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Introduction: Developmental delay (DD) in children is often caused by genetic abnormalities, which are challenging to diagnose due to the vast genetic variability., Methods: This study presents a detailed analysis of whole-exome sequencing (WES) on 90 children with DD at a single clinical center., Results: We identified pathogenic or likely pathogenic variants in 27.8% of cases, with 7.8% revealing variants of uncertain significance (VUS). Among the positive findings, 21 (84.0%) corresponded to the main clinical manifestations in patients, and 4 (16.0%) secondary findings provided new insights into the patient's conditions. Positive and inconclusive cases led to a revision of the diagnosis or management plan in 34.4% of cases. The positive genetic result in children with Developmental delay was higher in the presence of epilepsy or seizures (odds ratio - 5.4444; 95% CI 2.0176 to 14.6918; p = 0.0008) and more than 3 dysmorphic features (odds ratio - 7.1739; 95% CI 1.7791 to 28.9282; p = 0.0056). Variants compatible with the clinical manifestations were identified in 11.9% of children with autistic spectrum disorders., Conclusion: Our findings emphasize the utility of WES in clinical diagnostics, offering significant insights into patient management and potentially guiding therapeutic decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boyarchuk, Volianska, Smashna and Makukh.)

Introduction: Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, characterized by microcephaly, immunodeficiency, and impaired DNA repair. NBS is most prevalent among Slavic populations, including Ukraine. Our study aimed to comprehensively assess the prevalence, diagnosis, clinical data, immunological parameters, and treatment of NBS patients in Ukraine., Methods: We conducted a retrospective review that included 84 NBS patients from different regions of Ukraine who were diagnosed in 1999-2023. Data from the Ukrainian Registry of NBS and information from treating physicians, obtained using a developed questionnaire, were utilized for analysis., Results: Among 84 NBS patients, 55 (65.5%) were alive, 25 (29.8%) deceased, and 4 were lost to follow-up. The median age of patients was 11 years, ranging from 1 to 34 years. Most patients originate from western regions of Ukraine (57.8%), although in recent years, there has been an increase in diagnoses from central and southeastern regions, expanding our knowledge of NBS prevalence. The number of diagnosed patients per year averaged 3.4 and increased from 2.7 to 4.8 in recent years. The median age of NBS diagnosis was 4.0 years (range 0.1-16) in 1999-2007 and decreased to 2.7 in the past 6 years. Delayed physical development was observed in the majority of children up to the age of ten years. All children experienced infections, and 41.3% of them had recurrent infections. Severe infections were the cause of death in 12%. The second most common clinical manifestation of NBS was malignancies (37.5%), with the prevalence of lymphomas (63.3%). Malignancies have been the most common cause of death in NBS patients (72% of cases). Decreased levels of CD4+ and CD19+ were observed in 89.6%, followed by a reduction of CD3+ (81.8%) and CD8+ (62.5%). The level of NK cells was elevated at 62.5%. IgG concentration was decreased in 72.9%, and IgA - in 56.3%. Immunoglobulin replacement therapy was administered to 58.7% of patients. Regular immunoglobulin replacement therapy has helped reduce the frequency and severity of severe respiratory tract infections., Conclusion: Improvements in diagnosis, including prenatal screening, newborn screening, monitoring, and expanding treatment options, will lead to better outcomes for NBS patients., Competing Interests: Author HM is employed by Scientific Medical Genetic Center LeoGENE, LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boyarchuk, Kostyuchenko, Akopyan, Bondarenko, Volokha, Hilfanova, Savchak, Nazarenko, Yarema, Urbas, Hrabovska, Lysytsia, Budzyn, Tykholaz, Ivanchuk, Bastanohova, Patskun, Vasylenko, Stepanovskyy, Chernyshova and Makukh.)

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy., (Copyright © 2022. Published by Elsevier B.V.)

