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3. Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype

Author

Inzaghi, E., primary, Deodati, A., additional, Loddo, S., additional, Mucciolo, M., additional, Verdecchia, F., additional, Sallicandro, E., additional, Catino, G., additional, Cappa, M., additional, Novelli, A., additional, and Cianfarani, S., additional

Published
2021
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5. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Author

D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L. G., Hippolyte, L., Hanson, E., Maillard, A. M., Faucett, W. A., Mace, A., Pain, A., Bernier, R., Chawner, S. J. R. A., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gerard, M., Goin-Kochel, R. P., Grant, E., Hunter, J. V., Isidor, B., Jacquette, A., Jonch, A. E., Keren, B., Lacombe, D., Le Caignec, C., Martin, C. L., Mannik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M. J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J. A., Spence, S. J., Steinman, K. J., Tjernagel, J., Van Haelst, M., Shen, Y., Draganski, B., Sherr, E. H., Ledbetter, D. H., van den Bree, M. B. M., Beckmann, J. S., Spiro, J. E., Reymond, A., Jacquemont, S., Chung, W. K., Knoers, N. V. A. M., Martinet, D., Belfiore, M., Cuvellier, J. -C., Devries, B., Delrue, M. -A., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, M. A., Minet, J. -C., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, B. H., Koolen, D. A., Vulto-Van Silfhout, A., de Leeuw, N., Rosanfeld, J. A., Filges, I., Achatz, E., Roetzer, K. M., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, P. M., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, G. P., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Freminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, R. F., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A. L., Benedetti, M., Berg, J., Berman, J., Berry, L. N., Bibb, A. L., Blaskey, L., Brennan, J., Brewton, C. M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A. G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Endre, J., Evans, Y. L., Findlay, A., Fischbach, G. D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S. E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F. I., Jenkins, J., Jeremy, R. J., Johnson, K., Kanne, S. M., Kessler, S., Khan, S. Y., Ku, M., Kuschner, E., Laakman, A. L., Lam, P., Lasala, M. W., Lee, H., La, K., Levy, S., Lian, A., Llorens, A. V., Loftus, K., Luks, T. L., Marco, E. J., Martin, S., Martin, A. J., Marzano, G., Masson, C., Mcgovern, K. E., Keehn, R. M., Miller, D. T., Miller, F. K., Moss, T. J., Murray, R., Nagarajan, S. S., Nowell, K. P., Owen, J., Paal, A. M., Packer, A., Page, P. Z., Paul, B. M., Peters, A., Peterson, D., Poduri, A., Pojman, N. J., Porche, K., Proud, M. B., Qasmieh, S., Ramocki, M. B., Reilly, B., Roberts, T. P. L., Shaw, D., Sinha, T., Smith, B., Snow, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Blaumeiser, Bettina, Kooy, Frank, Other departments, Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, Knoers, VA., Martinet, D., Belfiore, M., Cuvellier, JC., de Vries, B., Delrue, MA., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Minet, JC., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, BH., Koolen, DA., Vulto-van Silfhout, A., de Leeuw, N., Rosenfeld, JA., Filges, I., Achatz, E., Roetzer, KM., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, PM., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, GP., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Fréminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, RF., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, AL., Benedetti, M., Berg, J., Berman, J., Berry, LN., Bibb, AL., Blaskey, L., Brennan, J., Brewton, CM., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, AG., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, JE., Evans, YL., Findlay, A., Fischbach, GD., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, SE., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, FI., Jenkins J.<Suffix>3rd</Suffix>, Jeremy, RJ., Johnson, K., Kanne, SM., Kessler, S., Khan, SY., Ku, M., Kuschner, E., Laakman, AL., Lam, P., Lasala, MW., Lee, H., LaGuerre, K., Levy, S., Lian Cavanagh, A., Llorens, AV., Loftus Campe, K., Luks, TL., Marco, EJ., Martin, S., Martin, AJ., Marzano, G., Masson, C., McGovern, KE., McNally Keehn, R., Miller, DT., Miller, FK., Moss, TJ., Murray, R., Nagarajan, SS., Nowell, KP., Owen, J., Paal, AM., Packer, A., Page, PZ., Paul, BM., Peters, A., Peterson, D., Poduri, A., Pojman, NJ., Porche, K., Proud, MB., Qasmieh, S., Ramocki, MB., Reilly, B., Roberts, TP., Shaw, D., Sinha, T., Smith-Packard, B., Snow Gallagher, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
Male, 0301 basic medicine, Proband, Pediatrics, Autism Spectrum Disorder, Developmental Disabilities, Chromosome Disorders, Comorbidity, Nonverbal learning disorder, Cohort Studies, Cognition, 0302 clinical medicine, Cerebellum, Chromosome Duplication, Gene duplication, Copy-number variation, Non-U.S. Gov't, Child, 2. Zero hunger, Intelligence quotient, Research Support, Non-U.S. Gov't, Middle Aged, Psychiatry and Mental health, Microcephaly, Female, Schizophrenic Psychology, Chromosome Deletion, Psychology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Research Support, Nervous System Malformations, Article, Chromosomes, Young Adult, 03 medical and health sciences, Intellectual Disability, Journal Article, medicine, Humans, Autistic Disorder, Preschool, Psychiatry, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Epilepsy, Pair 16, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Case-control study, Autism Spectrum Disorder/epidemiology, Autism Spectrum Disorder/genetics, Autistic Disorder/epidemiology, Autistic Disorder/genetics, Case-Control Studies, Cerebellum/abnormalities, Child, Preschool, Chromosome Disorders/epidemiology, Chromosome Disorders/genetics, Chromosomes, Human, Pair 16/genetics, Developmental Disabilities/epidemiology, Developmental Disabilities/genetics, Epilepsy/epidemiology, Epilepsy/genetics, Intellectual Disability/epidemiology, Intellectual Disability/genetics, Microcephaly/epidemiology, Microcephaly/genetics, Nervous System Malformations/epidemiology, Nervous System Malformations/genetics, Schizophrenia/epidemiology, Schizophrenia/genetics, medicine.disease, 030104 developmental biology, Chromosomes, Human, Pair 16, Schizophrenia, Autism, Human medicine, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 167711.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Published
2016
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6. Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gne syndrome

