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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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7. 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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8. 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

9. 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

15. 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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16. 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

17. 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

18. 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

19. 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

20. 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

22. 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

23. 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

25. (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

27. 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

30. 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

31. 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

32. 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

35. 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

36. Identification of rare alleles in an Italian population of 284 patients with 21- hydroxylase deficiency by complete sequencing of the CYP21 gene

Author

Baldazzi, L., Barbaro, M., Balsamo, A., Menabò, S., Barp, L., Greggio, N., Iughetti, Lorenzo, Garavelli, L., Cangemi, G., Antelli, A., Cicognani, A., L. Baldazzi, M. Barbaro, A. Balsamo, S. Menabò, L. Barp, N. Greggio, L. Iughetti, L. Garavelli, G. Cangemi, A. Antelli, and A. Cicognani

Subjects
CYP21 gene, deficiency, 21-hydoxylase
Abstract

The screening of the usually tested CYP21 gene alterations (the large gene deletion/conversion and the P30L, IVS2-13A/C>G, Ex 3 D8nt, Ex6 cluster, I172N, V281L, 1766-1767insT, Q318X, R356Q, P453S) by means of Southern blotting and Allele-Specific PCR in an Italian population of 284 patients with 21-hydroxylase deficiency led us to characterize 461 of the total 506 different alleles (91.1%), while 45 (8,9 %) remained uncharacterized. Some incongruent genotype/phenotype correlation was also observed. In order to reduce the number of uncharacterized alleles and possibly to identify additional alterations in some patients’ alleles, we reanalysed the entire population (128 classic and 156 nonclassic forms selected for stimulated 17-HP level>10 ng/ml) by complete sequencing of the CYP21 gene, promoter included. Identified mutations were verified in the available parents to confirm allele segregation. Result a: of the 461 characterized alleles, 10 present an additional/different known mutation from that previously identified (2.1% false positive/negative results); 7 showed a conversion extending from the promoter to the P30L mutation (3 cases) or the IVS2 (4 cases). Result b: of the 34 uncharacterized alleles, 16 showed rare mutations (1 M283V, 1 R316X, 4 R341P, 4 R356Q, 1 R426H, 4 P482S, 1 R483P); 7 showed as far as we know unique mutations, 2 (W19X, L480Xfs) with an obvious implication in the phenotype, and 5 affecting residues L142, I171, R341, V358, L446 currently being studied; 11 remained uncharacterized. A total of 43 (23 of pseudogene origin) SNPs, 15 in the promoter, 3 in the 3’ UTR and 25 in introns were identified: further studies will verify their frequency in controls and the possible implication in the phenotypes. The high frequence of complex, rare or unique alleles in the Italian population underlines the importance to routinely analyse the CY21 gene by complete sequencing to avoid false/incomplete results, identify new mutations or sequence variations and to improve the genotype/phenotype correlation, genetic counselling and treatment.

Published
2005

38. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype

Author

Wischmeijer, A., Laer, L. van, Tortora, G., Bolar, N.A., Camp, G. van, Fransen, E., Peeters, N., Bartolomeo, R. di, Pacini, D., Gargiulo, G., Turci, S., Bonvicini, M., Mariucci, E., Lovato, L., Brusori, S., Ritelli, M., Colombi, M., Garavelli, L., Seri, M., Loeys, B.L., Wischmeijer, A., Laer, L. van, Tortora, G., Bolar, N.A., Camp, G. van, Fransen, E., Peeters, N., Bartolomeo, R. di, Pacini, D., Gargiulo, G., Turci, S., Bonvicini, M., Mariucci, E., Lovato, L., Brusori, S., Ritelli, M., Colombi, M., Garavelli, L., Seri, M., and Loeys, B.L.

