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3. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

Author

Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., Kleefstra, T., Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., and Kleefstra, T.

Abstract

Item does not contain fulltext, De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Published
2023

4. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

Author

Peluso, F., Caraffi, S.G., Contrò, G., Valeri, L., Napoli, M., Carboni, G., Seth, A., Zuntini, R., Coccia, E., Astrea, G., Bisgaard, A.M., Ivanovski, I., Maitz, S., Brischoux-Boucher, E., Carter, M.T., Dentici, M.L., Devriendt, K., Bellini, M., Digilio, M.C., Doja, A., Dyment, D.A., Farholt, S., Ferreira, C.R., Wolfe, L.A., Gahl, W.A., Gnazzo, M., Goel, H., Grønborg, S.W., Hammer, T., Iughetti, L., Kleefstra, T., Koolen, D.A., Lepri, F.R., Lemire, G., Louro, P., McCullagh, G., Madeo, S.F., Milone, A., Milone, R., Nielsen, Jens Cosedis, Novelli, A., Ockeloen, C.W., Pascarella, R., Pippucci, T., Ricca, I., Robertson, S.P., Sawyer, S., Falkenberg Smeland, M., Stegmann, S., Stumpel, C.T., Goel, A., Taylor, J.M., Barbuti, D., Soresina, A., Bedeschi, M.F., Battini, R., Cavalli, A., Fusco, C., Iascone, M., Maldergem, L. Van, Venkateswaran, S., Zuffardi, O., Vergano, S., Garavelli, L., Bayat, A., Peluso, F., Caraffi, S.G., Contrò, G., Valeri, L., Napoli, M., Carboni, G., Seth, A., Zuntini, R., Coccia, E., Astrea, G., Bisgaard, A.M., Ivanovski, I., Maitz, S., Brischoux-Boucher, E., Carter, M.T., Dentici, M.L., Devriendt, K., Bellini, M., Digilio, M.C., Doja, A., Dyment, D.A., Farholt, S., Ferreira, C.R., Wolfe, L.A., Gahl, W.A., Gnazzo, M., Goel, H., Grønborg, S.W., Hammer, T., Iughetti, L., Kleefstra, T., Koolen, D.A., Lepri, F.R., Lemire, G., Louro, P., McCullagh, G., Madeo, S.F., Milone, A., Milone, R., Nielsen, Jens Cosedis, Novelli, A., Ockeloen, C.W., Pascarella, R., Pippucci, T., Ricca, I., Robertson, S.P., Sawyer, S., Falkenberg Smeland, M., Stegmann, S., Stumpel, C.T., Goel, A., Taylor, J.M., Barbuti, D., Soresina, A., Bedeschi, M.F., Battini, R., Cavalli, A., Fusco, C., Iascone, M., Maldergem, L. Van, Venkateswaran, S., Zuffardi, O., Vergano, S., Garavelli, L., and Bayat, A.

Abstract

Contains fulltext : 299952.pdf (Publisher’s version ) (Open Access), BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

Published
2023

6. Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies

Author

Maini, I., Ivanovski, I., Djuric, O., Caraffi, S. G., Errichiello, E., Marinelli, M., Franchi, F., Bizzarri, V., Rosato, S., Pollazzon, M., Gelmini, C., Malacarne, M., Fusco, C., Gargano, G., Bernasconi, S., Zuffardi, O., and Garavelli, L.

Published
2018
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8. Expanding the clinical spectrum of the ‘HDAC8-phenotype’ – implications for molecular diagnostics, counseling and risk prediction

Author

Parenti, I., Gervasini, C., Pozojevic, J., Wendt, K. S., Watrin, E., Azzollini, J., Braunholz, D., Buiting, K., Cereda, A., Engels, H., Garavelli, L., Glazar, R., Graffmann, B., Larizza, L., Lüdecke, H. J., Mariani, M., Masciadri, M., Pié, J., Ramos, F. J., Russo, S., Selicorni, A., Stefanova, M., Strom, T. M., Werner, R., Wierzba, J., Zampino, G., Gillessen-Kaesbach, G., Wieczorek, D., and Kaiser, F. J.

Published
2016
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9. Mowat-Wilson syndrome:growth charts

Author

Ivanovski I., Djuric O., Broccoli S., Caraffi S. G., Accorsi P., Adam M. P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D. M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J. E. K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R. S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M. L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E. T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M. E., Iughetti L., Bernasconi S., Giorgi Rossi P., Garavelli L., HUSLAB, Clinicum, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Ivanovski I., Djuric O., Broccoli S., Caraffi S.G., Accorsi P., Adam M.P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D.M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J.E.K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R.S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M.L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E.T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M.E., Iughetti L., Bernasconi S., Giorgi Rossi P., and Garavelli L.