Author

Disciglio, V, Rizzo, Cl, Mencarelli, Ma, Mucciolo, M, Marozza, A, Di Marco, C, Massarelli, A, Canocchi, V, Baldassarri, M, Ndoni, E, Frullanti, E, Amabile, S, Anderlid, Bm, Metcalfe, K, Caignec, Le, David, A, Fryer, A, Boute, O, Joris, A, Greco, D, Pecile, V, Battini, R, Novelli, A, Fichera, M, Romano, C, Mari, F, and Renieri, A

Published
2014

7. Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Author

Bijlsma, E.K., Collins, A., Papa, F.T., Tejada, M.I., Wheeler, P., Peeters, E.A.J., Gijsbers, A.C.J., van de Kamp, J.M., Kriek, M., Losekoot, M., Broekma, A.J., Crolla, J.A., Pollazzon, M., Mucciolo, M., Katzaki, E., Disciglio, V., Ferreri, M.I., Marozza, A., Mencarelli, M.A., Castagnini, C., Dosa, L., Ariani, F., Mari, F., Canitano, R., Hayek, G., Botella, M.P., Gener, B., Mínguez, M., Renieri, A., and Ruivenkamp, C.A.L.

Published
2012
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8. Investigation of modifier genes within copy number variations in Rett syndrome

Author

Artuso, R, Papa, Ft, Grillo, E, Mucciolo, M, Yasui, Dh, Dunaway, Kw, Disciglio, Vittoria, Mencarelli, Ma, Pollazzon, M, Zappella, M, Hayek, G, Mari, Francesca, Renieri, Alessandra, Lasalle, Jm, Ariani, Francesca, and Papa, FILOMENA TIZIANA

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Chromatin Immunoprecipitation, Microarray, DNA Copy Number Variations, Methyl-CpG-Binding Protein 2, Clinical Sciences, Rett syndrome, Biology, Neurodegenerative, Copy Number Variants, Article, Chromosomes, MECP2, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, modifier genes, Gene duplication, medicine, Complement C3b Inactivator Proteins, Genetics, Humans, 2.1 Biological and endogenous factors, Copy-number variation, Aetiology, Genetics (clinical), 030304 developmental biology, Pediatric, Genetics & Heredity, 0303 health sciences, Neurosciences, Blood Proteins, medicine.disease, Phenotype, Chromatin, Brain Disorders, Cytoskeletal Proteins, Chromosomes, Human, Pair 1, Pair 1, Female, Chromatin immunoprecipitation, 030217 neurology & neurosurgery, Human, copy number variants
Abstract

MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

Published
2011

9. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

Author

Hansen, Christina Halgren, Kjaergaard, S, Bak, M, Hansen, Claus, Elschich, Zahra, Anderson, Claire Marie, Henriksen, Karen Friis, Hjalgrim, Helle, Kirchhoff, M, Bijlsma, Ek, Nielsen, M, den Hollander, Ns, Ruivenkamp, Cal, Isidor, B, Le Caignec, C, Zannolli, R, Mucciolo, M, Renieri, A, Mari, F, Anderlid, B-M, Andrieux, J, Dieux, A, Tommerup, N, Bache, I, Hansen, Christina Halgren, Kjaergaard, S, Bak, M, Hansen, Claus, Elschich, Zahra, Anderson, Claire Marie, Henriksen, Karen Friis, Hjalgrim, Helle, Kirchhoff, M, Bijlsma, Ek, Nielsen, M, den Hollander, Ns, Ruivenkamp, Cal, Isidor, B, Le Caignec, C, Zannolli, R, Mucciolo, M, Renieri, A, Mari, F, Anderlid, B-M, Andrieux, J, Dieux, A, Tommerup, N, and Bache, I

Abstract

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.

Published
2011

11. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

Author

Halgren, C, primary, Kjaergaard, S, additional, Bak, M, additional, Hansen, C, additional, El-Schich, Z, additional, Anderson, CM, additional, Henriksen, KF, additional, Hjalgrim, H, additional, Kirchhoff, M, additional, Bijlsma, EK, additional, Nielsen, M, additional, den Hollander, NS, additional, Ruivenkamp, CAL, additional, Isidor, B, additional, Le Caignec, C, additional, Zannolli, R, additional, Mucciolo, M, additional, Renieri, A, additional, Mari, F, additional, Anderlid, B-M, additional, Andrieux, J, additional, Dieux, A, additional, Tommerup, N, additional, and Bache, I, additional

Published
2011
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13. Differences between Transient Neonatal Diabetes Mellitus Subtypes can Guide Diagnosis and Therapy