Abstract

Item does not contain fulltext, Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS). Our 3-year-old propositus underwent correction of an inguinal hernia at 3 months and substitution of the ascending aorta for pathologic dilation at 12 months of age. Family history reveals aortic dilation in his mother at 30 years, death due to aortic dissection of an 18-year-old maternal aunt, surgical replacement of the ascending aorta because of aneurysm in a maternal uncle at 19 years, postpartum death of the maternal grandmother at 24 years and surgical intervention because of thoracic aortic aneurysm in a brother of the propositus' grandmother at 54 years. The affected individuals present with several other signs of connective tissue disease, but the two adult patients evaluated revealed no radiologic evidence of osteoarthritis. Molecular testing of the TGFBR1 and TGFBR2 genes, involved in LDS, resulted negative, but analysis of SMAD3 disclosed the novel heterozygous loss-of-function mutation c.1170_1179del (p.Ser391AlafsX7) in exon 9 in all affected family members, confirming the diagnosis of AOS. SMAD3 mutations should be considered in patients of all ages with LDS-like phenotypes and negative TGFBR1/2 molecular tests, especially in the presence of aortic root or ascending aortic aneurysms, even though signs of early onset osteoarthritis are absent.

Published
2013

39. Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype

Author

Cordelli, Dm, Garavelli, L, Savasta, S, Guerra, A, Pellicciari, A, Giordano, L, Bonetti, S, Cecconi, I, Wischmeijer, A, Seri, M, Rosato, S, Gelmini, C, Della Giustina, E, Ferrari, Ar, Zanotta, N, Epifanio, R, Grioni, D, Malbora, B, Mammi, I, Mari, F, Buoni, S, Mostardini, R, Grosso, S, Pantaleoni, C, Doz, M, Poch Olivé, Ml, Rivieri, F, Sorge, G, Simonte, G, Licata, F, Tarani, L, Terazzi, E, Mazzanti, L, Cerruti Mainardi, P, Boni, A, Faravelli, F, Grasso, M, Bianchi, P, Zollino, Marcella, Franzoni, E., Zollino, Marcella (ORCID:0000-0003-4871-9519), Cordelli, Dm, Garavelli, L, Savasta, S, Guerra, A, Pellicciari, A, Giordano, L, Bonetti, S, Cecconi, I, Wischmeijer, A, Seri, M, Rosato, S, Gelmini, C, Della Giustina, E, Ferrari, Ar, Zanotta, N, Epifanio, R, Grioni, D, Malbora, B, Mammi, I, Mari, F, Buoni, S, Mostardini, R, Grosso, S, Pantaleoni, C, Doz, M, Poch Olivé, Ml, Rivieri, F, Sorge, G, Simonte, G, Licata, F, Tarani, L, Terazzi, E, Mazzanti, L, Cerruti Mainardi, P, Boni, A, Faravelli, F, Grasso, M, Bianchi, P, Zollino, Marcella, Franzoni, E., and Zollino, Marcella (ORCID:0000-0003-4871-9519)

Abstract

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.

Published
2013

40. Focal dermal hypoplasia (goltz-gorlin syndrome): A new case with a novel variant in the PORCN gene (c.1250T > C:p.F417S) and unusual spinal anomaly

Author

Garavelli, L, Simonte, G, Rosato, S, Wischmeijer, A, Albertini, E, Guareschi, E, Longo, C, Albertini, G, Gelmini, C, Greco, C, Errico, S, Pavanello, M, Happle, R, Unger, S, Superti Furga, A, Grzeschik, K, Savino, Gustavo, Savino, Gustavo (ORCID:0000-0002-9993-5986), Garavelli, L, Simonte, G, Rosato, S, Wischmeijer, A, Albertini, E, Guareschi, E, Longo, C, Albertini, G, Gelmini, C, Greco, C, Errico, S, Pavanello, M, Happle, R, Unger, S, Superti Furga, A, Grzeschik, K, Savino, Gustavo, and Savino, Gustavo (ORCID:0000-0002-9993-5986)

Abstract

Focal dermal hypoplasia (FDH; Goltz–Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder.

