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7. 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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17. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Author

Lorena, Travaglini, Francesco, Brancati, Jennifer, Silhavy, Miriam, Iannicelli, Elizabeth, Nickerson, Nadia, Elkhartoufi, Eric, Scott, Emily, Spencer, Stacey, Gabriel, Sophie, Thomas, Bruria, Ben Zeev, Enrico, Bertini, Eugen, Boltshauser, Malika, Chaouch, Maria, Roberta Cilio, Mirjam, M. de Jong, Hulya, Kayserili, Gonul, Ogur, Andrea, Poretti, Sabrina, Signorini, Graziella, Uziel, Maha, S. Zaki, Ali Pacha, L, Zankl, A, Leventer, R, Grattan Smith, P, Janecke, A, Koch, J, Freilinger, M, D'Hooghe, M, Sznajer, Y, Vilain, C, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Dakovic, I, Loncarevic, D, Mejaski Bosnjak, V, Petkovic, D, Abdel Salam GM, Abdel Aleem, A, Marti, I, Pinard, Jm, Quijano Roy, S, Sigaudy, S, de Lonlay, P, Romano, S, Verloes, A, Touraine, R, Koenig, M, Dollfus, H, Flori, E, Fradin, M, Lagier Tourenne, C, Messer, J, Collignon, P, Penzien, Jm, Bussmann, C, Merkenschlager, A, Philippi, H, Kurlemann, G, Grundmann, K, Dacou Voutetakis, C, Kitsiou Tzeli, S, Pons, R, Jerney, J, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, Sr, Girisha, Km, Doshi, H, Udani, V, Kaul, M, Stuart, B, Magee, A, Spiegel, R, Shalev, S, Mandel, H, Lev, D, Michelson, M, Idit, M, Ben Zeev, B, Gershoni Baruch, R, Ficcadenti, A, Fischetto, R, Gentile, M, Della Monica, M, Pezzani, M, Graziano, C, Seri, M, Benedicenti, F, Stanzial, F, Borgatti, R, Romaniello, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Pinelli, L, Boccone, L, Barone, R, Sorge, G, Briatore, E, Bigoni, S, Ferlini, A, Donati, Ma, Biancheri, R, Caridi, G, Divizia, Mt, Faravelli, F, Ghiggeri, G, Mirabelli, M, Pessagno, A, Rossi, A, Uliana, V, Amorini, M, Briguglio, M, Briuglia, S, Salpietro, Cd, Tortorella, G, Adami, A, Bonati, Mt, Castorina, P, D'Arrigo, S, Lalatta, F, Marra, G, Moroni, I, Pantaleoni, C, Riva, D, Scelsa, B, Spaccini, L, Del Giudice, E, Ludwig, K, Permunian, A, Suppiej, A, Macaluso, C, Pichiecchio, A, Battini, R, Di Giacomo, M, Priolo, M, Timpani, P, Pagani, G, Di Sabato ML, Emma, F, Leuzzi, V, Mancini, F, Majore, S, Micalizzi, A, Parisi, P, Romani, M, Stringini, G, Zanni, G, Ulgheri, L, Pollazzon, M, Renieri, Alessandra, Belligni, E, Grosso, E, Pieri, I, Silengo, M, Devescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al Tawari AA, Bastaki, L, Mégarbané, A, Sabolic Avramovska, V, Said, E, Stromme, P, Koul, R, Rajab, A, Azam, M, Barbot, C, Salih, Ma, Tabarki, B, Jocic Jakubi, B, Martorell Sampol, L, Rodriguez, B, Pascual Castroviejo, I, Gener, B, Puschmann, A, Starck, L, Capone, A, Lemke, J, Fluss, J, Niedrist, D, Hennekam, Rc, Wolf, N, Gouider Khouja, N, Kraoua, I, Ceylaner, S, Teber, S, Akgul, M, Anlar, B, Comu, S, Kayserili, H, Yüksel, A, Akcakus, M, Caglayan, Ao, Aldemir, O, Al Gazali, L, Sztriha, L, Nicholl, D, Woods, Cg, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Hemingway, C, Lees, M, Wakeling, E, Blair, E, Bernes, S, Sanchez, H, Clark, Ae, Demarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh, Ca, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, Karaca, E, Swoboda, Kj, Viskochil, D, Dobyns, Wb, Colin, Johnson, Tania, Attié Bitach, Joseph, G. Gleeson, Enza, Maria Valente, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, Paediatrics, OMÜ, University of Zurich, Valente, Enza Maria, Fluss, Joel Victor, Travaglini, L, Brancati, F, Silhavy, J, Iannicelli, M, Nickerson, E, Elkhartoufi, N, Scott, E, Spencer, E, Gabriel, S, Thomas, S, Ben Zeev, B, Bertini, E, Boltshauser, E, Chaouch, M, Cilio, Mr, de Jong, Mm, Kayserili, H, Ogur, G, Poretti, A, Signorini, S, Uziel, G, Zaki, M, Johnson, C, Atti? Bitach, T, Gleeson, Jg, Valente, Em, International JSRD Study, Group, and DEL GIUDICE, Ennio