The work describes a case of rare neonatal systemic juvenile xanthogranuloma with an initial damage of the scalp, limbs, back and abdomen, multiple damages of the parenchyma of both lungs, spleen and liver with the development of a severe form of congenital cholestatic hepatitis. The diagnosis was established on the basis of histopathological and immunohistochemical examination of the skin nodules. The child on the background of therapy under the Langerhans cell histiocytosis III program achieved a partial response, which was manifested by a reduction of granulomatous formations on the skin, elimination of liver failure, but retained hepatosplenomegaly, specific lesions of the lung parenchyma, liver, and left kidney. Against the background of cytostatic therapy, the patient developed secondary pancytopenia, perianal ulcerative-necrotic dermatitis with lesions on buttocks, stomatitis, protein-energy deficiency, acute liver failure. coagulopathy, disseminated intravascular coagulation syndrome, acute renal failure, respiratory failure of III degree, cardiovascular insufficiency of III degree, pulmonary edema, cerebral edema, cerebral coma of II-III degree, enterocolitis, intestinal paresis. Despite multicomponent intensive care, the child's condition progressively deteriorated, and the patient died. The aspects of differential diagnosis of neonatal systemic juvenile xanthogranuloma are discussed.

Severe combined immunodeficiency (SCID) is a group of inborn errors of immunity (IEI) characterized by severe T- and/or B-lymphopenia. At birth, there are usually no clinical signs of the disease, but in the first year of life, often in the first months the disease manifests with severe infections. Timely diagnosis and treatment play a crucial role in patient survival. In Ukraine, the expansion of hemostatic stem cell transplantation and the development of a registry of bone marrow donors in the last few years have created opportunities for early correction of IEI and improving the quality and life expectancy of children with SCID. For the first time in Ukraine, we initiated a pilot study on newborn screening for severe combined immunodeficiency and T-cell lymphopenia by determining T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs). The analysis of TREC and KREC was performed by real-time polymerase chain reaction (RT-PCR) followed by analysis of melting curves in neonatal dry blood spots (DBS). The DBS samples were collected between May 2020 and January 2022. In total, 10,350 newborns were screened. Sixty-five blood DNA samples were used for control: 25 from patients with ataxia-telangiectasia, 37 - from patients with Nijmegen breakage syndrome, 1 - with X-linked agammaglobulinemia, 2 - with SCID (JAK3 deficiency and DCLRE1C deficiency). Retest from the first DBS was provided in 5.8% of patients. New sample test was needed in 73 (0.7%) of newborns. Referral to confirm or rule out the diagnosis was used in 3 cases, including one urgent abnormal value. CID (T low B+NK+) was confirmed in a patient with the urgent abnormal value. The results of a pilot study in Ukraine are compared to other studies (the referral rate 1: 3,450). Approbation of the method on DNA samples of children with ataxia-telangiectasia and Nijmegen syndrome showed a high sensitivity of TRECs (a total of 95.2% with cut-off 2000 copies per 10 6 cells) for the detection of these diseases. Thus, the tested method has shown its effectiveness for the detection of T- and B-lymphopenia and can be used for implementation of newborn screening for SCID in Ukraine., Competing Interests: Authors VK, IS, and HM were employed by Scientific Medical Genetic Center LeoGENE, LTD, Lviv, Ukraine. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boyarchuk, Yarema, Kravets, Shulhai, Shymanska, Chornomydz, Hariyan, Volianska, Kinash and Makukh.)