Published
2013

41. De Barsy Syndrome: a genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction.

Author

Zampatti, S., Castori, M., Fischer, B., Ferrari, P., Garavelli, L., Dionisi-Vici, C., Agolini, E., Wischmeijer, A., Morava, E., Novelli, G., Haberle, J., Kornak, U., Brancati, F., Zampatti, S., Castori, M., Fischer, B., Ferrari, P., Garavelli, L., Dionisi-Vici, C., Agolini, E., Wischmeijer, A., Morava, E., Novelli, G., Haberle, J., Kornak, U., and Brancati, F.

Abstract

1 april 2012, Item does not contain fulltext

Published
2012

42. Simpson-Golabi-Behmel syndrome type 1 in a 27-week macrosomic preterm newborn: the diagnostic value of rib malformations and index nail and finger hypoplasia.

Author

Garavelli, L., Gargano, G., Simonte, G., Rosato, S., Wischmeijer, A., Melli, N., Braisanti, S., Gelmini, C., Forzano, Francesca, Pietrobono, Roberta, Pomponi, Maria Grazia, Andreucci, E, Toutain, A., Superti Furga, A., Neri, Giovanni, Garavelli, L., Gargano, G., Simonte, G., Rosato, S., Wischmeijer, A., Melli, N., Braisanti, S., Gelmini, C., Forzano, Francesca, Pietrobono, Roberta, Pomponi, Maria Grazia, Andreucci, E, Toutain, A., Superti Furga, A., and Neri, Giovanni

Abstract

The Simpson-Golabi-Behmel syndrome type 1 (SGBS1, OMIM #312870) is an X-linked overgrowth condition comprising abnormal facial appearance, supernumerary nipples, congenital heart defects, polydactyly, fingernail hypoplasia, increased risk of neonatal death and of neoplasia. It is caused by mutation/deletion of the GPC3 gene. We describe a macrosomic 27-week preterm newborn with SGBS1 who presents a novel GPC3 mutation and emphasize the phenotypic aspects which allow a correct diagnosis neonatally in particular the rib malformations, hypoplasia of index finger and of the same fingernail, and 2nd-3rd finger syndactyly.

Published
2012

43. Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice

Author

Rainger, J., Beusekom, E. van, Ramsay, J.K., 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, T.M., Schneider, A.S., Elcioglu, N., Ozkinay, F., Koenig, R., Megarbane, A., Semerci, C.N., Khan, A., Zafar, S., Hennekam, R., Sousa, S.B., Ramos, L., Garavelli, L., Furga, A.S., Wischmeijer, A., Jackson, I.J., Gillessen-Kaesbach, G., Brunner, H.G., Wieczorek, D., Bokhoven, J.H.L.M. van, FitzPatrick, D.R., Rainger, J., Beusekom, E. van, Ramsay, J.K., 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, T.M., Schneider, A.S., Elcioglu, N., Ozkinay, F., Koenig, R., Megarbane, A., Semerci, C.N., Khan, A., Zafar, S., Hennekam, R., Sousa, S.B., Ramos, L., Garavelli, L., Furga, A.S., Wischmeijer, A., Jackson, I.J., Gillessen-Kaesbach, G., Brunner, H.G., Wieczorek, D., Bokhoven, J.H.L.M. van, and FitzPatrick, D.R.

Abstract

Contains fulltext : 97086.pdf (publisher's version ) (Open Access), 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 SMOC1 (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 Smoc1 (Smoc1(tm1a)) that reduces mRNA to approximately 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/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

44. Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Author

Wilkie, AOM, Bowen, ME, Boyden, ED, Holm, IA, Campos-Xavier, B, Bonafe, L, Superti-Furga, A, Ikegawa, S, Cormier-Daire, V, Bovee, JV, Pansuriya, TC, de Sousa, SB, Savarirayan, R, Andreucci, E, Vikkula, M, Garavelli, L, Pottinger, C, Ogino, T, Sakai, A, Regazzoni, BM, Wuyts, W, Sangiorgi, L, Pedrini, E, Zhu, M, Kozakewich, HP, Kasser, JR, Seidman, JG, Kurek, KC, Warman, ML, Wilkie, AOM, Bowen, ME, Boyden, ED, Holm, IA, Campos-Xavier, B, Bonafe, L, Superti-Furga, A, Ikegawa, S, Cormier-Daire, V, Bovee, JV, Pansuriya, TC, de Sousa, SB, Savarirayan, R, Andreucci, E, Vikkula, M, Garavelli, L, Pottinger, C, Ogino, T, Sakai, A, Regazzoni, BM, Wuyts, W, Sangiorgi, L, Pedrini, E, Zhu, M, Kozakewich, HP, Kasser, JR, Seidman, JG, Kurek, KC, and Warman, ML

Abstract

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.