Author

Riccardo Bonfanti, Dario Iafusco, Ivana Rabbone, Giacomo Diedenhofen, Carla Bizzarri, Patrizia Ippolita Patera, Petra Reinstadler, Francesco Costantino, Valeria Calcaterra, Lorenzo Iughetti, Silvia Savastio, Anna Favia, Francesca Cardella, Donatella Lo Presti, Ylenia Girtler, Sarah Rabbiosi, Giuseppe D’Annunzio, Angela Zanfardino, Alessia Piscopo, Francesca Casaburo, Letizia Pintomalli, Lucia Russo, Valeria Grasso, Nicola Minuto, Mafalda Mucciolo, Antonio Novelli, Antonella Marucci, Barbara Piccini, Sonia Toni, Francesca Silvestri, Paola Carrera, Andrea Rigamonti, Giulio Frontino, Michela Trada, Davide Tinti, Maurizio Delvecchio, Novella Rapini, Riccardo Schiaffini, Corrado Mammì, Fabrizio Barbetti, Monica Aloe, Simona Amadeo, Claudia Arnaldi, Marta Bassi, Luciano Beccaria, Marzia Benelli, Giulia Maria Berioloi, Enrica Bertelli, Martina Biagioni, Adriana Bobbio, Stefano Boccato, Oriana Bologna, Franco Bontempi, Clara Bonura, Giulia Bracciolini, Claudia Brufani, Patrizia Bruzzi, Pietro Buono, Roberta Cardani, Giuliana Cardinale, Alberto Casertano, Maria Cristina Castiglione, Vittoria Cauvin, Valentino Cherubini, Franco Chiarelli, Giovanni Chiari, Stefano Cianfarani, Dante Cirillo, Felice Citriniti, Susanna Coccioli, Anna Cogliardi, Santino Confetto, Giovanna Contreas, Anna Corò, Elisa Corsini, Nicoletta Cresta, Fiorella De Berardinis, Valeria De Donno, Giampaolo De Filippo, Rosaria De Marco, Annalisa Deodati, Elena Faleschini, Valentina Fattorusso, Valeria Favalli, Barbara Felappi, Lucia Ferrito, Graziella Fichera, Franco Fontana, Elena Fornari, Roberto Franceschi, Francesca Franco, Adriana Franzese, Anna Paola Frongia, Alberto Gaiero, Francesco Gallo, Luigi Gargantini, Elisa Giani, Chiara Giorgetti, Giulia Bianchi, Vanna Graziani, Antonella Gualtieri, Monica Guasti, Gennaro Iannicelli, Antonio Iannilli, Ignaccolo Giovanna, Dario Ingletto, Stefania Innaurato, Elena Inzaghi, Brunella Iovane, Peter Kaufmann, Alfonso La Loggia, Rosa Lapolla, Anna Lasagni, Nicola Lazzaro, Lorenzo Lenzi, Riccardo Lera, Gabriella Levantini, Fortunato Lombardo, Antonella Lonero, Silvia Longhi, Sonia Lucchesi, Lucia Paola Guerraggio, Sergio Lucieri, Patrizia Macellaro, Claudio Maffeis, Bendetta Mainetti, Giulio Maltoni, Chiara Mameli, Francesco Mammì, Maria Luisa Manca-Bitti, Melania Manco, Monica Marino, Matteo Mariano, Marco Marigliano, Alberto Marsciani, Costanzo Mastrangelo, Maria Cristina Matteoli, Elena Mazzali, Franco Meschi, Antonella MIgliaccio, Anita Morandi, Gianfranco Morganti, Enza Mozzillo, Gianluca Musolino, Rosa Nugnes, Federica Ortolani, Daniela Pardi, Filomena Pascarella, Stefano Passanisi, Annalisa Pedini, Cristina Pennati, Angelo Perrotta, Sonia Peruzzi, Paola Peverelli, Giulia Pezzino, Anita Claudia Piona, Gavina Piredda, Carmelo Pistone, Elena Prandi, Barbara Pedieri, Procolo Di Bonito, Anna Pulcina, Maria Quinci, Emioli Randazzo, Rossella Ricciardi, Carlo Ripoli, Rosanna Roppolo, Irene Rutigliano, Alberto Sabbio, Silvana salardi, Alessandro Salvatoni, Anna Saporiti, Rita Sardi, Mariapiera Scanu, Andrea Scaramuzza, Eleonardo Schiven, Andrea Secco, Linda Sessa, Paola Sogno Valin, Silvia Sordelli, Luisa Spallino, Stefano Stagi, Filomena Stamati, Tosca Suprani, Valentina Talarico, Tiziana Timapanaro, Antonella Tirendi, Letizia Tomaselli, Gianluca Tornese, Adolfo Andrea Trettene, Stefano Tumini, Giuliana Valerio, Claudia Ventrici, Matteo Viscardi, Silvana Zaffani, Maria Zampolli, Giorgio Zanette, Clara Zecchino, Maria Antonietta Zedda, Silvia Zonca, Stefano Zucchini, Bonfanti, R., Iafusco, D., Rabbone, I., Diedenhofen, G., Bizzarri, C., Patera, P. I., Reinstadler, P., Costantino, F., Calcaterra, V., Iughetti, L., Savastio, S., Favia, A., Cardella, F., Presti, D. L., Girtler, Y., Rabbiosi, S., D'Annunzio, G., Zanfardino, A., Piscopo, A., Casaburo, F., Pintomalli, L., Russo, L., Grasso, V., Minuto, N., Mucciolo, M., Novelli, A., Marucci, A., Piccini, B., Toni, S., Silvestri, F., Carrera, P., Rigamonti, A., Frontino, G., Trada, M., Tinti, D., Delvecchio, M., Rapini, N., Schiaffini, R., Mammi, C., and Barbetti, F.