Subjects
Male, Ciliata -- Anatomy, Proband, 10039 Institute of Medical Genetics, Meckel syndrome, RPGRIP1L, Syndromes, INPP5E, MODIFIER, Phosphoric Monoester Hydrolases/genetics, Ciliopathies, Polycystic Kidney Diseases/diagnosis/genetics, CILIUM, 0302 clinical medicine, Gene Frequency, Cerebellum, Prenatal Diagnosis, RETINAL DEGENERATION, Prevalence, MECKEL, ciliopathies, Joubert syndrome and related disorders, Eye Abnormalities, Child, Genetics (clinical), Encephalocele, Joubert syndrome, Genetics, Polycystic Kidney Diseases, 0303 health sciences, ddc:618, Cerebellar Diseases/diagnosis/genetics, Kidney Diseases, Cystic, Pedigree, 3. Good health, Phenotype, Child, Preschool, Medical genetics, Female, Retinitis Pigmentosa, FORM, Ciliary Motility Disorders, Heterozygote, medicine.medical_specialty, 2716 Genetics (clinical), Adolescent, Molecular Sequence Data, Encephalocele/diagnosis/genetics, AHI1, 610 Medicine & health, Biology, Retina, Article, Ciliopathies, INPP5E, Joubert syndrome and related disorders, Meckel syndrome, NO, Ciliary Motility Disorders/diagnosis/genetics, 03 medical and health sciences, 1311 Genetics, Cerebellar Diseases, REVEALS, medicine, Humans, Abnormalities, Multiple, Amino Acid Sequence, Kidney Diseases, Cystic/diagnosis/genetics, abnormalities, multiple, adolescent, amino acid sequence, cerebellar diseases, cerebellum, child, preschool, ciliary motility disorders, encephalocele, eye abnormalities, female, heterozygote, humans, infant, kidney diseases, cystic, male, molecular sequence data, pedigree, phosphoric monoester hydrolases, polycystic kidney diseases, prenatal diagnosis, prevalence, retina, gene frequency, mutation, phenotype, 030304 developmental biology, Eye Abnormalities/diagnosis/genetics, COACH SYNDROME, Retina/abnormalities, Genetic heterogeneity, Respiration disorders -- Therapy, Infant, medicine.disease, Phosphoric Monoester Hydrolases, INPP5E mutation, 10036 Medical Clinic, Mutation, 030217 neurology & neurosurgery
Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS foetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus., peer-reviewed

Published
2013

21. Germline BRAF mutations in Noonan, LEOPARD and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum

Author

Sarkozy, A, Carta, A, Moretti, S, Zampino, G, Digilio, Mc, Pantaleoni, F, Scioletti, Ap, Esposito, G, Cordeddu, V, Lepri, F, Petrangeli, V, Dentici, Ml, Mancini, Gms, Selicorni, A, Rossi, C, Mazzanti, L, Marino, B, Ferrero, Giovanni Battista, Cirillo, Margherita, Faravelli, F, Stuppia, L, Puxeddu, E, Gelb, Bd, Dallapiccola, B, and Tartaglia, M.

Published
2009

22. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

Author

Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D?arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., Mejaski-Bosnjak, V., Pantaleoni, C., Rigoli, L., Salpietro, C. D., Signorini, S., Stringini, G. R., Verloes, A., Zabloka, D., Dallapiccola, B., Gleeson, J. G., Valente, E. M., Zankl, A., Leventer, R., Smith, P. G., Janecke, A., D?hooghe, M., Sznajer, Y., Van Coster, R., Demerleir, L., Dias, K., Moco, C., Moreira, A., Ae Kim, C., Maegawa, G., Petkovic, D., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., Sigaudy, S., De Lonlay, P., Romano, S., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Collignon, P., Wolf, N., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Phadke, S. R., Udani, V., Stuart, B., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Benedicenti, F., Stanzial, F., Borgatti, R., Accorsi, P., Battaglia, S., Giordano, L., Pinelli, L., Boccone, L., Bigoni, S., Ferlini, A., Donati, M. A., Caridi, G., Divizia, M. T., Faravelli, F., Ghiggeri, G., Pessagno, A., Briuglia, S., Tortorella, G., Adami, A., Castorina, P., Lalatta, F., Marra, G., Riva, D., Scelsa, B., Spaccini, L., Uziel, G., Giudice, E. D., Laverda, A. M., Ludwig, K., Permunian, A., Suppiej, A., Uggetti, C., Battini, R., Giacomo, M. D., Cilio, M. R., Di Sabato, M. L., Leuzzi, V., Parisi, P., Pollazzon, M., Silengo, M., De Vescovi, R., Greco, D., Romano, C., Cazzagon, M., Simonati, A., Al-Tawari, A. A., Bastaki, L., M('e)garban('e), A., Sabolic Avramovska, V., De Jong, M. M., Stromme, P., Koul, R., Rajab, A., Azam, M., Barbot, C., Martorell Sampol, L., Rodriguez, B., Pascual-Castroviejo, I., Teber, S., Anlar, B., Comu, S., Karaca, E., Kayserili, H., Y, Brancati, F, Iannicelli, M, Travaglini, L, Mazzotta, A, Bertini, E, Boltshauser, E, D'Arrigo, S, Emma, F, Fazzi, E, Gallizzi, R, Gentile, M, Loncarevic, D, Mejaski Bosnjak, V, Pantaleoni, C, Rigoli, L, Salpietro, Cd, Signorini, S, Stringini, Gr, Verloes, A, Zabloka, D, Dallapiccola, B, Gleeson, Jg, Valente, Em, International, JSRD Study Group, DEL GIUDICE, Ennio, and Pediatric surgery