Published
2011

45. Clinical utility gene card for: Mowat-Wilson syndrome

Author

Zollino, Marcella, Garavelli, L, Rauch, A., Zollino, Marcella (ORCID:0000-0003-4871-9519), Zollino, Marcella, Garavelli, L, Rauch, A., and Zollino, Marcella (ORCID:0000-0003-4871-9519)

Abstract

N/A

Published
2011

46. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus

Author

Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, Mancini, G.M.S. (Grazia), Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, and Mancini, G.M.S. (Grazia)

Abstract

The combination of megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (MPPH) is a rare syndrome of unknown cause. We observed two first cousins affected by an MPPH-like phenotype with a submicroscopic chromosome 5q35 deletion as a result of an unbalanced der(5)t(5;20)(q35.2;q13.3) translocation, including the NSD1 Sotos syndrome locus. We describe the phenotype and the deletion breakpoints of the two MPPH-li

Published
2010
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47. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients.

Author

Prattichizzo, C., Macca, M., Novelli, V., Giorgio, G., Barra, A., Franco, B., Abdulla, F., Abramowicz, M., Amy, S., Schafer, I., Bankier, A., White, S., Barcina, M.G., Bartoshesky, L.E., Jenny, K., Beemer, F.A., Benke, P.J., Betz, R.C., Bianchini, G., Garavelli, L., Bigoni, S., Bird, L., Chibuk, J., Masser-Frye, D., Brunetti, N., Scarcella, A., Brunner, H.G., Burn, J., Carmi, R., Castellan, C., Castelluccio, P., Castle, B., Chiong, M.A., Cutiongco, E.M., Collins, F., Couchon, E., Curry, A., Pastore, M., Curry, C.J., Swenerton, A., Treisman, T., Dean, J., Devriendt, K., Matthijs, G., Dunlap, J.W., Shashi, V., Elcioglu, N., Farndon, P., Ferrero, G.B., Ferrier, R., Foulds, N., Friedman, J., Gal, A., Orth, U., Gardner, M., Gerola, O., Gillessen-Kaesbach, G., Giuliano, F., Turc-Carel, C., Godde, E., Graber, V., Graham, G.E., Gurrieri, F., Harbour, L., Henderson, A., Jones, E., Heran, H., Homfrey, T., Taylor, R., Iwarsson, E., Jensen, P.S., Jezela-Stanek, A., Joss, S., Taylor, G., Keeling, S.l., Klatt, R., Teebi, A., Klehr-Martinelli, M., Kotzot, D., Lees, M., Loughlin, S., Lhotta, K., Macdonald, F., Mari, F., Renieri, A., Marlin, S., McGaughran, J., McKenzie, F., McLeod, D.R., Megarbane, A., Mota, C.R., Mucke, J., Tzschach, A., Obersztyn, E., Okhowat, R., Shinzel, A., Pfau, R., Pober, B., Raymond, F.L., Prattichizzo, C., Macca, M., Novelli, V., Giorgio, G., Barra, A., Franco, B., Abdulla, F., Abramowicz, M., Amy, S., Schafer, I., Bankier, A., White, S., Barcina, M.G., Bartoshesky, L.E., Jenny, K., Beemer, F.A., Benke, P.J., Betz, R.C., Bianchini, G., Garavelli, L., Bigoni, S., Bird, L., Chibuk, J., Masser-Frye, D., Brunetti, N., Scarcella, A., Brunner, H.G., Burn, J., Carmi, R., Castellan, C., Castelluccio, P., Castle, B., Chiong, M.A., Cutiongco, E.M., Collins, F., Couchon, E., Curry, A., Pastore, M., Curry, C.J., Swenerton, A., Treisman, T., Dean, J., Devriendt, K., Matthijs, G., Dunlap, J.W., Shashi, V., Elcioglu, N., Farndon, P., Ferrero, G.B., Ferrier, R., Foulds, N., Friedman, J., Gal, A., Orth, U., Gardner, M., Gerola, O., Gillessen-Kaesbach, G., Giuliano, F., Turc-Carel, C., Godde, E., Graber, V., Graham, G.E., Gurrieri, F., Harbour, L., Henderson, A., Jones, E., Heran, H., Homfrey, T., Taylor, R., Iwarsson, E., Jensen, P.S., Jezela-Stanek, A., Joss, S., Taylor, G., Keeling, S.l., Klatt, R., Teebi, A., Klehr-Martinelli, M., Kotzot, D., Lees, M., Loughlin, S., Lhotta, K., Macdonald, F., Mari, F., Renieri, A., Marlin, S., McGaughran, J., McKenzie, F., McLeod, D.R., Megarbane, A., Mota, C.R., Mucke, J., Tzschach, A., Obersztyn, E., Okhowat, R., Shinzel, A., Pfau, R., Pober, B., and Raymond, F.L.

