Browsing by Author "Mellado, Cecilia"

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    Action against birth defects: if not now, when?
    (2024) Strong, Kathleen; Robb-McCord, Judith; Walani, Salimah; Mellado, Cecilia; Botto, Lorenzo D.; Lay-Son, Guillermo; Diaz, Theresa; Banu, Tahmina; Lakhoo, Kokila; Banerjee, Anshu
    Background: More children are surviving through interventions to address the infectious causes of under-5 mortality; subsequently, the proportion of deaths caused by birth defects is increasing. Prevention, diagnosis, treatment and care interventions for birth defects are available but are needed where the burden is highest, low-and-middle-income countries. Objectives: A selection of birth defect focused publications, conferences, and World Health Assembly resolutions from 2000 to 2017 show that global efforts were made to raise the profile of birth defects in global public health. However, recent donor support and national government interest has waned. Without concerted global action to improve primary prevention and care for children born with birth defects, the Sustainable Development Goal targets for child survival will not be met. Results: Birth defects make up 8% and 10% of global under-5 and neonatal deaths respectively, making them significant contributors to preventable loss of life for children. Survivors face long-term morbidity and lifelong disability which compounds the health and economic woes of individuals, families, communities and society as a whole. Demographic changes in sub-Saharan Africa portend a growing number of births with 1.6 billion projected from 2021 to 2050. More births and better survival without effective prevention and treatment for birth defects translates into more mortality and disability from birth defects. Conclusions: We recommend interventions for prevention of birth defects. These are evidenced-based and affordable, but require low- and middle-income countries to strengthened their health systems. Action against birth defects now will prevent premature deaths and long-term disability, and lead to stronger, more resilient health systems.
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    Candidate Gene Sequencing of LHX2, HESX1, and SOX2 in a Large Schizencephaly Cohort
    (WILEY, 2010) Mellado, Cecilia; Poduri, Annapurna; Gleason, Danielle; Elhosary, Princess C.; Barry, Brenda J.; Partlow, Jennifer N.; Chang, Bernard S.; Shaw, Gary M.; Barkovich, A. James; Walsh, Christopher A.
    Schizencephaly is a malformation of cortical development characterized by gray matter-lined clefts in the cerebral cortex and a range of neurological presentations. In some cases, there are features of septo-optic dysplasia concurrently with schizencephaly. The etiologies of both schizencephaly and septo-optic dysplasia are thought to be heterogeneous, but there is evidence that at least some cases have genetic origin. We hypothesized that these disorders may be caused by mutations in three candidate genes: LHX2, a gene with an important cortical patterning role, and HESX1 and SOX2, genes that have been associated with septo-optic dysplasia. We sequenced a large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, for mutations in these genes. No pathogenic mutations were observed, suggesting that other genes or non-genetic factors influencing genes critical to brain development must be responsible for schizencephaly. (C) 2010 Wiley-Liss, Inc.
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    Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