Subjects
Pathology, medicine.medical_specialty, TMEM67, DNA Mutational Analysis, Molecular Sequence Data, education, Biology, Article, Joubert syndrome, NO, MKS3, COACH, Multiple Abnormalities, Nephronophthisis, Amino Acid Sequence, Base Sequence, Humans, Liver, Magnetic Resonance Imaging, Membrane Proteins, Mutation, Phenotype, RNA Splice Sites, Syndrome, Genetics, medicine, congenital hepatic fibrosis, Abnormalities, Multiple, Meckel syndrome, COACH syndrome, Joubert syndrome and related disorders, Genetics (clinical), Aplasia, medicine.disease, MKS3/TMEM67 mutation, COACH Syndrome, Ciliopathy, RPGRIP1L, Congenital hepatic fibrosis, human activities
Abstract

MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert syndrome related disorder with liver involvement. The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

Published
2009

23. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome

Author

Cantagrel, V, Silhavy, Jl, Bielas, S, Swistun, D, Marsh, Se, Bertrand, J, Audollent, S, Attié Bitach, T, Holden, Kr, Dobyns, Wb, Traver, D, Al Gazali, L, Ali, Br, Lindner, Th, Caspary, T, Otto, Ea, Hildebrandt, F, Glass, Ia, Logan, Cv, Johnson, Ca, Bennett, C, Brancati, F, Grattan Smith, P, Leventer, J, Van Coster, R, Dias, K, Moco, C, Moreira, Ae Kim, C, Akiss, A, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Marti, I, Quijano Roy, S, de Lonlay, P, Verloes A, A., Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Magee, A, Stuart, B, Lev, D, Michelson, M, Ben Zeev, B, Fischetto, R, Gentile, M, Battaglia, Giordano, L, Boccone, L, Ruggieri, M, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Lapi, E, Genuardi, M, Caridi, G, Faravelli, F, Ghiggeri, G, Briuglia, Silvana, Tortorella, Gaetano, Rigoli, Luciana Concetta, SALPIETRO DAMIANO, Carmelo, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Laverda, Am, Permunian, A, Bova, S, Fazz, Ei, Sabrina, S, Battini, R, Bertini, E, Dallapiccola, B, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Ahmad Aqueel, A, Jong, Mm, Koul, R, Rajab, A, Sztriha, L, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Eugen Boltshauser, E, Hulya, H, Comu, S, Akcakus, M, Sahin, Y, Phadke, Sr, Melick, N, Mikati, M, Nicholl, D, Hurst, J, Hennekam, Rcm, Bernes, S, Sanchez, H, Clark, Ae, Wynshaw Boris, A, Donahue, C, Sherr, Eh, Barkovich, Aj, Hahn, D., Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh CA, Soul, Jmckanna, T, Joanne Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Amy Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Cruse, Rp, Lotzete, Swoboda, Kj, Viskochil, Dh, Valente, Em, Woods, Cg, and Gleeson, Jg

Subjects
Cerebellum, Ataxia, TMEM67, Molecular Sequence Data, Biology, Joubert Syndrome, Joubert syndrome, Article, cilia gene ARL13B, mutation, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, INPP5E, medicine, Genetics, Animals, Humans, Genetics(clinical), Abnormalities, Multiple, Genetic Predisposition to Disease, Cilia, Genetics (clinical), Conserved Sequence, Zebrafish, 030304 developmental biology, Neurons, 0303 health sciences, Brain Diseases, ADP-Ribosylation Factors, Cilium, Chromosome Mapping, Computational Biology, Syndrome, Mutation, medicine.disease, Cell biology, medicine.anatomical_structure, RPGRIP1L, medicine.symptom, Abnormalities, Multiple, 030217 neurology & neurosurgery
Abstract

Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the “molar tooth sign” on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Published
2008

25. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Author

Brancati, F., Barrano, G., Silhavy, J. L., Marsh, S. E., Travaglini, L., Bielas, S. L., Amorini, M., Zablocka, D., Kayserili, H., Al-Gazali, L., Bertini, E., Boltshauser, E., D'Hooghe, M., Fazzi, Eleonora, Fenerci, E. Y., Hennekam, R. C. M., Kiss, A., Lees, M. M., Marco, E., Phadke, S. R., Rigoli, L., Romano, S., Salpietro, C. D., Sherr, E. H., Signorini, S., Stromme, P., Stuart, B., Sztriha, L., Viskochil, D. H., Yuksel, A., Dallapiccola, B., Valente, E. M., Gleeson, J. G., Grattan-Smith, P., Leventer, R., Janecke, A., Van Coster, R., Dias, K., Moco, C., MOREIRA DA SILVA, CLAUDIA ALEXANDRA, Chong, A. K., Maegawa, G., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., De Lonlay, P., Verloes, A., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Gentile, M., Battaglia, S., Giordano, L., Boccone, L., Ruggieri, M., Bigoni, S., Ferlini, A., Donati, M. A., Procopio, E., Caridi, G., Faravelli, F., Ghiggeri, G., Briuglia, S., Tortorella, G., D'Arrigo, S., Pantaleoni, C., Riva, D., Uziel, G., Lavercla, A. M., Permunian, A., Bova, S., Battini, Roberta, Cilio, M. R., DI SABATO, Manuela, Emma, F., Leuzzi, V., Parisi, P., Simonati, A., Al-Tawari, A. A., Bastaki, L., Aqeel, A., De Jong, M. M., Koul, R., Rajab, A., Azam, M., Barbot, C., Rodriguez, B., Pascual-Castroviejo, I., Comu, S., Akcakus, M., Nicholl, D., Woods, C. G., Bennett, C., Hurst, J., Walsh, C. A., Bernes, S., Sanchez, H., Clark, A. E., Donahue, C., Hahn, J., Sanger, T. D., Gallager, T. E., Dobyns, W. B., Daugherty, C., Krishnamoorthy, K. S., Sarco, D., Mckanna, T., Milisa, J., Chung, W. K., De Vivo, D. C., Raynes, H., Schubert, R., Seward, A., Brooks, D. G., Goldstein, A., Caldwell, J., Finsecke, E., Maria, B. L., Holden, K., Cruse, R. P., Swoboda, K. J., ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatric Genetics

Subjects
Male, Pathology, DNA Mutational Analysis, Cell Cycle Proteins, medicine.disease_cause, Ciliopathies, Ocular Motility Disorders, Cohort Studies, Joubert syndrome–related disorders, CEP290, Genetics(clinical), Child, Genetics (clinical), Genetics, Mutation, Brain, Syndrome, Phenotype, Magnetic Resonance Imaging, Kidney Diseases, Molar, Neoplasm Proteins, Child, Preschool, Abnormalities, Multiple, Adolescent, Adult, Antigens, Neoplasm, Female, Humans, Abnormalities, Multiple, medicine.medical_specialty, Biology, Article, Joubert syndrome, Central nervous system disease, medicine, Antigens, Preschool, Genetic heterogeneity, medicine.disease, Cytoskeletal Proteins, Situs inversus, Neoplasm
Abstract

Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Löken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

Published
2007

27. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Author

Brancati, F, Barrano, G, Silhavy, Jl, Marsh, Se, Travaglini, L, Bielas, Sl, Amorini, M, Zablocka, D, Kayserili, H, Al Gazali, L, Bertini, E, Boltshauser, E, D'Hooghe, M, Fazzi, E, Fenerci, Ey, Hennekam, Rc, Kiss, A, Lees, Mm, Marco, E, Phadke, Sr, Rigoli, L, Romano, S, Salpietro, Cd, Sherr, Eh, Signorini, S, Stromme, P, Stuart, B, Sztriha, L, Viskochil, Dh, Yuksel, A, Dallapiccola, [International JSRD Study Group], Valente, Em, Gleeson, Jg, Smith, P, Leventer, R, Janecke, A, Van Coster, R, Dias, K, Moco, C, Moreira, A, Chong, Ak, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Martu, I, Quijano Roy, S, De Lonlay, P, Verloes, A, Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdotir, J, Ludvigsson, P, Magee, A, Lev, D, Michelson, M, Ben Zev, B, Fischetto, R, Gentile, M, Battaglia, S, Giordano, L, Boccone, L, Ruggieri, Martino, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Cardidi, G, Faravelli, F, Ghiggeri, G, Briuglia, S, Tortorella, G, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Lavercla, Am, Permunian, A, Bova, S, Battini, R, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Aqeel, A, De Jong MM, Koul, R, Rajab, A, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Comu, S, Akcakus, M, Nicholl, D, Woods, Cg, Bennet, C, Hurst, J, Walsh, Ca, Bernes, S, Sanchez, H, Clark, Ae, Donahue, C, Hahn, J, Sanger, Td, Gallager, Te, Dobyns, Wb, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, and Swoboda, Kj

Published
2007

30. Possible influence of a non-synonymous polymorphism located in the NGF precursor on susceptibility to late-onset Alzheimer's disease and mild cognitive impairment.