Subjects
Proband, Male, Pediatrics, Potassium Channels, Endocrinology, Diabetes and Metabolism, Datasets as Topic, Diagnosis, Differential, Diagnostic Techniques, Endocrine, Female, Humans, Infant, Infant, Newborn, Italy, Mutation, Potassium Channels, Inwardly Rectifying, Remission Induction, Retrospective Studies, Sulfonylurea Receptors, Diabetes Mellitus, Infant, Newborn, Diseases, Diseases, Gastroenterology, Diabetes mellitus genetics, Endocrinology, Settore MED/13, Retrospective Studie, Diagnosis, Medicine, Endocrine pancreas, Transient Neonatal Diabetes Mellitus, 6q24 TNDM, KATP TNDM, Sulfonylureas, Sulfonylureas, Sulfonylurea Receptor, biology, Diabetes Mellitu, General Medicine, Metformin, Inwardly Rectifying, Settore MED/03, 6q24 TNDM, medicine.symptom, Endocrine, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Human, endocrine system, medicine.medical_specialty, KATP TNDM, ABCC8, Transient Neonatal Diabetes Mellitus, Internal medicine, Diabetes mellitus, Macroglossia, Endocrine pancreas, business.industry, medicine.disease, Newborn, Diagnostic Techniques, Transient neonatal diabetes mellitus, Differential, biology.protein, Sulfonylurea receptor, business
Abstract

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Published
2021

14. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012
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15. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, 610 Medicine & health, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Temporal lobe, Epilepsy, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Copy-number variation, Child, Molecular Biology, Genetics (clinical), Chromosomes, Human, Pair 15, Infant, General Medicine, Odds ratio, medicine.disease, Epilepsy, Rolandic, Rolandic epilepsy, Exact test, Chromosomes, Human, Pair 1, Child, Preschool, Female, Chromosomes, Human, Pair 16
Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Published
2014
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16. 9q31.1q31.3 deletion in two patients with similar clinical features: a newly recognized microdeletion syndrome?

Author

Pamela Magini, F. Tavalazzi, Marco Seri, Alessandra Renieri, Claudio Graziano, Mafalda Mucciolo, Francesca Mari, Maria Antonietta Mencarelli, Annabella Marozza, Giuseppe Hayek, Patrizia Mongelli, Mucciolo, M, Magini, P, Marozza, A, Mongelli, P, Mencarelli, Ma, Hayek, G, Tavalazzi, F, Mari, F, Seri, M, Renieri, A, and Graziano, C.

Subjects
Adult, Chromosome Disorders, Chromosome 9, body mass index, Short stature, Diagnosis, Differential, Chromosome Breakpoints, Young Adult, chromosome 9q deletion, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Segmental duplication, Comparative Genomic Hybridization, Base Sequence, biology, Breakpoint, Facies, Membrane Proteins, Sequence Analysis, DNA, Syndrome, Twins, Monozygotic, Gibbus, Microdeletion syndrome, biology.organism_classification, Phenotype, Chromosomes, Human, Pair 1, intellectual disability, array comparative genomic hybridization, Female, Chromosome Deletion, medicine.symptom, Chromosomes, Human, Pair 9, Haploinsufficiency, cardiomyopathy, dilated, Microsatellite Repeats, Comparative genomic hybridization, non-homologous DNA end joining
Abstract

Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region.

Published
2014

17. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011
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18. Exploring the Clinical Spectrum of HUWE1-Related Neurodevelopmental Disorder: Five New Patients and Literature Review.

Author

De Falco A, Minale EMP, Meossi C, Pagano S, Trovato R, Agolini E, Mucciolo M, Novelli A, Bartolini E, Santorelli FM, and Piscopo C

Abstract

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder associated with variants in the HUWE1 gene on chromosome Xp11. The condition is characterized by variable phenotypes, including global developmental delay, intellectual disability, and distinctive facial dysmorphisms, with inheritance patterns ranging from X-linked recessive to de novo mutations in females. Here, we describe five probands in two families, highlighting their clinical features and genetic findings. Trio whole-exome sequencing identified a de novo variant in HUWE1 in the proband in one family and a maternally inherited hemizygous variant in three boys in a second family. A comprehensive review of HUWE1-associated cases from the literature assisted genotype-phenotype correlations, revealing consistent features such as intellectual disability, skeletal anomalies, and facial dysmorphisms as well as instances of intrafamilial variability. Our findings confirm the phenotypic variability of MRXST and underscore the significance of the HUWE1 gene product in neurodevelopment. We propose a baseline monitoring protocol to aid in diagnosis and management, contributing to the development of specific guidelines for patient follow-up., (© 2024 Wiley Periodicals LLC.)

Published
2024
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19. The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022.

Author

Rapini N, Delvecchio M, Mucciolo M, Ruta R, Rabbone I, Cherubini V, Zucchini S, Cianfarani S, Prandi E, Schiaffini R, Bizzarri C, Piccini B, Maltoni G, Predieri B, Minuto N, Di Paola R, Giordano M, Tinto N, Grasso V, Russo L, Tiberi V, Scaramuzza A, Frontino G, Maggio MC, Musolino G, Piccinno E, Tinti D, Carrera P, Mozzillo E, Cappa M, Iafusco D, Bonfanti R, Novelli A, and Barbetti F

Subjects
Humans, Italy epidemiology, Infant, Newborn, Male, Female, Infant, High-Throughput Nucleotide Sequencing, Infant, Newborn, Diseases epidemiology, Infant, Newborn, Diseases genetics, Genetic Testing methods, Insulin Resistance genetics, Mutation, Incidence, Retrospective Studies, Diabetes Mellitus epidemiology, Diabetes Mellitus genetics
Abstract

Context: In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM)., Objective: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS)., Methods: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset., Results: Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin., Conclusion: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Published
2024
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20. Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Author

Dentici ML, Niceta M, Lepri FR, Mancini C, Priolo M, Bonnard AA, Cappelletti C, Leoni C, Ciolfi A, Pizzi S, Cordeddu V, Rossi C, Ferilli M, Mucciolo M, Colona VL, Fauth C, Bellini M, Biasucci G, Sinibaldi L, Briuglia S, Gazzin A, Carli D, Memo L, Trevisson E, Schiavariello C, Luca M, Novelli A, Michot C, Sweertvaegher A, Germanaud D, Scarano E, De Luca A, Zampino G, Zenker M, Mussa A, Dallapiccola B, Cavé H, Digilio MC, and Tartaglia M

Subjects
Humans, Female, Male, Child, Child, Preschool, Infant, Loss of Function Mutation, Adolescent, Repressor Proteins genetics, Adult, Craniosynostoses genetics, Craniosynostoses pathology, Noonan Syndrome genetics, Noonan Syndrome pathology, Phenotype
Abstract

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Published
2024
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22. Monogenic diabetes clinic (MDC): 3-year experience.