    (2024) Rots, Dmitrijs; Choufani, Sanaa; Faundes, Victor; Dingemans, Alexander J. M.; Joss, Shelagh; Foulds, Nicola; Jones, Elizabeth A.; Stewart, Sarah; Vasudevan, Pradeep; Dabir, Tabib; Park, Soo-Mi; Jewell, Rosalyn; Brown, Natasha; Pais, Lynn; Jacquemont, Sebastien; Jizi, Khadije; van Ravenswaaij-Arts, Conny M. A.; Kroes, Hester Y.; Stumpel, Constance T. R. M.; Ockeloen, Charlotte W.; Diets, Illja J.; Nizon, Mathilde; Vincent, Marie; Cogne, Benjamin; Besnard, Thomas; Kambouris, Marios; Anderson, Emily; Zackai, Elaine H.; McDougall, Carey; Donoghue, Sarah; O'Donnell-Luria, Anne; Valivullah, Zaheer; O'Leary, Melanie; Srivastava, Siddharth; Byers, Heather; Leslie, Nancy; Mazzola, Sarah; Tiller, George E.; Vera, Moin; Shen, Joseph J.; Boles, Richard; Jain, Vani; Brischoux-Boucher, Elise; Kinning, Esther; Simpson, Brittany N.; Giltay, Jacques C.; Harris, Jacqueline; Keren, Boris; Guimier, Anne; Marijon, Pierre; de Vries, Bert B. A.; Motter, Constance S.; Mendelsohn, Bryce A.; Coffino, Samantha; Gerkes, Erica H.; Afenjar, Alexandra; Visconti, Paola; Bacchelli, Elena; Maestrini, Elena; Delahaye-Duriez, Andree; Gooch, Catherine; Hendriks, Yvonne; Adams, Hieab; Thauvin-Robinet, Christel; Josephi-Taylor, Sarah; Bertoli, Marta; Parker, Michael J.; Rutten, Julie W.; Caluseriu, Oana; Vernon, Hilary J.; Kaziyev, Jonah; Zhu, Jia; Kremen, Jessica; Frazier, Zoe; Osika, Hailey; Breault, David; Nair, Sreelata; Lewis, Suzanne M. E.; Ceroni, Fabiola; Viggiano, Marta; Posar, Annio; Brittain, Helen; Giovanna, Traficante; Giulia, Gori; Quteineh, Lina; Leuchter, Russia Ha-Vinh; Zonneveld-Huijssoon, Evelien; Mellado, Cecilia; Marey, Isabelle; Coudert, Alicia; Aracena Alvarez, Mariana Ines; Kennis, Milou G. P.; Bouman, Arianne; Roifman, Maian; Amoros Rodriguez, Maria Inmaculada; Dario Ortigoza-Escobar, Juan; Vernimmen, Vivian; Sinnema, Margje; Pfundt, Rolph; Brunner, Han G.; Vissers, Lisenka E. L. M.; Kleefstra, Tjitske; Weksberg, Rosanna; Banka, Siddharth
    Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, similar to 15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.
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    Phenotypic and mutational spectrum of ROR2-related Robinow syndrome
    (2022) Lima, A.R.; Ferreira, B.M.; Zhang, C.; Jolly, A.; Du, H.; White, J.J.; Dawood, M.; Lins, T.C.; Chiabai, M.A.; van Beusekom, E.; Cordoba, M.S.; Caldas Rosa, E.C.C.; Kayserili, H.; Kimonis, V.; Wu, E.; Mellado, Cecilia; Aggarwal, V.; Richieri-Costa, A.; Brunoni, D.; Canó, T.M.; Jorge, A.A.L.; Kim, C.A.; Honjo, R.; Bertola, D.R.; Dandalo-Girardi, R.M.; Bayram, Y.; Gezdirici, A.; Yilmaz-Gulec, E.; Gumus, E.; Yilmaz, G.C.; Okamoto, N.; Ohashi, H.; Coban–Akdemir, Z.; Mitani, T.; Jhangiani, S.N.; Muzny, D.M.; Regattieri, N.A.P.; Pogue, R.; Pereira, R.W.; Otto, P.A.; Gibbs, R.A.; Ali, B.R.; van Bokhoven, H.; Brunner, H.G.; Sutton, V.R.; Lupski, J.R.; Vianna-Morgante, A.M.; Carvalho, C.M.B.; Mazzeu, J.F.
    Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.
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    STURGE-WEBER SYNDROME: CLINICAL AND RADIOLOGICAL CORRELATES IN 86 PATIENTS
    (2013) Fogarasi, Andras; Loddenkemper, Tobias; Mellado, Cecilia; Tuxhorn, Ingrid; Evers, Georg; Sarco, Dean; Burgess, Richard C.; Halasz, Peter; Barsi, Peter; Gyorsok, Zsuzsanna; Gyimesi, Csilla; Kobor, Jeno; Siegler, Zsuzsanna; Janszky, Jozsef; Jakus, Rita; Rasonyi, Gyoergy; Ebner, Alois; Woermann, Friedrich G.; Sahin, Mustafa
    Backgrounds and purpose - To correlate the extent of the leptomeningeal angiomatosis with clinical features in Sturge-Weber syndrome (SWS).
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    Trastornos neurológicos en niños con síndrome de Down
    (SOC MEDICA SANTIAGO, 2012) Gaete, Beatriz; Mellado, Cecilia; Hernandez, Marta
    Background: Neurological disturbances are common problems in children with Down Syndrome (DS). Aim: To determine the prevalence of neurological disorders affecting children with Down Syndrome. Patients and Methods: Review of medical records of 253 children aged from 1 day to 23 years affected with DS, attended at a public hospital and a University clinic. Results: The overall prevalence of neurological disorders was 38.7%. The most common problems were ocular motor disorders in 26% of cases and epilepsy in 12%. Conclusions: Neurological disorders are more common in children with DS than in the general population. Motor ocular disorders and epilepsy are the predominant disturbances detected. (Rev Med Chile 2012; 140: 214-219).