Aim: To determine the frequency of NOD2 gene c.3019-3020insC (rs5743293) and c.2104C>T (rs2066844) allelic variants in the patients with Crohn's disease (CD), colorectal cancer (CRC) and in the control groups and to study the association of these mutations with the onset time of the diseases, gender and surgical interventions., Materials and Methods: The diagnoses of CD and CRC were established based on standard clinical examination and laboratory tests. Molecular genetic study of a frameshift 3020insC mutations of NOD2 gene were performed in 54 patients with CD; missense R702W mutations of the NOD2 gene - in 41 CD patients and 38 healthy controls. In CRC group, 3020insC mutation was tested in 48 patients, R702W mutation - in 40 patients and 40 healthy controls. PCR-RFLP technique was used to identify the mutations., Results: The frequency of the minor allele (M) of 3020insC mutation of NOD2 gene in the patients with CD was significantly higher than in the control group (р = 0.01). The age at CD onset in females carrying 3020insC mutation was significantly lower (22.5 ± 1.6 years) when compared with females without the mutation (32.7 ± 2.5 years) (p = 0.002). There was no significant difference in the allele frequencies and genotype distributions of R702W mutation in the patients with CD in comparison with the controls. The mean age at CD onset in the patients carrying R702W mutation was significantly lower (28.4 ± 1.4 years) compared with the patients without the mutation (39.4 ± 2.8 years) (p < 0.01). Surgical interventions for CD was required in 40.0% of 3020insC mutation carriers. Among patients with CRC, only 4.2% carried 3020insC mutation and 20.0% R702W mutation. Our study suggests that R702W and 3020insC mutations are not associated with the risk of CRC in Ukrainian patients. There was no statistically significant difference in mean age at CRC onset in patients with/without R702W mutation. Only one patient with CRC had two mutations., Conclusion: The earlier age at CD onset was associated with 3020insC mutation, but only in female patients. The association between R702W mutation and the earlier age of CD onset was found. Patients with 3020insC mutation showed a trend to a higher frequency of surgical interventions for CD.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes., Methods: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis., Results: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function)., Conclusion: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes., Competing Interests: Conflict of interest: A. Jung has nothing to disclose. Conflict of interest: A. Orenti has nothing to disclose. Conflict of interest: F. Dunlevy reports support for the present manuscript from Chiesi Farmaceutici SpA. Conflict of interest: E. Aleksejeva has nothing to disclose. Conflict of interest: E. Bakkeheim has nothing to disclose. Conflict of interest: V. Bobrovnichy has nothing to disclose. Conflict of interest: S.B. Carr reports receiving speaker honoraria from Vertex and Chiesi, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Vertex, Profile Pharma and Chiesi, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from UK CF Trust; PI for Pharmacovigilance study, payment to institution from Pharmaxis, outside the submitted work. Conflict of interest: C. Colombo has nothing to disclose. Conflict of interest: H. Corvol has nothing to disclose. Conflict of interest: R. Cosgrif declares outside the submitted work to be the director of the Cystic Fibrosis Trust. Conflict of interest: G. Daneau has nothing to disclose. Conflict of interest: D. Dogru has nothing to disclose. Conflict of interest: P. Drevinek reports grants or contracts from Ministry of Health, Czech Republic, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex Pharmaceuticals and Actelion Pharmaceuticals, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Vertex Pharmaceuticals, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Society for Medical Microbiology, outside the submitted work. Conflict of interest: A.D. Vukic has nothing to disclose. Conflict of interest: I. Fajac reports grants or contracts from Boehringer Ingelheim, Celtaxsys, Corbus Pharmaceuticals, and Vertex Pharmaceuticals, outside the submitted work; consulting fees from Boehringer Ingelheim and Vertex Pharmaceuticals, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex Pharmaceuticals and Boehringer Ingelheim, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for European Cystic Fibrosis Society. Conflict of interest: A. Fox support for the present manuscript from Chiesi Farmaceutici SpA. Conflict of interest: S. Fustik has nothing to disclose. Conflict of interest: V. Gulmans has nothing to disclose. Conflict of interest: S. Harutyunyan has nothing to disclose. Conflict of interest: E. Hatziagorou has nothing to disclose. Conflict of interest: I. Kasmi has nothing to disclose. Conflict of interest: H. Kayserová has nothing to disclose. Conflict of interest: E. Kondratyeva reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from All-Russian online school with international participation, outside the submitted work. Conflict of interest: U. Krivec has nothing to disclose. Conflict of interest: H. Makukh has nothing to disclose. Conflict of interest: K. Malakauskas has nothing to disclose. Conflict of interest: E.F. McKone reports grants or contracts from vertex, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex Pharmaceuticals and Roche Pharmaceuticals, outside the submitted work; support for attending meetings and/or travel from A Menarini, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Insmed and Janssen Pharmaceuticals, outside the submitted work. Conflict of interest: M. Mei-Zahav has nothing to disclose. Conflict of interest: I. de Monestrol reports grant from Vertex for an academic research study regarding gastrointestinal outcome in CF patients taking Orkambi medication, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Swedish CF Registry and the Swedish Society of Medicine's CF working group. Conflict of interest: H.V. Olesen has nothing to disclose. Conflict of interest: R. Padoan has nothing to disclose. Conflict of interest: T. Parulava has nothing to disclose. Conflict of interest: M.D. Pastor-Vivero has nothing to disclose. Conflict of interest: L. Pereira has nothing to disclose. Conflict of interest: G. Petrova reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from TEVA Pharmaceuticals, Mylan and Alvogen, outside the submitted work. Conflict of interest: A. Pfleger has nothing to disclose. Conflict of interest: L. Pop has nothing to disclose. Conflict of interest: J.G. van Rens has nothing to disclose. Conflict of interest: M. Rodić has nothing to disclose. Conflict of interest: M. Schlesser has nothing to disclose. Conflict of interest: V. Storms has nothing to disclose. Conflict of interest: O. Turcu has nothing to disclose. Conflict of interest: L. Woźniacki has nothing to disclose. Conflict of interest: P. Yiallouros has nothing to disclose. Conflict of interest: A. Zolin has nothing to disclose. Conflict of interest: D.G. Downey has nothing to disclose. Conflict of interest: L. Naehrlich reports support for the present manuscript from Chiesi Farmaceutici SpA; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ArticulateScience LLC, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Trial Steering committee of CF Storm, outside the submitted work; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Society for German CF Registry European CF Patient Registry, outside the submitted work; other financial or nonfinancial interests from Vertex Pharmaceuticals and Boehringer Ingelheim; Institutional fees for site participation (PI) in clinical trials from Vertex Pharmaceuticals and Boehringer Ingelheim., (Copyright ©The authors 2021.)