Author

Rapini N, Patera PI, Schiaffini R, Ciampalini P, Pampanini V, Cristina MM, Deodati A, Bracaglia G, Porzio O, Ruta R, Novelli A, Mucciolo M, Cianfarani S, and Barbetti F

Subjects
Humans, Child, Genetic Testing, Mutation, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 2 diagnosis, Diabetes Complications genetics, Hyperglycemia genetics
Abstract

Aim: In the pediatric diabetes clinic, patients with type 1 diabetes mellitus (T1D) account for more than 90% of cases, while monogenic forms represent about 6%. Many monogenic diabetes subtypes may respond to therapies other than insulin and have chronic diabetes complication prognosis that is different from T1D. With the aim of providing a better diagnostic pipeline and a tailored care for patients with monogenic diabetes, we set up a monogenic diabetes clinic (MDC)., Methods: In the first 3 years of activity 97 patients with non-autoimmune forms of hyperglycemia were referred to MDC. Genetic testing was requested for 80 patients and 68 genetic reports were available for review., Results: In 58 subjects hyperglycemia was discovered beyond 1 year of age (Group 1) and in 10 before 1 year of age (Group 2). Genetic variants considered causative of hyperglycemia were identified in 25 and 6 patients of Group 1 and 2, respectively, with a pick up rate of 43.1% (25/58) for Group 1 and 60% (6/10) for Group 2 (global pick-up rate: 45.5%; 31/68). When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes, while pick-up rate was 18.1% (4/22) in patients with mute family history for diabetes. Specific treatments for each condition were administered in most cases., Conclusion: We conclude that MDC may contribute to provide a better diabetes care in the pediatric setting., (© 2022. The Author(s).)

Published
2023
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24. Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.

Author

McClenaghan C, Rapini N, De Rose DU, Gao J, Roeglin J, Bizzarri C, Schiaffini R, Tiberi E, Mucciolo M, Deodati A, Perri A, Vento G, Barbetti F, Nichols CG, and Cianfarani S

Subjects
Blood Glucose, Child, Gain of Function Mutation, Humans, Infant, Newborn, KATP Channels genetics, Sulfonylurea Compounds therapeutic use, Sulfonylurea Receptors genetics, Diabetes Mellitus genetics, Infant, Newborn, Diseases drug therapy, Infant, Newborn, Diseases genetics, Potassium Channels, Inwardly Rectifying genetics
Abstract

Background/aims: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases., Methods: Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis., Results: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide., Conclusions: In this subject, the KCNJ11 (c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations., (© 2022 S. Karger AG, Basel.)

Published
2022
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25. Unusual Presentation of Denys-Drash Syndrome in a Girl with Undisclosed Consumption of Biotin

Author

Bizzarri C, Antonella Giannone G, Gervasoni J, Benedetti S, Albanese F, Dello Strologo L, Guzzo I, Mucciolo M, Diomedi Camassei F, Emma F, Cappa M, and Porzio O

Subjects
Adolescent, Castration, Denys-Drash Syndrome complications, Denys-Drash Syndrome diagnosis, Denys-Drash Syndrome therapy, Diagnostic Errors, Female, Humans, Hyperandrogenism blood, Hyperandrogenism diagnosis, Hyperandrogenism surgery, Immunoassay, Kidney Failure, Chronic etiology, Predictive Value of Tests, Testosterone blood, Biotin adverse effects, Denys-Drash Syndrome genetics, Dietary Supplements adverse effects
Abstract

We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Published
2021
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26. Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy.

Author

Bonfanti R, Iafusco D, Rabbone I, Diedenhofen G, Bizzarri C, Patera PI, Reinstadler P, Costantino F, Calcaterra V, Iughetti L, Savastio S, Favia A, Cardella F, Lo Presti D, Girtler Y, Rabbiosi S, D'Annunzio G, Zanfardino A, Piscopo A, Casaburo F, Pintomalli L, Russo L, Grasso V, Minuto N, Mucciolo M, Novelli A, Marucci A, Piccini B, Toni S, Silvestri F, Carrera P, Rigamonti A, Frontino G, Trada M, Tinti D, Delvecchio M, Rapini N, Schiaffini R, Mammì C, and Barbetti F

Subjects
Datasets as Topic, Diagnosis, Differential, Diagnostic Techniques, Endocrine standards, Female, Humans, Infant, Infant, Newborn, Italy, Male, Mutation, Potassium Channels, Inwardly Rectifying genetics, Remission Induction methods, Retrospective Studies, Sulfonylurea Receptors genetics, Diabetes Mellitus classification, Diabetes Mellitus congenital, Diabetes Mellitus diagnosis, Diabetes Mellitus genetics, Diabetes Mellitus therapy, Infant, Newborn, Diseases classification, Infant, Newborn, Diseases diagnosis, Infant, Newborn, Diseases genetics, Infant, Newborn, Diseases therapy
Abstract

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features., Design: Retrospective analysis of the Italian data set of patients with TNDM., Methods: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared., Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy., Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Published
2021
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27. Providing more evidence on LZTR1 variants in Noonan syndrome patients.

