a new case of ‘‘cri duchat syndrome’’ having distal deletion of 5p anddistal duplication of 5q defined by the molecularcytogenetic techniques of fluorescence in situhybridization (FISH) and comparative genomichybridization (CGH). This is the first patient with‘‘cri du chat syndrome’’ born to parents without adetectablepericentricinversionofchromosome5intheir blood cells.Theindexpatientwas a full term male infant borntononconsanguineous healthyparents(motherandfather: 24 and 33 years old, respectively) after anuneventful gestation. The pedigree revealed amiscarriageatthe3rdmonthofgestation.Thepatientwas referred to Medical Genetics Department ofAnkaraUniversityFacultyofMedicinewithmultiplecongenital abnormalities and distinctive high-pitched mewing cry. He was 2,350 g by weight (3rdcentile) (2,600 g at birth), 46 cm in length (3rdcentile), and had a 31.5 cm head circumferences(3rd centile) at 11th day. The physical examinationshowed a round face, hypertelorism, epicanthalfolds, downward slanting of the palpebral fissures,microretrognathia,bilateralincompletehelicalarchi-tecture of horizontally asymmetric low set ears,preauricular skin tag on the left, long philtrum,bilateralsingletransversecrease,andbilateralhallux

The aim of this study was to describe the characteristics and outcome in a group of pediatric patients with hematological malignancies who developed hemophagocytosis at diagnosis or during the disease course. Eight patients with hematological malignancy and associated hemophagocytosis were included. The initial diagnosis was juvenile myelomonocytic leukemia (JMML) in five, nonlymphoblastic leukemia (ANLL) in two, and T-cell lymphoma associated with myeloproliferative syndrome in one patient. Hemophagocytosis was concomitantly present at the time of diagnosis of the primary disease in four of the five patients with JMML and in the two patients with ANLL. Three had abnormalities related to chromosome 8 [(trisomy 8, monosomy 8, and t (8;13) (p11; p12)], and one had inversion 16. Multiple chromosomal losses were present in one patient, including both chromosomes 8 and 16. Bone marrow karyotyping revealed 46, XX; 47, XXX mosaicism in one patient. Two patients had PTPN11 mutation and one patient k-RAS mutation. The patients with JMML and neurofibromatosis (n = 2), the patient with lymphoma and t (8;13) positive AML, and a fourth patient with PTPN11 mutation did not remit and had unfavorable outcomes.

Summary Multiple myeloma (MM) is a malignant plasma cell disorder that involves multiple genetic abnormalities. Chimeric transcription factors, created by gene fusion as a result of chromosomal translocations, have been implicated in the pathogenesis of the disease. Here, we report the conventional cytogenetic analysis of a MM patient that showed a complex set of novel chromosomal rearrangements, including t(13;16)(q14;q24) and t(1;15)(q10;q26). This is probably the result of fusion of previously known genes, and would contribute to prognostic significance of the disease.