Author

Di Maria E, Giorgio E, Uliana V, Bonvicini C, Faravelli F, Cammarata S, Novello MC, Galimberti D, Scarpini E, Zanetti O, Gennarelli M, Tabaton M, Di Maria, Emilio, Giorgio, Elisa, Uliana, Vera, Bonvicini, Cristian, Faravelli, Francesca, Cammarata, Sergio, Novello, Maria Cristina, and Galimberti, Daniela

Abstract

The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment. Three independent case-control samples, with individuals aged >60 years, were collected in Italian Alzheimer Units. One polymorphism located in the proNGF region, rs6330, demonstrated a minor allele frequency >5% and was used in the association study. The minor allele of rs6330 was more frequent in patients from the three sample series as compared to respective normal controls. Multivariate logistic regression showed a significant association under the dominant model in one cohort (OR 1.83, 95% CI 1.00-3.54) and in the pooled case-control sample (OR 1.47, 95% CI 1.03-2.08). These findings further suggest that proNGF may play a role in Alzheimer-type neurodegeneration and that genetic variations in the NGF locus may influence the occurrence of sporadic, late-onset Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Published
2012
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31. Molecular characterization of Italian nevoid basal cell carcinoma syndrome patients.

Author

Pastorino, L., Cusano, R., Nasti, S., Faravelli, F., Forzano, F., Baldo, C., Barile, M., Gliori, S., Muggianu, M., Ghigliotti, G., Lacaita, M.G., Lo Muzio, L., and Bianchi-Scarra, G.

Abstract

Mutations in the PTCH gene, the human homolog of the Drosophila patched gene, have been found to lead to the autosomal dominant disorder termed Nevoid Basal Cell Carcinoma Syndrome (NBCCS, also called Gorlin Syndrome). Patients display an array of developmental anomalies and are prone to develop a variety of tumors, with multiple Basal Cell Carcinomas occurring frequently. We provide here the results of molecular testing of a set of Italian Nevoid Basal Cell Carcinoma Syndrome patients. Twelve familial patients belonging to 7 kindreds and 5 unaffected family members, 6 non-familial patients and an additional set of 7 patients with multiple Basal Cell Carcinoma but no other criteria for the disease were examined for mutations in the PTCH gene. All of the Nevoid Basal Cell Carcinoma Syndrome patients were found to carry variants of the PTCH gene. We detected nine novel mutations (1 of which occurring twice): 1 missense mutation (c.1436T>G [p.L479R]), 1 nonsense mutation (c.1138G>T [p.E380X]), 6 frameshift mutations (c.323_324ins2, c.2011_2012dup, c.2535_2536dup, c.2577_2583del, c.3000_3005del, c.3050_3051del), 1 novel splicing variant (c.6552A>T) and 3 mutations that have been previously reported (c.3168+5G>A, c.1526G>T [p.G509V], and c.3499G>A [p.G1167R]). None of the patients with multiple Basal Cell Carcinoma but no other criteria for the syndrome, carried germline coding region mutations. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2005
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32. SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome

Author

Chiara Migliore, Anna Vendramin, Shane McKee, Paolo Prontera, Francesca Faravelli, Rani Sachdev, Patricia Dias, Martina Mascaro, Danilo Licastro, Germana Meroni, Migliore, C., Vendramin, A., Mckee, S., Prontera, P., Faravelli, F., Sachdev, R., Dias, P., Mascaro, M., Licastro, D., and Meroni, G.

Subjects
SPECC1L gene, Hypospadias, MID1 gene, Opitz G/BBB Syndrome, Genetics, hypospadias, Hypospadia, Genetics (clinical)
Abstract

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo–tracheo–esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of ‘SPECC1L syndrome’ to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo–tracheo–esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification.