Author

Chinton J, Huckstadt V, Mucciolo M, Lepri F, Novelli A, Gravina LP, and Obregon MG

Subjects
Adolescent, Adult, Argentina epidemiology, Child, Child, Preschool, Facies, Female, Heart Defects, Congenital pathology, Humans, Infant, Male, Middle Aged, Mutation, Noonan Syndrome epidemiology, Noonan Syndrome pathology, Pedigree, Phenotype, Proto-Oncogene Proteins c-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Young Adult, Genetic Predisposition to Disease, Heart Defects, Congenital genetics, Noonan Syndrome genetics, Transcription Factors genetics
Abstract

Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain-of-function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients., (© 2019 Wiley Periodicals, Inc.)

Published
2020
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28. SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review.

Author

Baban A, Olivini N, Lepri FR, Calì F, Mucciolo M, Digilio MC, Calcagni G, di Mambro C, Dallapiccola B, Adorisio R, Novelli A, and Drago F

Subjects
Child, Preschool, Female, Humans, Infant, Male, Young Adult, Cardiomyopathies complications, Cardiomyopathies genetics, Heart Defects, Congenital complications, Heart Defects, Congenital genetics, Mutation genetics, Noonan Syndrome complications, Noonan Syndrome genetics, SOS1 Protein genetics
Abstract

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs., (© 2019 Wiley Periodicals, Inc.)

Published
2019
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29. Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.

Author

Ponzi E, Alesi V, Lepri FR, Genovese S, Loddo S, Mucciolo M, Novelli A, Dionisi-Vici C, and Maiorana A

Subjects
Adolescent, Dwarfism pathology, Glycogen Storage Disease Type III pathology, Humans, Male, Uniparental Disomy pathology, Chromosomes, Human, Pair 1 genetics, Dwarfism genetics, Glycogen Storage Disease Type III genetics, Phenotype, Uniparental Disomy genetics
Abstract

Background: Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18-year-old boy with a profound growth retardation (<3 SD) besides typical clinical features of GSDIII, whereby endocrinological studies were negative., Methods and Results: Molecular analysis of AGL gene revealed the homozygous reported variant c.3903&#95;3904insA. Since discordant results from segregation studies showed the carrier status in one parent only, SNP array and short tandem repeats analyses were performed, revealing a paternal disomy of chromosome 1 (UPD1)., Conclusion: This study describes the first case of GSDIII resulting from UPD1. UPD can play an important role even in case of imprinted genes. DIRAS3 is a maternally imprinted tumor suppressor gene, located on chromosome 1p31, and implicated in growth and oncogenesis. It can be speculated that DIRAS3 overexpression might have a role in the severe short stature of our patient. The study emphasizes the importance of parental segregation analysis especially in patients with recessive conditions to look for specific genetic causes of disease and to estimate properly the risk of family recurrence., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Published
2019
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30. Renal Tubular Dysfunction Fully Accounts for Plasma Biochemical Abnormalities in Type 1A Pseudohypoparathyroidism.

Author

Labbadia R, Bizzarri C, Mucciolo M, Di Zazzo G, Guzzo I, Cappa M, Emma F, and Dello Strologo L

Subjects
Calcium blood, Child, Chromogranins genetics, Female, GTP-Binding Protein alpha Subunits, Gs genetics, Humans, Kidney Transplantation, Phosphates blood, Pseudohypoparathyroidism complications, Pseudohypoparathyroidism genetics, Renal Insufficiency blood, Renal Insufficiency etiology, Renal Insufficiency surgery, Vitamin D blood, Kidney Tubules physiopathology, Parathyroid Hormone blood, Pseudohypoparathyroidism blood, Renal Insufficiency physiopathology
Abstract

Context: Type 1A pseudohypoparathyroidism (PHP-1A) is characterized by target organ resistance to PTH. Patients can present with various dysmorphic features; however, renal failure has not been classically described., Case Description: A female patient came to our attention at the age of 7 years with characteristic signs of PTH resistance (i.e., hypocalcemia, hyperphosphatemia, and high serum PTH levels). She also presented with hypothyroidism, early-onset obesity, short metacarpal bones, and multiple subcutaneous ossifications, leading to a clinical diagnosis of pseudohypoparathyroidism. In addition to her genetic condition, she had bilateral renal hypodysplasia that was slowly progressing to end-stage kidney disease. She received a kidney transplant at the age of 16 years and, after transplantation, experienced rapidly normalized calcium, phosphate, and PTH levels, allowing f withdrawal of vitamin D supplementation., Conclusions: To the best of our knowledge, ours is the first report of a patient with PHP-1A undergoing kidney transplantation. Normalization of biochemical parameters after the procedure demonstrated that renal tubular resistance to PTH is sufficient to explain the calcium/phosphate abnormalities observed in PHP-1A.

Published
2019
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31. Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism.

Author

Ponzi E, Maiorana A, Lepri FR, Mucciolo M, Semeraro M, Taurisano R, Olivieri G, Novelli A, and Dionisi-Vici C

Subjects
Adolescent, Child, Child, Preschool, Chronic Disease, Cohort Studies, DNA Mutational Analysis methods, Genetic Predisposition to Disease epidemiology, Gluconeogenesis physiology, Glycogen Storage Disease diagnosis, Glycogen Storage Disease genetics, High-Throughput Nucleotide Sequencing methods, Humans, Infant, Infant, Newborn, Italy, Male, Mitochondrial Diseases diagnosis, Mitochondrial Diseases genetics, Retrospective Studies, Sensitivity and Specificity, Carbohydrate Metabolism, Inborn Errors diagnosis, Carbohydrate Metabolism, Inborn Errors genetics, Genomics methods, Hypoglycemia diagnosis, Hypoglycemia genetics
Abstract

Objectives: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia., Study Design: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data., Results: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders., Conclusions: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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32. Complete Scrotal Agenesis: New Surgical Approach Using Self-inflating Tissue Expander.