Subjects
Male, 0301 basic medicine, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, Pediatrics, Microcephaly, FEATURES, lcsh:Medicine, CHILDREN, 030105 genetics & heredity, Head circumference, DISEASE, 0302 clinical medicine, Intellectual disability, Medicine and Health Sciences, Genetics(clinical), Pharmacology (medical), Mowat-Wilson syndrome, Child, Genetics (clinical), Body mass index, ZEB2, 2. Zero hunger, education.field_of_study, 0303 health sciences, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, Mowat-Wilson syndrome, ZEB2, Growth charts, Weight, Length, Height, Head circumference, Body mass index, BM, 1184 Genetics, developmental biology, physiology, General Medicine, STATISTICS, 3. Good health, MORFOMETRIA, Italy, 030220 oncology & carcinogenesis, Female, medicine.medical_specialty, Mowat–Wilson syndrome, Length, Population, BMI, Growth charts, Height, Weight, Growth chart, 03 medical and health sciences, AGE, Intellectual Disability, medicine, Humans, In patient, Hirschsprung Disease, education, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Physical development, MUTATIONS, business.industry, Research, lcsh:R, Infant, Newborn, Facies, Infant, medicine.disease, Repressor Proteins, DELINEATION, INDIVIDUALS, 030104 developmental biology, 3111 Biomedicine, business
Abstract

Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2,865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Published
2020

10. The fate of orally administered sialic acid: First insights from patients with N-acetylneuraminic acid synthase deficiency and control subjects

Author

Tran, C., Turolla, L., Ballhausen, D., Buros, S.C., Teav, T., Gallart-Ayala, H., Ivanisevic, J., Faouzi, M., Lefeber, D.J., Ivanovski, I., Giangiobbe, S., Caraffi, S.G., Garavelli, L., Superti-Furga, A., Tran, C., Turolla, L., Ballhausen, D., Buros, S.C., Teav, T., Gallart-Ayala, H., Ivanisevic, J., Faouzi, M., Lefeber, D.J., Ivanovski, I., Giangiobbe, S., Caraffi, S.G., Garavelli, L., and Superti-Furga, A.

Abstract

Contains fulltext : 238690.pdf (Publisher’s version ) (Open Access)

Published
2021

12. Mandibuloacral Dysplasia Type A in Childhood

Author

Garavelli, L., DʼApice, M. R., Rivieri, F., Bertoli, M., Wischmeijer, A., Gelmini, C., De Nigris, V., Albertini, E., Rosato, S., Virdis, R., Bacchini, E., Dal Zotto, R., Banchini, G., Iughetti, L., Bernasconi, S., Superti-Furga, A., and Novelli, G.

Published
2009
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13. Mowat–Wilson Syndrome: Facial Phenotype Changing With Age: Study of 19 Italian Patients and Review of the Literature

Author

Garavelli, L., Zollino, M., Mainardi, Cerruti P., Gurrieri, F., Rivieri, F., Soli, F., Verri, R., Albertini, E., Favaron, E., Zignani, M., Orteschi, D., Bianchi, P., Faravelli, F., Forzano, F., Seri, M., Wischmeijer, A., Turchetti, D., Pompilii, E., Gnoli, M., Cocchi, G., Mazzanti, L., Bergamaschi, R., De Brasi, D., Sperandeo, M. P., Mari, F., Uliana, V., Mostardini, R., Cecconi, M., Grasso, M, Sassi, S., Sebastio, G., Renieri, A., Silengo, M., Bernasconi, S., Wakamatsu, N., and Neri, G.

Published
2009
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20. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Author

Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), Garavelli, L. (Livia), Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), and Garavelli, L. (Livia)

Abstract

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluatio

Published
2018
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21. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Author

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, Garavelli, L, Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, and Garavelli, L

Published
2018

22. Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11

Author

De Bernardi, M. L., Ivanovski, I., Caraffi, S. G., Maini, I., Street, M. E., Bayat, A., Zollino, Marcella, Lepri, F. R., Gnazzo, M., Errichiello, E., Superti-Furga, A., Garavelli, L., Zollino M. (ORCID:0000-0003-4871-9519), De Bernardi, M. L., Ivanovski, I., Caraffi, S. G., Maini, I., Street, M. E., Bayat, A., Zollino, Marcella, Lepri, F. R., Gnazzo, M., Errichiello, E., Superti-Furga, A., Garavelli, L., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon–intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.