Published
2022

33. Aneurysm syndromes caused by mutations in the TGF-ß receptor.

Author

Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, and De Paepe AM

Published
2006

34. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Author

S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T

Subjects
Liver Cirrhosis, 2716 Genetics (clinical), meckelin, Ciliopathies, Joubert syndrome, Genotype, congenital hepatic fibrosis, coach syndrome, mks3, meckel syndrome, joubert syndrome, tmem67, TMEM67, Meckel syndrome, DNA Mutational Analysis, 610 Medicine & health, Biology, medicine.disease_cause, MKS3, COACH syndrome, Article, NO, 1311 Genetics, Nephronophthisis, Pregnancy, Prenatal Diagnosis, Genetics, medicine, COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67, Missense mutation, Humans, Abnormalities, Multiple, Genetics (clinical), Mutation, Cilium, Membrane Proteins, Kidney Diseases, Cystic, medicine.disease, Phenotype, 10036 Medical Clinic, Female
Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Published
2010

35. Epilepsy in Mowat-Wilson syndrome: Delineation of the electroclinical phenotype

Author

Laura Mazzanti, Chiara Gelmini, Roberta Epifanio, Maria Luisa Poch-Olive, Livia Garavelli, Duccio Maria Cordelli, Alessandro Pellicciari, Luigi Tarani, Isabella Mammi, Paolo Emilio Bianchi, Morena Doz, Marina Grasso, Elvio Della Giustina, Baris Malbora, Graziella Simonte, Marcella Zollino, Emanuela Terazzi, Silvia Bonetti, Antonella Boni, Salvatore Savasta, Sabrina Buoni, Azzurra Guerra, Francesca Mari, Anita Wischmeijer, Simonetta Rosato, Paola Cerruti Mainardi, Francesca Licata, I. Cecconi, Chiara Pantaleoni, Nicoletta Zanotta, Emilio Franzoni, Salvatore Grosso, Anna Rita Ferrari, Francesca Rivieri, Marco Seri, Francesca Faravelli, Rosa Mostardini, Daniele Grioni, Giovanni Sorge, Lucio Giordano, 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 M, and Franzoni E.

Subjects
Male, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, ZEB2 gene, Atypical absence seizures, Mowat–Wilson syndrome, DNA Mutational Analysis, Settore MED/03 - GENETICA MEDICA, zeb2, Young Adult, Epilepsy, Intellectual Disability, mowat-wilson syndrome, Genetics, medicine, Humans, Hirschsprung Disease, epilepsy, seizures, eeg, Preschool, Child, Genetics (clinical), Retrospective Studies, Zinc Finger E-box Binding Homeobox 2, Slow-wave sleep, Homeodomain Proteins, Valproic Acid, business.industry, Seizure types, Facies, Spike-and-wave, Electroencephalography, medicine.disease, Repressor Proteins, Phenotype, Child, Preschool, Mutation, Anticonvulsants, Female, business, medicine.drug
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

36. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Author

Fiorella Gurrieri, Francesca Rivieri, D. De Brasi, Daniela Turchetti, Vera Uliana, R. Bergamaschi, Marco Seri, Livia Garavelli, Silvia Sassi, Giovanni Neri, S. Bernasconi, Eva Pompilii, M. Zignani, Francesca Faravelli, Rosa Mostardini, Alessandra Renieri, N. Wakamatsu, P. Cerruti Mainardi, Paolo Emilio Bianchi, Maurizia Grasso, Maria Pia Sperandeo, Margherita Silengo, Francesca Mari, Anita Wischmeijer, Maria Gnoli, F. Forzano, Daniela Orteschi, Gianfranco Sebastio, Guido Cocchi, F. Soli, Marcella Zollino, E. Favaron, R. Verri, Massimiliano Cecconi, Enrico Albertini, Laura Mazzanti, Garavelli L., Zollino M., Cerruti Mainardi 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.

Subjects
Male, Pediatrics, Aging, Chromosomes, Artificial, Bacterial, Indoles, Hirschsprung disease, facial phenotype, Disease, medicine.disease_cause, Polymerase Chain Reaction, Craniofacial Abnormalities, Epilepsy, ZEB2 GENE, Mowat-Wilson syndrome, Young adult, Agenesis of the corpus callosum, Child, Genetics (clinical), In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, ZEB2, Mutation, Nucleic Acid Hybridization, Dextrans, Syndrome, 2Q21-Q23 MICRODELETIONS, Phenotype, Italy, Child, Preschool, Female, medicine.medical_specialty, Heterozygote, Adolescent, Mowat–Wilson syndrome, Young Adult, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Fluorescent Dyes, Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, business.industry, Infant, medicine.disease, Repressor Proteins, Hypospadias, business
Abstract

Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617–623], ∼179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21–q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition. © 2009 Wiley-Liss, Inc.