Abstract

Contains fulltext : 70803.pdf (publisher's version ) (Closed access), Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.

Published
2008

48. Wolf-Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16

Author

Zollino, Marcella, Lecce, Rosetta, Murdolo, Marina, Orteschi, Daniela, Marangi, Giuseppe, Selicorni, A., Midro, A., Sorge, G., Zampino, Giuseppe, Memo, L., Battaglia, Domenica Immacolata, Petersen, M., Pandelia, E., Gyftodymou, Y., Faravelli, F., Tenconi, R., Garavelli, L., Mazzanti, L., Fischetto, R., Cavalli, P., Savasta, S., Rodriguez, L., Neri, Giovanni, Zollino, Marcella (ORCID:0000-0003-4871-9519), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zampino, Giuseppe (ORCID:0000-0003-3865-3253), Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Zollino, Marcella, Lecce, Rosetta, Murdolo, Marina, Orteschi, Daniela, Marangi, Giuseppe, Selicorni, A., Midro, A., Sorge, G., Zampino, Giuseppe, Memo, L., Battaglia, Domenica Immacolata, Petersen, M., Pandelia, E., Gyftodymou, Y., Faravelli, F., Tenconi, R., Garavelli, L., Mazzanti, L., Fischetto, R., Cavalli, P., Savasta, S., Rodriguez, L., Neri, Giovanni, Zollino, Marcella (ORCID:0000-0003-4871-9519), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zampino, Giuseppe (ORCID:0000-0003-3865-3253), and Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021)

Published
2007

49. A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome

Author

Zollino, Marcella, Lecce, Rosetta, Selicorni, A, Murdolo, Marina, Mancuso, Irene, Marangi, Giuseppe, Zampino, Giuseppe, Garavelli, L, Ferrarini, A, Rocchi, Massimiliano, Opitz, Jm, Neri, Giovanni, Zollino, Marcella (ORCID:0000-0003-4871-9519), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zampino, Giuseppe (ORCID:0000-0003-3865-3253), Ferrarini, A (ORCID:0000-0001-9390-7004), Zollino, Marcella, Lecce, Rosetta, Selicorni, A, Murdolo, Marina, Mancuso, Irene, Marangi, Giuseppe, Zampino, Giuseppe, Garavelli, L, Ferrarini, A, Rocchi, Massimiliano, Opitz, Jm, Neri, Giovanni, Zollino, Marcella (ORCID:0000-0003-4871-9519), Marangi, Giuseppe (ORCID:0000-0002-6898-8882), Zampino, Giuseppe (ORCID:0000-0003-3865-3253), and Ferrarini, A (ORCID:0000-0001-9390-7004)

Abstract

A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --> p16.1::8p23 --> pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --> q32::4p15.3 --> qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --> 4p16.3::8p23 --> 8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.

Published
2004

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