Author

Spagnoli A, Borsellino A, Crucianelli S, Bizzarri C, Mucciolo M, Trucchi A, and Ferro F

Subjects
Equipment Design, Humans, Infant, Male, Urologic Surgical Procedures, Male instrumentation, Scrotum abnormalities, Scrotum surgery, Tissue Expansion Devices
Abstract

Complete agenesis of the scrotum is an extremely rare entity: to date, only 8 cases have been reported. The authors describe 1 case carrying a heterozygous genomic variant in exon 17 of the MAP3K1 gene, whose surgical treatment included osmotic prosthesis implant to achieve reconstruction of a new scrotum. By constant and gradual expansion, self-inflating prothesis avoids patient discomfort and facilitates orchiopexy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2018
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33. Next-Generation Sequencing Identifies Different Genetic Defects in 2 Patients with Primary Adrenal Insufficiency and Gonadotropin-Independent Precocious Puberty.

Author

Guzzetti C, Bizzarri C, Pisaneschi E, Mucciolo M, Bellacchio E, Ibba A, Casula L, Novelli A, Loche S, and Cappa M

Subjects
Adrenal Hyperplasia, Congenital complications, Adrenal Hyperplasia, Congenital genetics, Adrenal Insufficiency complications, Child, Child, Preschool, DNA Mutational Analysis methods, High-Throughput Nucleotide Sequencing, Humans, Male, Phenotype, Puberty, Precocious complications, Sequence Analysis, DNA, Adrenal Insufficiency genetics, DAX-1 Orphan Nuclear Receptor genetics, Puberty, Precocious genetics, Steroid 11-beta-Hydroxylase genetics
Abstract

Background: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis., Methods: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders., Results: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging., Conclusions: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible., (© 2018 S. Karger AG, Basel.)

Published
2018
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34. Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency.

Author

Bizzarri C, Pisaneschi E, Mucciolo M, Pedicelli S, Galeazzi D, Novelli A, and Cappa M

Subjects
Female, Humans, Infant, Italy, Steroidogenic Acute Regulatory Protein, Adrenal Hyperplasia, Congenital genetics, Disorder of Sex Development, 46,XY genetics, Mutation, Phosphoproteins genetics
Abstract

Background: Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations., Case Presentation: A female infant of Italian origin came to our attention in late infancy with a clinical picture of acute adrenal insufficiency. The study of the STAR gene revealed two genomic variants c.562C > T and c.577C > T in compound heterozygosity. At the protein level, the two mutations determine the p.Arg188Cys variant (rs104894090) and the p.Arg193Ter variant (rs387907235), respectively. Sanger sequencing was used to confirm the identified variants and to perform familial study. The mother carried the p.Arg188Cys variant, while the father carried the p.Arg193Ter variant., Conclusion: To our knowledge this is the second case of classic lipoid congenital adrenal hyperplasia reported in the Italian population. STAR mutations resulting in lipoid congenital adrenal hyperplasia should be considered all over the world in the differential diagnosis of newborn babies and infants with primary adrenal insufficiency.

Published
2017
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35. Next Generation Sequencing Approach in a Prenatal Case of Cardio-Facio-Cutaneus Syndrome.

Author

Mucciolo M, Dello Russo C, D'Emidio L, Mesoraca A, and Giorlandino C

Abstract

Cardiofaciocutaneous syndrome (CFCS) belongs to a group of developmental disorders due to defects in the Ras/Mitogen-Activated Protein Kinase (RAS/MAPK) signaling pathway named RASophaties. While postnatal presentation of these disorders is well known, the prenatal and neonatal characteristics are less recognized. Noonan syndrome, Costello syndrome, and CFCS diagnosis should be considered in pregnancies with a normal karyotype and in the case of ultrasound findings such as increased nuchal translucency, polyhydramnios, macrosomia and cardiac defect. Because all the RASopathies share similar clinical features, their molecular characterization is complex, time consuming and expensive. Here we report a case of CFCS prenatally diagnosed through Next Generation Prenatal Diagnosis (NGPD), a new targeted approach that allows us to concurrently investigate all the genes involved in the RASophaties.

Published
2016
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36. Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).

Author

Dhanraj S, Gunja SM, Deveau AP, Nissbeck M, Boonyawat B, Coombs AJ, Renieri A, Mucciolo M, Marozza A, Buoni S, Turner L, Li H, Jarrar A, Sabanayagam M, Kirby M, Shago M, Pinto D, Berman JN, Scherer SW, Virtanen A, and Dror Y

Subjects
Alleles, Animals, Bone Marrow Diseases metabolism, Child, DNA Mutational Analysis, Developmental Disabilities metabolism, Female, Genetic Testing, Humans, Infant, Male, Middle Aged, Myelin Sheath genetics, Myelin Sheath pathology, Telomere Homeostasis genetics, Young Adult, Zebrafish, Bone Marrow Diseases genetics, Developmental Disabilities genetics, Exoribonucleases genetics, Mutation, Missense, Sequence Deletion
Abstract

Background: Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN., Methods: We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease., Results: We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease., Conclusions: Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Published
2015
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37. Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome.

