Kyriaki Kekou

National and Kapodistrian University of Athens

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Christalena Sofocleous

National and Kapodistrian University of Athens

Joanne Traeger‐Synodinos

National and Kapodistrian University of Athens

Maria Svingou

National and Kapodistrian University of Athens

Constantinos Papadopoulos

Red Cross Hospital

George K. Papadimas

National and Kapodistrian University of Athens

Konstantina Kosma

National and Kapodistrian University of Athens

Danai Veltra

National and Kapodistrian University of Athens

Nikolaos M. Marinakis

National and Kapodistrian University of Athens

Ariadni Mavrou

Genetic Analysis (Norway)

Faidon‐Nikolaos Tilemis

National and Kapodistrian University of Athens

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National and Kapodistrian University of Athens

Children's Hospital Agia Sophia

Boston Children's Hospital

Athens Medical Center

Eginition Hospital

Iaso Children’s Hospital

Athens State University

Panagiotis & Aglaia Kyriakou Children's Hospital

Aristotle University of Thessaloniki

Newcastle University

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Evaluation of Genotypes and Epidemiology of Spinal Muscular Atrophy in Greece: A Nationwide Study Spanning 24 Years

Journal of Neuromuscular Diseases (2020)

Kyriaki Kekou Maria Svingou Christalena Sofocleous Niki Mourtzi Evangelia Nitsa

Background: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients’ quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients. Objective: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations. Methods: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset. Results: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5–15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6). Conclusions: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.

10.3233/jnd-190466

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Clinical utility of Whole Exome Sequencing for rare Mendelian disorders: phenotypic-driven strategy for a high diagnostic yield and identification of 48 novel variants

Authorea (Authorea) (2020)

Nikolaos M. Marinakis Danai Veltra Maria Sviggou Christalena Sofocleous Kyriaki Kekou

About 6,000 to 7,000 different rare disorders with suspected genetic etiologies have been described and in almost 4,500 of them the causative gene(s) have been identified. The advent of Next-Generation Sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in identification of pathogenic genetic variations. WES facilitates a faster and more cost-effective route for definite diagnosis of rare genetic disorders, minimizing previous “diagnostic odysseys” for the patients. Due to the limitation that WES is not reimbursed in Greece, we aimed to minimize cost per patient/family through applying WES in the proband, followed by targeted family segregation studies when necessary. Furthermore, for variant filtration and interpretation we applied a phenotypic-driven strategy in close collaboration with clinical geneticists or referring clinicians. In this study we report the clinical application of WES in the diagnosis of 162 cases referred to investigate patients with undiagnosed genetic disorders. The overall molecular diagnostic yield reached 52.5%. Our experience as an academic diagnostic laboratory using WES, although limited to the last two years, allowed characterization of 94 pathogenic variants in 85 positive cases, 48 of which were novel, contributing information to the community of disease and variant databases.

Proband

Mendelian inheritance

Identification

Molecular diagnostics

10.22541/au.160425547.72459540/v1

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Author's Reply: Myotonic dystrophy: The occurrence of early-onset cataract

Neurology India (2017)

Constantinos Papadopoulos Grigoris Panagopoulos Kyriaki Kekou Vassilios Fardis Sofia Kitsiou‐Tzeli

10.4103/neuroindia.ni_481_17

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Retrospective analysis of persistent HyperCKemia with or without muscle weakness in a case series from Greece highlights vast DMD variant heterogeneity

Expert Review of Molecular Diagnostics (2023)

Kyriaki Kekou Maria Svingou Nikos Vogiatzakis Evangelia Nitsa Danai Veltra

Persistent hyperCKemia results from muscle dysfunction often attributed to genetic alterations of muscle-related genes, such as the dystrophin gene (DMD). Retrospective assessment of findings from DMD analysis, in association with persistent HyperCKemia, was conducted.Evaluation of medical records from 1354 unrelated cases referred during the period 1996-2021. Assessment of data concerning the detection of DMD gene rearrangements and nucleotide variants.A total of 730 individuals (657 cases, 569 of Greek and 88 of Albanian origins) were identified, allowing an overall estimation of dystrophinopathy incidence at ~1:3800 live male births. The heterogeneous spectrum of 275 distinct DMD alterations comprised exon(s) deletions/duplications, nucleotide variants, and rare events, such as chromosome translocation {t(X;20)}, contiguous gene deletions, and a fused gene involving the DMD and the DOCK8 genes. Ethnic-specific findings include a common founder variant in exon 36 ('Hellenic' variant).Some 50% of hyperCKemia cases were characterized as dystrophinopathies, highlighting that DMD variants may be considered the most common cause of hyperCKemia in Greece. Delineation of the broad genetic and clinical heterogeneity is fundamental for actionable public health decisions and theragnosis, as well as the establishment of guidelines addressing ethical considerations, especially related to the mild asymptomatic patient subgroup.