Published
2018

25. NANS-mediated synthesis of sialic acid is required for brain and skeletal development

Author

Karnebeek, C.D. van, Bonafe, L., Wen, X.Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., Ashikov, A.M., Garavelli, L., Mammi, I., Donnai, D., Cormier, V., Heron, D., Nishimura, G., Uchikawa, S., Campos-Xavier, B., Rossi, A., Hennet, T., Brand-Arzamendi, K., Rozmus, J., Harshman, K., Girardi, E., Superti-Furga, G., Dewan, T., Collingridge, A., Halparin, J., Ross, C.J., Allen, M.I. van, Rossi, A, Engelke, U.F.H., Kluijtmans, L.A., Heeft, E. van der, Renkema, H., Brouwer, A.P. de, Huijben, K., Zijlstra, F.S., Heisse, T., Boltje, T.J., Wasserman, W.W., Rivolta, C., Unger, S., Lefeber, D.J., Wevers, R.A., Superti-Furga, A., Karnebeek, C.D. van, Bonafe, L., Wen, X.Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., Ashikov, A.M., Garavelli, L., Mammi, I., Donnai, D., Cormier, V., Heron, D., Nishimura, G., Uchikawa, S., Campos-Xavier, B., Rossi, A., Hennet, T., Brand-Arzamendi, K., Rozmus, J., Harshman, K., Girardi, E., Superti-Furga, G., Dewan, T., Collingridge, A., Halparin, J., Ross, C.J., Allen, M.I. van, Rossi, A, Engelke, U.F.H., Kluijtmans, L.A., Heeft, E. van der, Renkema, H., Brouwer, A.P. de, Huijben, K., Zijlstra, F.S., Heisse, T., Boltje, T.J., Wasserman, W.W., Rivolta, C., Unger, S., Lefeber, D.J., Wevers, R.A., and Superti-Furga, A.

Abstract

Item does not contain fulltext

Published
2017

27. Optimizing the molecular diagnosis of GALNS: Novel methods to define and characterize morquio-A syndrome-associated mutations

Author

Caciotti, A. Tonin, R. Rigoldi, M. Ferri, L. Catarzi, S. Cavicchi, C. Procopio, E. Donati, M.A. Ficcadenti, A. Fiumara, A. Barone, R. Garavelli, L. Rocco, M.D. Filocamo, M. Antuzzi, D. Scarpa, M. Mooney, S.D. Li, B. Skouma, A. Bianca, S. Concolino, D. Casalone, R. Monti, E. Pantaleo, M. Giglio, S. Guerrini, R. Parini, R. Morrone, A.

Abstract

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. © 2014 WILEY PERIODICALS, INC.

Published
2015

29. SHOX region mutation in Leri-Weill dischondrosteosis (LWS)

Author

Iughetti L, Capone L, Arrigo T, Bernasconi S, Buzzi F, Cavallo L, Chiarelli F, Cisternino M, Danesino C, Garavelli L, Lorini R, Liotta A, Marsciani A, Pasquino A, Percesepe A, Porcelli P, Radetti G, Seri M, Salvatoni A, Tenconi R, Predieri B, Forabosco A., WEBER , GIOVANNA, Iughetti, L, Capone, L, Arrigo, T, Bernasconi, S, Buzzi, F, Cavallo, L, Chiarelli, F, Cisternino, M, Danesino, C, Garavelli, L, Lorini, R, Liotta, A, Marsciani, A, Pasquino, A, Percesepe, A, Porcelli, P, Radetti, G, Seri, M, Salvatoni, A, Tenconi, R, Weber, Giovanna, Predieri, B, and Forabosco, A.

Subjects
SHOX gene, Leri-Weill syndrome
Published
2010

30. Phenotype and genotype in Nicolaides-Baraitser syndrome

Author

Sousa, S. B., Hennekam, R. C., Abdul-Rahman, O., Alders, M., Azzarello-Burri, S., Bottani, A., Bowdin, S., Castori, M., Cormier-Daire, V., Deardorff, M., Del Campo Casanelles, M., Devriendt, K., Fauth, C., Filges, I., Fryer, A., Garavelli, L., Gillessen-Kaesback, G., Hall, B., Hirofumi, O., Holder, S., Hoyer, J., Jenkins, L., Klapeki, J., Krajewska-Walasek, M., Kosho, T., Kuechler, A., Macdermot, K., Magee, A., Mari, F., Mathieu-Dramard, M., Napier, M., Perez-Jurado, L. A., Picard, F. M., Morin, G., Murday, V., Pilch, J., Ronan, A., Rosser, E., Santen, G. W. E., Scott, R., Selicorni, A., Shannon, N., Santos-Simarro, F., Stewart, H., van den Boogaard, M. -J., Vilain, C., Vermeesch, J., Vogels, A., Wakeling, E., Wieczorek, D., Yesil, G., Zuffardi, O., and Zweier, C.