The aim of the study was to determine the TREC/KREC levels in the patients diagnosed with ataxia-telangiectasia (AT) and to establish their informative value for early diagnosis of this pathology. TRECs and KREC assay was performed using real-time polymerase chain reaction on the DNA of 25 patients diagnosed with AT aged 3 to 14 years and of 173 healthy individuals of the control group aged 1 to 12 years. Clinical and laboratory characteristics of patients were ascertained using their medical records. In the patients with AT, the mean level of TRECs was 542.84 per 10 6 cells, ranging from 4 to 4720, while mean level of KRECs was 1317.64 per 10 6 cells, ranging from 146 to 9300. In 84% of the patients, TREC levels were less than 1000, which was significantly lower than in the control group, while KREC levels were reduced in 48% of the patients. A correlation was found between the levels of TREC and the absolute values of CD4 (r = 0.5455). Measurement of TREC/KREC levels opens new opportunities for early AT detection in children as a part of the newborn screening. Reduced time to diagnosis will allow to carry out timely in-depth immunological and genetic testing, prevent the development of severe infections, and improve quality of life., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Azerbaijani 28-year-old female showed weakness (MRC (Medical Research Council Scale for Muscle Strength) grade 4 in the proximal part of the upper and MRC grade 2-3 in the lower extremities), difficulty in stair lifting, positive symptom of Hoover's rising, «waddling gait», decline deep reflexes symmetrical, lack of surface reflexes, positive Babinsky's reflex on the right, urinary incontinence during sneezing, prolonged walking and exercise from puberty. Additional methods made it possible to identify minor violations of conduction of the left ventricle, electromyography signs of primary muscular disease with predominant involvement of the proximal muscles of the lower extremities, elevation of serum creatine kinase (746.81 U/l), active foci of demyelination in the left frontal lobe, intrathecal synthesis of oligoclonal IgG bands (type 2) in cerebrospinal fluid, atrophy and fatty degeneration of all muscles of the shins, homozygous Variant of Uncertain Significance (VUS) c.1855C > T (p.Pro619Ser) in TRIM32 gene and heterozygous VUS c.2300C > G (p.Thr767Arg) in KIF5A , c.2840G > A (p.Arg947Lys) in MYH2 , c.1502G > C (p.Gly501Ala) in POMT1 genes. Comparison of the phenotypes of the mutations that have been identified with the clinical picture of the patient suggests that VUS c.1855C > T (p.Pro619Ser) in the TRIM32 gene can be pathological. Summarizing, it can be argued that the cause of the identified disorders is a homozygous variant c.1855C > T (p.Pro619Ser) in TRIM32 gene that causes LGMDR8 in a patient with MS.

Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF)., Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection., Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133)., Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination., Competing Interests: Declaration of Competing Interest Dr. Naehrlich reports that he has received institutional fees for site participation in clinical trials from Vertex Pharmaceuticals and Boehringer Ingelheim; Dr. Orenti has nothing to disclose; Dr. Dunlevy reports institutional grants from Chiesi, during the conduct of the study; Dr. Kasmi has nothing to disclose; Dr. Harutyunyan has nothing to disclose; Dr. Pfleger has nothing to disclose; Dr. Bobrovnichy has nothing to disclose;Dr. Keegan has nothing to disclose; Dr. Daneau has nothing to disclose; Dr. Petrova has nothing to disclose; Dr. Bambir has nothing to disclose; Dr. Vukić Dugac has nothing to disclose; Dr. Tješić-Drinković has nothing to disclose; Dr. Yiallouros has nothing to disclose; Dr. Drevinek reports personal fees from Vertex Pharmaceuticals, outside the submitted work; Prof. Milan Macek reports grants from Vertex Pharmaceuticals,  outside the submitted workr r; Mrs. Bilkova has nothing to disclose; Dr. Olesen has nothing to disclose; Dr. Burgel reports personal fees from Astra-Zeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Insmed, personal fees from Novartis, personal fees from Pfizer, grants and personal fees from Vertex, personal fees from Zambon, outside the submitted work; Dr. Corvol has nothing to disclose; Ms. Lemmonier has nothing to disclose; Dr. Parulava has nothing to disclose; Dr. Hatziagorou has nothing to disclose; Dr. Diamantea has nothing to disclose; Dr. Párniczky has nothing to disclose; G. Fletcher has nothing to disclose; Prof. McKone reports travel support from A Menarini, speaker fees from Roche Pharmaceuticals, consultancy fees from Insmed, consultancy fees from Janssen Pharmaceuticals, grants to institution and consultancy fees from Vertex, outside the submitted work; Dr. Mei-Zahav has nothing to disclose; Dr. Padoan has nothing to disclose; Dr. Salvatore has nothing to disclose; Dr. Colombo has nothing to disclose; Dr. Aleksejeva has nothing to disclose; Dr. Malakauskas has nothing to disclose; Dr. Schlesser has nothing to disclose; Dr. Fustik has nothing to disclose; Dr. Turcu has nothing to disclose; V. Gulmans has nothing to disclose; D. Zomer-van Ommen has nothing to disclose; Dr. Wathne has nothing to disclose; Dr. Bakkeheim has nothing to disclose; Dr. Wozniacki has nothing to disclose; Dr. Pereira has nothing to disclose; Dr. Pop has nothing to disclose; Dr. Kondratyeva has nothing to disclose; Dr. Amelina has nothing to disclose; Dr. Zhekaite has nothing to disclose; Dr. O. Simonova has nothing to disclose; Dr. Kashirskaya has nothing to disclose; Dr. Rodic has nothing to disclose; Dr. Kayserova has nothing to disclose; Dr. Krivec has nothing to disclose; Dr. Mondejar-Lopez has nothing to disclose; Dr. Pastor-Vivero has nothing to disclose; Dr. de Monestrol reports grants from Vertex, outside the submitted work; Dr. Lindblad has nothing to disclose; Dr. Dogru has nothing to disclose; Dr. Gokdemir has nothing to disclose; Dr. Pekcan has nothing to disclose; Dr. Makukh has nothing to disclose; Dr. Brownlee has nothing to disclose; Ms. Cosgriff has nothing to disclose; Mr. McClenaghan has nothing to disclose; Dr. Carr reports personal fees from Chiesi Pharmaceuticals, personal fees and non-financial support from Vertex, personal fees from Zambon, personal fees from Insmed, outside the submitted work; Dr. Lammertyn has nothing to disclose; Dr. Zolin has nothing to disclose; Ms.. Fox reports grants from ECFS, during the conduct of the study; Mr Krasnyk has nothing to disclose; Mrs. Van Rens has nothing to disclose; Dr. van Koningsbruggen-Rietschel reports grants and personal fees from Algipharma (HORIZON2020), personal fees from Deutsches Zentrum für Infektionsforschung, personal fees from Antabio, personal fees from Proteostasis, personal fees from Roche, personal fees from Vertex, outside the submitted work; Dr. Jung reports grants from Chiesi Pharmaceuticals, during the conduct of the study., (Copyright © 2021. Published by Elsevier B.V.)