Muscle weakness

10.1080/14737159.2023.2264181

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Early onset cataract: prominent feature in myotonic dystrophy type 2

Neuromuscular Disorders (2017)

Constantinos Papadopoulos Sophia Xirou Kyriaki Kekou S. Kitsiou‐Tzeli Evangelia Kararizou

10.1016/j.nmd.2017.06.313

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The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

Human Mutation (2015)

Catherine L. Bladen David Salgado Soledad Monges María Eugenia Foncuberta Kyriaki Kekou

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

10.1002/humu.22758

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Citations (607)

043 Spinal muscular atrophy in Greece

European Journal of Paediatric Neurology (1999)

Sotiris Youroukos Kyriaki Kekou Georgios A. Konstantinidis Chrysanthy Bili L. Florentin

10.1016/s1090-3798(99)91312-0

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Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

Journal of Neuromuscular Diseases (2017)

Zaïda Koeks Catherine L. Bladen David Salgado Erik W. van Zwet Oksana Pogoryelova

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is req

10.3233/jnd-170280

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Tall Stature, Insulin Resistance, and Disturbed Behavior in a Girl with the Triple X Syndrome Harboring Three SHOX Genes: Offspring of a Father with Mosaic Klinefelter Syndrome but with Two Maternal X Chromosomes

Hormone Research in Paediatrics (2004)

Christina Kanaka‐Gantenbein Sophia Kitsiou Ariadni Mavrou Lela Stamoyannou Aggeliki Kοlialexi

Aims: To describe the tall stature and its possible underlying mechanism in a Caucasian girl (age 12 years and 10 months) with 46,XX (28%)/47,XXX (72%) mosaicism and to identify the parental origin of her extra X chromosome. Methods: The fasting glucose-to-insulin ratio was studied. The karyotypes of the girl and her parents as well as the presence of SHOX copies and the parental origin of her extra X chromosome were assessed. Results: Clinical examination revealed a tall stature and severe acne, and endocrinological/metabolic assessment revealed insulin resistance. Fluorescence in situ hybridization cytogenetic analysis depicted the presence of three SHOX genes in the 47,XXX cell line of the patient. Karyotyping of her parents showed a normal 46,XX karyotype in the mother and 46,XY(93%)/47,XXY(7%) Klinefelter mosaicism in the father. However, DNA analysis unequivocally showed maternal origin of the extra X chromosome of the patient. Conclusions: This report suggests that SHOX gene triplication may produce a tall stature, even in the presence of preserved ovarian function. X triplication might predispose to insulin resistance and behavioral disorders.

Klinefelter syndrome

10.1159/000076532

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Social/ economic burden and health-related quality of life in patients with Spinal Muscular Atrophy (SMA) in Greece

Journal of Health Policy & Outcomes Research (2023)

Vasileios Kontogiannis Marios Athanasios Loupas Mary Adamopoulou Dimitris Athanasiou Georgia Moraiti

Objective: The objective of this study was to determine the economic burden and health-related quality of life (HRQoL) of patients with SMA and their caregivers in Greece, which is still unknown, and explore the economic impact of the implementation of a reproductive carrier screening (RCS) program. Methods: A cross-sectional study was conducted in which an online questionnaire was completed by caregivers of SMA patients. A cost of illness (COI) model was developed in which costs per patient were calculated from a societal perspective and extrapolated to the Greek SMA population. Parents’/caregivers’ HRQoL was measured using the 36-item PedsQL™ Family Impact Module. Resources for the implementation of RCS program were estimated and its short-term impact was assessed. Results: The COI was estimated at €261,785 per patient in 2022. When extrapolating this across all affected persons, the average annual cost ranged from €49,739,395 to €91,036,017 depending on the prevalence considered. Out-of-pocket expenses accounted for 8% of the total. Results of the analysis on HRQoL indicated a high burden on parents/ caregivers with the majority of scores falling below 50 and a mean total score of 45. Depending on the scenario used, an RCS program could save the Greek healthcare system at least €167,181 or increase its costs by €564,804. Conclusions: SMA imposes a significant economic burden in affected patients, caregivers, and health care system. The cost-saving magnitude of a potential implementation of a CRS program is dependent on the parents' reproductive choices following a positive screening result.

Cross-sectional study

10.7365/jhpor.2023.2.6

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