Published
2009

37. Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients

Author

Angelo Selicorni, Lidia Larizza, Cristina Gervasini, Francesca Atzeri, L. Giordano, Federica Mottadelli, Francesca Faravelli, Maria Teresa Divizia, Paola Castronovo, Stefano Manzini, Patrizia Colapietro, Donatella Milani, Maria Francesca Bedeschi, Giovanni Neri, Angela Bentivegna, Maria L Giovannucci Uzielli, Bentivegna, A, Milani, D, Gervasini, C, Castronovo, P, Mottadelli, F, Manzini, S, Colapietro, P, Giordano, L, Atzeri, F, Divizia, M, Uzielli, M, Neri, G, Bedeschi, M, Faravelli, F, Selicorni, A, and Larizza, L

Subjects
Adult, Male, lcsh:Internal medicine, MED/03 - GENETICA MEDICA, Adolescent, lcsh:QH426-470, DNA Mutational Analysis, Molecular Sequence Data, Nuclear Localization Signals, medicine.disease_cause, Frameshift mutation, medicine, Genetics, Missense mutation, Humans, Point Mutation, Genetics(clinical), Amino Acid Sequence, CREB-binding protein, Child, lcsh:RC31-1245, Genetics (clinical), Sequence Deletion, Rubinstein-Taybi Syndrome, Mutation, Rubinstein–Taybi syndrome, biology, Point mutation, medicine.disease, Molecular biology, CREB-Binding Protein, Pedigree, lcsh:Genetics, Italy, Rubinstein–Taybi syndrome, CREB binding protein, Child, Preschool, biology.protein, Mutation testing, Female, Sequence Alignment, Congenital disorder, Research Article
Abstract

BackgroundRubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBPorCBP) in 16p13.3. To date mutations inCREBBPhave been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions.MethodsOur study is based on the mutation analysis ofCREBBPin 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments.ResultsWe identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected.ConclusionA high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.

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38. Expanding the phenotype of UPF3B-related disorder: Case reports and literature review.

Author

Romano F, Haanpää MK, Pomianowski P, Peraino AR, Pollard JR, Di Feo MF, Traverso M, Severino M, Derchi M, Henzen E, Zara F, Faravelli F, Capra V, and Scala M

Subjects
Humans, Male, Female, Child, RNA-Binding Proteins genetics, Genetic Association Studies, Child, Preschool, Mutation genetics, Adolescent, Intellectual Disability genetics, Intellectual Disability pathology, Genetic Predisposition to Disease, Phenotype
Abstract

UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core-member of the nonsense-mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood-onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra-rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants-the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively-while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype-phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B-related disorders, but also to ameliorate the clinical management of affected individuals., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Published
2024
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39. Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing's syndrome and acral cutaneous mucinosis.

Author

McGlacken-Byrne SM, Abdelmaksoud A, Haini M, Palm L, Ashworth M, Li J, Wang W, Wang X, Wang J, Callaghan B, Kinsler VA, Faravelli F, and Dattani MT

Subjects
Humans, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits genetics, Phenotype, Infant, Adrenal Hyperplasia, Congenital genetics, Cushing Syndrome diagnosis, Mucinoses complications
Abstract

Significance Statement: We describe a mosaic PRKACA duplication in a young infant who presented with a Carney-like complex: bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens the extra-adrenal phenotype of PRKACA-associated Cushing's syndrome. Our data suggest that Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities can exist on a spectrum. We emphasise the value of ascertaining a genetic diagnosis for PRKACA-mediated adrenal and extra-adrenal disease to guide individualised and targeted care., (© 2022 European Society of Endocrinology.)

Published
2022
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41. SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.

Author

Migliore C, Vendramin A, McKee S, Prontera P, Faravelli F, Sachdev R, Dias P, Mascaro M, Licastro D, and Meroni G

Subjects
Esophagus abnormalities, Female, Humans, Male, Mutation, Phenotype, Syndrome, Hypertelorism genetics, Hypertelorism pathology, Hypospadias genetics, Hypospadias pathology
Abstract

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of ' SPECC1L syndrome' to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo-tracheo-esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification.

Published
2022
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42. Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals.

Author

Ricci E, Fetta A, Garavelli L, Caraffi S, Ivanovski I, Bonanni P, Accorsi P, Giordano L, Pantaleoni C, Romeo A, Arena A, Bonetti S, Boni A, Chiarello D, Di Pisa V, Epifanio R, Faravelli F, Finardi E, Fiumara A, Grioni D, Mammi I, Negrin S, Osanni E, Raviglione F, Rivieri F, Rizzi R, Savasta S, Tarani L, Zanotta N, Dormi A, Vignoli A, Canevini M, and Cordelli DM

Abstract

Background: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population., Methods: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed., Results: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam., Conclusions: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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43. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome.

Author

Vabres P, Sorlin A, Kholmanskikh SS, Demeer B, St-Onge J, Duffourd Y, Kuentz P, Courcet JB, Carmignac V, Garret P, Bessis D, Boute O, Bron A, Captier G, Carmi E, Devauchelle B, Geneviève D, Gondry-Jouet C, Guibaud L, Lafon A, Mathieu-Dramard M, Thevenon J, Dobyns WB, Bernard G, Polubothu S, Faravelli F, Kinsler VA, Thauvin C, Faivre L, Ross ME, and Rivière JB

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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44. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome.