Subjects
Foot Deformities, Adult, Nicolaides-baraitser syndrome, Genotype, Adolescent, Foot Deformities, Congenital, Natural history, Hypotrichosis, Congenital, Young Adult, Intellectual Disability, SMARCA2, Humans, Abnormalities, Multiple, Preschool, Child, Genetic Association Studies, Epilepsy, BAF (SWI/SNF) complex, Intellectual disability, Phenotype, Child, Preschool, Face, Facies, Hair, Skin Abnormalities, Transcription Factors, Mutation, Abnormalities, Multiple
Abstract

Nicolaides-Baraitser syndrome (NCBRS) is an intellectual disability (ID)/multiple congenital anomalies syndrome caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex. We analyzed 61 molecularly confirmed cases, including all previously reported patients (n = 47) and 14 additional unpublished individuals. NCBRS is clinically and genetically homogeneous. The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present. There is variability however, as ID can range from severe to mild, and sparse hair may be present only in certain age groups. There may be a correlation between the severity of the ID and presence of seizures, absent speech, short stature and microcephaly. SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect. There may be some genotype-phenotype correlations (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes) but numbers are still too small to draw definitive conclusions.

Published
2014

32. Il gene Nemo tra le cause di disturbi dell'apprendimento

Author

Pizzamiglio MR, Piccardi L, Bianchini F, Canzano L, Palermo L, Fusco F, D'Antuono G, Gelmini C, Garavelli L, and Ursini MV.

Abstract

Alterazioni del gene responsabile dell'Incontinentia pigmenti possono provocare, in età scolare, difficoltà nella lettura e nel calcolo. Lo suggerisce, per la prima volta, uno studio dell'Igb-Cnr di Napoli, in collaborazione con l'Irccs-Fondazione Santa Lucia di Roma. I risultati sono stati pubblicati su Plos One

Published
2014

33. Noonan syndrome-like disorder with loose anagen hair: A second case with neuroblastoma

Author

Garavelli, L, Cordeddu, V, Errico, S, Bertolini, P, Street, M, Rosato, S, Pollazzon, M, Wischmeijer, A, Ivanovski, I, Daniele, P, Bacchini, E, Lombardi, A, Izzi, G, Biasucci, G, Del Rossi, C, Corradi, D, Cazzaniga, G, Dominici, C, Rossi, C, De Luca, A, Bernasconi, S, Riccardi, R, Legius, E, Tartaglia, M, Garavelli, Livia, Cordeddu, Viviana, Errico, Stefania, Bertolini, Patrizia, Street, Maria Elisabeth, Rosato, Simonetta, Pollazzon, Marzia, Wischmeijer, Anita, Ivanovski, Ivan, Daniele, Paola, Bacchini, Ermanno, Lombardi, Alfonsa Anna, Izzi, Giancarlo, Biasucci, Giacomo, Del Rossi, Carmine, Corradi, Domenico, Cazzaniga, Giovanni, Dominici, Carlo, Rossi, Cesare, De Luca, Alessandro, Bernasconi, Sergio, Riccardi, Riccardo, Legius, Eric, Tartaglia, Marco, Garavelli, L, Cordeddu, V, Errico, S, Bertolini, P, Street, M, Rosato, S, Pollazzon, M, Wischmeijer, A, Ivanovski, I, Daniele, P, Bacchini, E, Lombardi, A, Izzi, G, Biasucci, G, Del Rossi, C, Corradi, D, Cazzaniga, G, Dominici, C, Rossi, C, De Luca, A, Bernasconi, S, Riccardi, R, Legius, E, Tartaglia, M, Garavelli, Livia, Cordeddu, Viviana, Errico, Stefania, Bertolini, Patrizia, Street, Maria Elisabeth, Rosato, Simonetta, Pollazzon, Marzia, Wischmeijer, Anita, Ivanovski, Ivan, Daniele, Paola, Bacchini, Ermanno, Lombardi, Alfonsa Anna, Izzi, Giancarlo, Biasucci, Giacomo, Del Rossi, Carmine, Corradi, Domenico, Cazzaniga, Giovanni, Dominici, Carlo, Rossi, Cesare, De Luca, Alessandro, Bernasconi, Sergio, Riccardi, Riccardo, Legius, Eric, and Tartaglia, Marco

Abstract

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.