Ovarian cancer (OC) represents the most lethal malignancy in gynaecologic oncology practice and shows a high recurrence rate due to its early chemoresistance to first-line chemotherapy. Yet, timely selection of the correct treatment strategy is likely to prolong a patient's survival. MicroRNAs (miRNAs) are a class of short non-coding RNAs responsible for the expression of 30%-60% of human genes. In numerous studies, miRNAs have been used to provide the overall prognosis for patients and analyse the process's prevalence and responses to chemotherapy. In particular, miRNAs as markers for predicting the sensitivity of OC to platinum- and taxane-based chemotherapeutics can significantly improve the treatment efficacy. This article highlights two families of miRNAs: miR-200 and let-7, which are promising for further research on OC and its chemosensitivity., Competing Interests: The authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin ( NBN) gene (c.657&#95;661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p =0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) ( n =42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p =0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy ( n =7) and immunodeficiency ( n =6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sharapova, Pashchenko, Bondarenko, Vakhlyarskaya, Prokofjeva, Fedorova, Savchak, Mareika, Valiev, Popa, Tuzankina, Vlasova, Sakovich, Polyakova, Rumiantseva, Naumchik, Kulyova, Aleshkevich, Golovataya, Minakovskaya, Belevtsev, Latysheva, Latysheva, Beznoshchenko, Akopyan, Makukh, Kozlova, Varabyou, Ballow, Ong, Walter, Kondratenko, Kostyuchenko and Aleinikova.)

Turner syndrome (TS) is a chromosomal condition that affects development in females. The case of TS in the mother whose child was diagnosed with acute leukemia at the age of 1.5 years is presented. FANCI gene in child was detected among 94 genes associated- with hematologic malignancies. Acute lymphoblastic leukemia, common-B ІІ, L1, associated with t(12;21)(p13;q22), TEL/AML1 (ETV6/RUNX1) in a child was detected during a prophylactic examination. During the treatment of the baby, the mother had a second pregnancy, which ended in miscarriage at 8 weeks. Upon cytogenetic examination in the mother TS was revealed - mos45,Х[23]/46, ХХ[7], and the father's karyotype was without abnormalities (46, ХУ). After chemotherapy, the child is in clinical-hematological remission. It could be suggested that chromosomal abnormalities in mother with TS may cause the chromosomal instability and hematological malignancy in offspring.