Author

Vabres P, Sorlin A, Kholmanskikh SS, Demeer B, St-Onge J, Duffourd Y, Kuentz P, Courcet JB, Carmignac V, Garret P, Bessis D, Boute O, Bron A, Captier G, Carmi E, Devauchelle B, Geneviève D, Gondry-Jouet C, Guibaud L, Lafon A, Mathieu-Dramard M, Thevenon J, Dobyns WB, Bernard G, Polubothu S, Faravelli F, Kinsler VA, Thauvin C, Faivre L, Ross ME, and Rivière JB

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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45. Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome.

Author

Vabres P, Sorlin A, Kholmanskikh SS, Demeer B, St-Onge J, Duffourd Y, Kuentz P, Courcet JB, Carmignac V, Garret P, Bessis D, Boute O, Bron A, Captier G, Carmi E, Devauchelle B, Geneviève D, Gondry-Jouet C, Guibaud L, Lafon A, Mathieu-Dramard M, Thevenon J, Dobyns WB, Bernard G, Polubothu S, Faravelli F, Kinsler VA, Thauvin C, Faivre L, Ross ME, and Rivière JB

Subjects
Humans, Neurocutaneous Syndromes pathology, Mosaicism, Mutation, Neurocutaneous Syndromes etiology, Skin Pigmentation genetics, Zygote, rhoA GTP-Binding Protein genetics
Abstract

Hypopigmentation along Blaschko's lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.

Published
2019
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46. A novel homozygous variant in CANT1 in a patient with Kim-type Desbuquois dysplasia.

Author

Menzies L, Cullup T, Calder A, Wilson L, and Faravelli F

Subjects
Facies, Genetic Testing, Humans, Phenotype, Radiography, Craniofacial Abnormalities diagnosis, Craniofacial Abnormalities genetics, Dwarfism diagnosis, Dwarfism genetics, Homozygote, Joint Instability diagnosis, Joint Instability genetics, Mutation, Nucleotidases genetics, Ossification, Heterotopic diagnosis, Ossification, Heterotopic genetics, Polydactyly diagnosis, Polydactyly genetics
Published
2019
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47. P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9.

Author

Magini P, Marco-Marin C, Escamilla-Honrubia JM, Martinelli D, Dionisi-Vici C, Faravelli F, Forzano F, Seri M, Rubio V, and Panza E

Subjects
Adult, Animals, Humans, Male, Mutation, Pedigree, Sf9 Cells, Aldehyde Dehydrogenase genetics, Bone and Bones abnormalities, Cataract genetics, Growth Disorders genetics, Spastic Paraplegia, Hereditary genetics
Abstract

In 2015-2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia. In vitro production of the ALDH18A1 product, Δ 1 -pyrroline-5-carboxylate synthetase (P5CS), appeared necessary for cracking SPG9 disease-causing mechanisms. We now describe a baculovirus-insect cell system that yields mgs of pure human P5CS and that has proven highly valuable with two novel P5CS mutations reported here in new SPG9B patients. We conclude that both mutations are disease-causing, that SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Published
2019
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48. FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene.

Author

Fernández E, Gennaro E, Pirozzi F, Baldo C, Forzano F, Turolla L, Faravelli F, Gastaldo D, Coviello D, Grasso M, and Bagni C

Abstract

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.

Published
2018
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49. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management.

Author

Chandler N, Best S, Hayward J, Faravelli F, Mansour S, Kivuva E, Tapon D, Male A, DeVile C, and Chitty LS

Subjects
Cohort Studies, Decision Making, Female, Fetus diagnostic imaging, Fetus physiopathology, High-Throughput Nucleotide Sequencing, Humans, Osteochondrodysplasias diagnosis, Osteochondrodysplasias diagnostic imaging, Osteochondrodysplasias physiopathology, Parents, Pathology, Molecular methods, Pregnancy, Ultrasonography, Prenatal, Exome genetics, Genetic Counseling methods, Osteochondrodysplasias genetics, Prenatal Diagnosis methods
Abstract

Purpose: Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar., Methods: Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias., Results: Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty., Conclusion: Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.

Published
2018
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50. 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 DM, 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, Hjortshøj TD, Epifanio R, Faravelli F, Fiumara A, Formisano D, Giordano L, Grasso M, Grønborg 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, Møller 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 A, Zollino M, Rauch A, Zweier C, and Garavelli L

Subjects
Abnormalities, Multiple genetics, Adolescent, Adult, Child, Child, Preschool, Facies, Female, Genetic Association Studies methods, Genotype, Humans, Infant, Male, Mutation, Phenotype, Zinc Finger E-box Binding Homeobox 2 genetics, Hirschsprung Disease diagnosis, Hirschsprung Disease genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Microcephaly diagnosis, Microcephaly genetics
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 evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations., Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Published
2018
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