Published
2015

34. Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations

Author

Caciotti, A, Tonin, R, Rigoldi, M, Ferri, L, Catarzi, S, Cavicchi, C, Procopio, E, Donati, Ma, Ficcadenti, A, Fiumara, A, Barone, R, Garavelli, L, Rocco, Md, Filocamo, M, Antuzzi, Daniela, Scarpa, M, Mooney, Sd, Li, B, Skouma, A, Bianca, S, Concolino, D, Casalone, R, Monti, E, Pantaleo, M, Giglio, S, Guerrini, R, Parini, R, Morrone, A., Antuzzi, Daniela (ORCID:0000-0002-2951-5425), Caciotti, A, Tonin, R, Rigoldi, M, Ferri, L, Catarzi, S, Cavicchi, C, Procopio, E, Donati, Ma, Ficcadenti, A, Fiumara, A, Barone, R, Garavelli, L, Rocco, Md, Filocamo, M, Antuzzi, Daniela, Scarpa, M, Mooney, Sd, Li, B, Skouma, A, Bianca, S, Concolino, D, Casalone, R, Monti, E, Pantaleo, M, Giglio, S, Guerrini, R, Parini, R, Morrone, A., and Antuzzi, Daniela (ORCID:0000-0002-2951-5425)

Abstract

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression.

Published
2015

36. (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author

Rainger, J, van Beusekom, E, Ramsay, JK, McKie, L, Al-Gazali, L, Pallotta, R, Saponari, A, Branney, P, Fisher, M, Morrison, H, Bicknell, L, Gautier, P, Perry, P, Sokhi, K, Sexton, D, Bardakjian, TM, Schneider, AS, Elcioglu, N, Ozkinay, F, Koenig, R, Megarbane, A, Semerci, CN, Khan, A, Zafar, S, Hennekam, R, Sousa, SB, Ramos, L, Garavelli, L, Furga, AS, Wischmeijer, A, Jackson, IJ, Gillessen-Kaesbach, G, Brunner, HG, Wieczorek, D, van Bokhoven, H, and FitzPatrick, DR

Abstract

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOCI (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site-and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of SmoCI (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

Published
2011

38. Modelling the dispersal of Cape hake ichthyoplankton

Author

Garavelli, L., Grüss, A., Grote, B., Chang, N., Smith, M., Stenevik, Erling Kåre, Kaplan, D. M., and Lett, C.

Subjects
fish larvae, gyting, spawning, fiskelarver, VDP::Agriculture and fishery disciplines: 900::Fisheries science: 920::Resource biology: 921
Published
2010

40. SHOX region mutation in Leri-Weil dischondrosteosis (LWS)

Author

Iughetti, L., Capone, L., Arrigo, T., Bernasconi, S., Buzi, F., Cavallo, L., Chiarelli, F., Cisternino, M., Danesino, C., Garavelli, L., Lorini, R., Liotta, A., Marsciani, A., Pasquino, A. M., Percesepe, A., Porcelli, P., Radetti, G., Seri, M., Salvatoni, Alessandro, Tenconi, R., Weber, G., Predieri, B., and Forabosco, A.

Published
2010

42. Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Author

Gardeitchik, T., Mohamed, M., Fischer, B., Lammens, M.M., Lefeber, D.J., Lace, B., Parker, M., Kim, K.J., Lim, B.C., Haberle, J., Garavelli, L., Jagadeesh, S., Kariminejad, A., Guerra, D., Leao, M., Keski-Filppula, R., Brunner, H.G., Nijtmans, L.G.J., Heuvel, B. van den, Wevers, R.A., Kornak, U., Morava, E., Gardeitchik, T., Mohamed, M., Fischer, B., Lammens, M.M., Lefeber, D.J., Lace, B., Parker, M., Kim, K.J., Lim, B.C., Haberle, J., Garavelli, L., Jagadeesh, S., Kariminejad, A., Guerra, D., Leao, M., Keski-Filppula, R., Brunner, H.G., Nijtmans, L.G.J., Heuvel, B. van den, Wevers, R.A., Kornak, U., and Morava, E.