The Roma Diaspora-traditionally known as Gypsies-remains among the least explored population migratory events in historical times. It involved the migration of Roma ancestors out-of-India through the plateaus of Western Asia ultimately reaching Europe. The demographic effects of the Diaspora-bottlenecks, endogamy, and gene flow-might have left marked molecular traces in the Roma genomes. Here, we analyze the whole-genome sequence of 46 Roma individuals pertaining to four migrant groups in six European countries. Our analyses revealed a strong, early founder effect followed by a drastic reduction of ∼44% in effective population size. The Roma common ancestors split from the Punjabi population, from Northwest India, some generations before the Diaspora started, <2,000 years ago. The initial bottleneck and subsequent endogamy are revealed by the occurrence of extensive runs of homozygosity and identity-by-descent segments in all Roma populations. Furthermore, we provide evidence of gene flow from Armenian and Anatolian groups in present-day Roma, although the primary contribution to Roma gene pool comes from non-Roma Europeans, which accounts for >50% of their genomes. The linguistic and historical differentiation of Roma in migrant groups is confirmed by the differential proportion, but not a differential source, of European admixture in the Roma groups, which shows a westward cline. In the present study, we found that despite the strong admixture Roma had in their diaspora, the signature of the initial bottleneck and the subsequent endogamy is still present in Roma genomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Roma population is a European ethnic minority characterized by recent and multiple dispersals and founder effects. After their origin in South Asia around 1,500 years ago, they migrated West. In Europe, they diverged into ethnolinguistically distinct migrant groups that spread across the continent. Previous genetic studies based on genome-wide data and uniparental markers detected Roma founder events and West-Eurasian gene flow. However, to the best of our knowledge, it has not been assessed whether these demographic processes have equally affected both sexes in the population. The present study uses the largest and most comprehensive dataset of complete mitochondrial and Y chromosome Roma sequences to unravel the sex-biased patterns that have shaped their genetic history. The results show that the Roma maternal genetic pool carries a higher lineage diversity from South Asia, as opposed to a single paternal South Asian lineage. Nonetheless, the European gene flow events mainly occurred through the maternal lineages; however, a signal of this gene flow is also traceable in the paternal lineages. We also detect a higher female migration rate among European Roma groups. Altogether, these results suggest that sociocultural factors influenced the emergence of sex-biased genetic patterns at global and local scales in the Roma population through time.

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective., Competing Interests: The authors have declared that no competing interests exist.

The Roma, also known as 'Gypsies', represent the largest and the most widespread ethnic minority of Europe. There is increasing evidence, based on linguistic, anthropological and genetic data, to suggest that they originated from the Indian subcontinent, with subsequent bottlenecks and undetermined gene flow from/to hosting populations during their diaspora. Further support comes from the presence of Indian uniparentally inherited lineages, such as mitochondrial DNA M and Y-chromosome H haplogroups, in a significant number of Roma individuals. However, the limited resolution of most genetic studies so far, together with the restriction of the samples used, have prevented the detection of other non-Indian founder lineages that might have been present in the proto-Roma population. We performed a high-resolution study of the uniparental genomes of 753 Roma and 984 non-Roma hosting European individuals. Roma groups show lower genetic diversity and high heterogeneity compared with non-Roma samples as a result of lower effective population size and extensive drift, consistent with a series of bottlenecks during their diaspora. We found a set of founder lineages, present in the Roma and virtually absent in the non-Roma, for the maternal (H7, J1b3, J1c1, M18, M35b, M5a1, U3, and X2d) and paternal (I-P259, J-M92, and J-M67) genomes. This lineage classification allows us to identify extensive gene flow from non-Roma to Roma groups, whereas the opposite pattern, although not negligible, is substantially lower (up to 6.3%). Finally, the exact haplotype matching analysis of both uniparental lineages consistently points to a Northwestern origin of the proto-Roma population within the Indian subcontinent.

Insulin-like growth factor-2 (IGF-2) is a mitogen, growth and differentiation modulator for many cell types. It is mainly expressed during the prenatal development, and its activity strongly depends on the genomic imprinting. Genomic imprinting in the chorionic tissues of spontaneously eliminated human embryos has been studied on the model of 820-AG (Apa1) of the IGF-2 gene locus. Molecular and genetic analysis was performed on the polymorphic 820-AG IGF2 locus in 107 samples of DNA extracted from the chorionic tissues of spontaneously eliminated human embryos within 5-10 weeks of gestation. Presence of AG genotype Apa1 single nucleotide polymorphisms of the IGF-2 was shown to cause more than a 7-fold increase in the risk of embryo elimination. Thus, the loss of genomic imprinting of the IGF-2 gene may be an important cause of the miscarriages in human.

The Romani, the largest European minority group with approximately 11 million people, constitute a mosaic of languages, religions, and lifestyles while sharing a distinct social heritage. Linguistic and genetic studies have located the Romani origins in the Indian subcontinent. However, a genome-wide perspective on Romani origins and population substructure, as well as a detailed reconstruction of their demographic history, has yet to be provided. Our analyses based on genome-wide data from 13 Romani groups collected across Europe suggest that the Romani diaspora constitutes a single initial founder population that originated in north/northwestern India ~1.5 thousand years ago (kya). Our results further indicate that after a rapid migration with moderate gene flow from the Near or Middle East, the European spread of the Romani people was via the Balkans starting ~0.9 kya. The strong population substructure and high levels of homozygosity we found in the European Romani are in line with genetic isolation as well as differential gene flow in time and space with non-Romani Europeans. Overall, our genome-wide study sheds new light on the origins and demographic history of European Romani., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Vlad III The Impaler, also known as Dracula, descended from the dynasty of Basarab, the first rulers of independent Wallachia, in present Romania. Whether this dynasty is of Cuman (an admixed Turkic people that reached Wallachia from the East in the 11(th) century) or of local Romanian (Vlach) origin is debated among historians. Earlier studies have demonstrated the value of investigating the Y chromosome of men bearing a historical name, in order to identify their genetic origin. We sampled 29 Romanian men carrying the surname Basarab, in addition to four Romanian populations (from counties Dolj, N = 38; Mehedinti, N = 11; Cluj, N = 50; and Brasov, N = 50), and compared the data with the surrounding populations. We typed 131 SNPs and 19 STRs in the non-recombinant part of the Y-chromosome in all the individuals. We computed a PCA to situate the Basarab individuals in the context of Romania and its neighboring populations. Different Y-chromosome haplogroups were found within the individuals bearing the Basarab name. All haplogroups are common in Romania and other Central and Eastern European populations. In a PCA, the Basarab group clusters within other Romanian populations. We found several clusters of Basarab individuals having a common ancestor within the period of the last 600 years. The diversity of haplogroups found shows that not all individuals carrying the surname Basarab can be direct biological descendants of the Basarab dynasty. The absence of Eastern Asian lineages in the Basarab men can be interpreted as a lack of evidence for a Cuman origin of the Basarab dynasty, although it cannot be positively ruled out. It can be therefore concluded that the Basarab dynasty was successful in spreading its name beyond the spread of its genes.

The chromosomal anomalies, microdeletions of AZF region of Y-chromosome and CFTR gene mutations have been studied among 80 infertile men with idiopathic spermatogenetic failure: 36 (45%) patients with aspermia, 19 (24%) patients with azoospermia and 25 (31%) patients with severe oligoasthenoteratozoospermia. In total 30% males with spermatogenetic failure genetic factor of infertility was observed. Karyotype anomalies were observed in 17.5% of infertile men, within 16.2% numerical and structural gonosomal anomalies and in 1.3%--Robertsonian translocation were revealed. In 11% males with spermatogenetic failure, Y-chromosome AZF region microdeletions were detected. The frequency of CFTR major mutation F508del among infertile men was 6.25%. 5T allele of polymorphic locus IVS8polyT was detected in 7.5% of examined men. The results obtained indicate the high complexity of cytogenetic and molecular-genetic studies of male infertility.

We present the first comprehensive report on the distribution and genotype-phenotype correlations of CF-causing mutations in Western Ukraine (former Galicia). The 2184insA mutation was identified in 17 unrelated CF patients, 2 of whom are homozygotes for this allele. This mutation is associated with the classical form of CF. The high frequency of 2184insA mutation (7.20% of all mutated CF chromosomes) suggests that it is likely of Galician origin, from where it has spread throughout Europe and beyond. The achieved 83.71% mutation detection rate fulfills the minimal pre-requisite for introduction of the "two-tier" (IRT/DNA) newborn screening program., (Copyright © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)