Abstract

Contains fulltext : 137634.pdf (publisher's version ) (Closed access), Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

Published
2014

43. Optimizing the Molecular Diagnosis of GALNS: Novel Methods to Define and Characterize Morquio A Syndrome-Associated Mutations

Author

Caciotti, A, Tonin, R, Rigoldi, M, Ferri, L, Catarsi, S, Cavicchi, C, Procopio, Emiliano, Donati, Ma, Ficcadenti, A, Fiumara, A, Barone, R, Garavelli, L, Rocco, Md, Filocamo, M, Antuzzi, Daniela, Scarpa, M, Mooney, Sd, Li, B, Skouma, A, Bianca, S, Concolino, D, Casalone, R, Monti, E, Pantaleo, M, Giglio, Simona, Guerrini, R, Parini, R, Morrone, A., Antuzzi, Daniela (ORCID:0000-0002-2951-5425), Caciotti, A, Tonin, R, Rigoldi, M, Ferri, L, Catarsi, S, Cavicchi, C, Procopio, Emiliano, Donati, Ma, Ficcadenti, A, Fiumara, A, Barone, R, Garavelli, L, Rocco, Md, Filocamo, M, Antuzzi, Daniela, Scarpa, M, Mooney, Sd, Li, B, Skouma, A, Bianca, S, Concolino, D, Casalone, R, Monti, E, Pantaleo, M, Giglio, Simona, Guerrini, R, Parini, R, Morrone, A., and Antuzzi, Daniela (ORCID:0000-0002-2951-5425)

Abstract

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IVA patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterise about 15% of the patients' GALNS alleles. To address this drawback and uncover potential gross GALNS rearrangements we developed molecular procedures [CNVs (copy number variation assays), QF- PCRs (quantitative fluorescent- PCRs)], endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. This article is protected by copyright. All rights reserved.

Published
2014

44. CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases

Author

Wenger, Tl, Harr, M, Ricciardi, Stefania, Bhoj, E, Santani, A, Adam, Mp, Barnett, S, Ganetzky, R, Mcdonald Mcginn, Dm, Battaglia, Domenica Immacolata, Bigoni, S, Selicorni, A, Sorge, G, Monica, Md, Mari, F, Andreucci, E, Romano, S, Cocchi, G, Savasta, S, Malbora, B, Marangi, Giuseppe, Garavelli, L, Zollino, Marcella, Zackai, Eh, Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zollino, Marcella (ORCID:0000-0003-4871-9519), Wenger, Tl, Harr, M, Ricciardi, Stefania, Bhoj, E, Santani, A, Adam, Mp, Barnett, S, Ganetzky, R, Mcdonald Mcginn, Dm, Battaglia, Domenica Immacolata, Bigoni, S, Selicorni, A, Sorge, G, Monica, Md, Mari, F, Andreucci, E, Romano, S, Cocchi, G, Savasta, S, Malbora, B, Marangi, Giuseppe, Garavelli, L, Zollino, Marcella, Zackai, Eh, Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), and Zollino, Marcella (ORCID:0000-0003-4871-9519)

Abstract

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.

Published
2014

50. The italian XLMR bank: a clinical and molecular database

Author

Pescucci, C., Caselli, R., Mari, F., Speciale, C., Ariani, F., Bruttini, M., Sampieri, K., Mencarelli, M. A., Scala, E., Longo, I., Artuso, R., Renieri, A., Meloni, I., The Members Of The Xlmr Italian Network Amoroso, A. Bassi M. T., Battaglia, A., Bedeschi, M. F., Bigoni, S., Borgatti, R., Carnevale, F., Caruso, U., Cavalli, P., Chiurazzi, P., D Alessandro, E., D’avanzo, G., Marchi, M., Di Rocco, M., Faravelli, F., Ferrero, G., Fichera, M., Fischetto, R., Galasso, C., Garavelli, L., Renzo Guerrini, Hladnik, U., giancarlo la marca, Lerone, M., Marchina, E., Mazzanti, L., Memo, L., Micheli, V., Moro, F., Murgia, A., Neri, G., Pantaleoni, C., Pergola, E. M., Priolo, M., Rinaldi, M. M., Rinaldi, R., Romano, C., Russo, S., Scarano, G., Selicorni, A., Sestini, S., Stangoni, G., Strisciuglio, P., Tenconi, R., Toniolo, D., Turolla, L., Verri, A., Zammarchi, Enrico, Zelante, L., and Zuffardi, O.

Published
2007

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