Author

Disciglio V, Lo Rizzo C, Mencarelli MA, Mucciolo M, Marozza A, Di Marco C, Massarelli A, Canocchi V, Baldassarri M, Ndoni E, Frullanti E, Amabile S, Anderlid BM, Metcalfe K, Le Caignec C, David A, Fryer A, Boute O, Joris A, Greco D, Pecile V, Battini R, Novelli A, Fichera M, Romano C, Mari F, and Renieri A

Subjects
Child, Child, Preschool, Comparative Genomic Hybridization, Diagnosis, Differential, Facies, Female, Humans, Infant, Male, Phenotype, Syndrome, Chromosome Deletion, Chromosome Disorders diagnosis, Chromosome Disorders genetics, Chromosomes, Human, Pair 22 genetics, Nerve Tissue Proteins genetics
Abstract

Phelan-McDermid syndrome (22q13.3 deletion syndrome) is a contiguous gene disorder resulting from the deletion of the distal long arm of chromosome 22. SHANK3, a gene within the minimal critical region, is a candidate gene for the major neurological features of this syndrome. We report clinical and molecular data from a study of nine patients with overlapping interstitial deletions in 22q13 not involving SHANK3. All of these deletions overlap with the largest, but not with the smallest deletion associated with Phelan-McDermid syndrome. The deletion sizes and breakpoints varied considerably among our patients, with the largest deletion spanning 6.9 Mb and the smallest deletion spanning 2.7 Mb. Eight out of nine patients had a de novo deletion, while in one patient the origin of deletion was unknown. These patients shared clinical features common to Phelan-McDermid syndrome: developmental delay (11/12), speech delay (11/12), hypotonia (9/12), and feeding difficulties (7/12). Moreover, the majority of patients (8/12) exhibited macrocephaly. In the minimal deleted region, we identified two candidate genes, SULT4A1 and PARVB (associated with the PTEN pathway), which could be associated in our cohort with neurological features and macrocephaly/hypotonia, respectively. This study suggests that the haploinsufficiency of genes in the 22q13 region beside SHANK3 contributes to cognitive and speech development, and that these genes are involved in the phenotype associated with the larger Phelan-McDermid syndrome 22q13 deletions. Moreover, because the deletions in our patients do not involve the SHANK3 gene, we posit the existence of a new contiguous gene syndrome proximal to the smallest terminal deletions in the 22q13 region., (© 2014 Wiley Periodicals, Inc.)

Published
2014
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38. Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA.

Author

Yamamoto T, Mencarelli MA, Di Marco C, Mucciolo M, Vascotto M, Balestri P, Gérard M, Mathieu-Dramard M, Andrieux J, Breuning M, Hoffer MJ, Ruivenkamp CA, Shimada S, Sangu N, Shimojima K, Umezu R, Kawame H, Matsuo M, Saito K, Renieri A, and Mari F

Subjects
Adolescent, Child, Preschool, Chromosome Banding, DNA Copy Number Variations, Female, Genotype, Humans, In Situ Hybridization, Fluorescence, Male, Phenotype, Transcriptional Elongation Factors, Young Adult, Chromosome Deletion, Chromosomes, Human, Pair 15 genetics, Genetic Association Studies methods, Intellectual Disability genetics, Nuclear Proteins genetics, Nuclear Receptor Subfamily 1, Group F, Member 1 genetics
Abstract

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions., (Crown Copyright © 2014. Published by Elsevier Masson SAS. All rights reserved.)

Published
2014
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39. Investigation of modifier genes within copy number variations in Rett syndrome.

Author

Artuso R, Papa FT, Grillo E, Mucciolo M, Yasui DH, Dunaway KW, Disciglio V, Mencarelli MA, Pollazzon M, Zappella M, Hayek G, Mari F, Renieri A, Lasalle JM, and Ariani F

Subjects
Blood Proteins genetics, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 1 genetics, Complement C3b Inactivator Proteins genetics, Cytoskeletal Proteins genetics, Female, Humans, Methyl-CpG-Binding Protein 2 genetics, Methyl-CpG-Binding Protein 2 metabolism, Phenotype, DNA Copy Number Variations, Rett Syndrome genetics
Abstract

MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

Published
2011
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40. Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2.

Author

Uliana V, Marcocci E, Mucciolo M, Meloni I, Izzi C, Manno C, Bruttini M, Mari F, Scolari F, Renieri A, and Salviati L

Subjects
Adult, Child, Comparative Genomic Hybridization, Female, Humans, Introns genetics, Leiomyomatosis, Male, Molecular Sequence Data, Nephritis, Hereditary genetics, Pedigree, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Base Sequence genetics, Collagen Type IV genetics, Sequence Deletion genetics
Abstract

Alport syndrome (ATS) is a nephropathy characterized by the association of progressive hematuric nephritis with ultrastructural changes of the glomerular basement membrane (thinning, thickening, and splitting), sensorineural deafness, and variable ocular abnormalities (anterior lenticonus, macular flecks, and cataracts). The most common mode of transmission is X-linked inheritance, due to COL4A5 mutations. X-linked ATS is rarely associated with diffuse leiomyomatosis (DL), a benign hypertrophy of the visceral smooth muscle in gastrointestinal, respiratory, and female reproductive tracts. The ATS-DL complex is due to deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes and include the bidirectional promoter. In this paper, we described 3 ATS-DL cases, 2 familial and 1 sporadic bearing a deletion encompassing the 5'-end of both the COL4A5 and COL4A6 genes, as identified by multiplex ligation-dependent probe amplification (MLPA) analysis. The array-CGH technique allowed a better definition of deletion size, confirming that the proximal breakpoint was within COL4A6 intron 2 in 2 cases. Surprisingly, 1 case had a deletion extending proximally beyond exon 3 of COL4A6, as confirmed by qPCR analysis. This is the largest deletion reported to date that has been associated with ATS-DL and this case should lead us to reconsider the mechanisms that might be involved in the development of diffuse leiomyomatosis.

Published
2011
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41. 3.2 Mb microdeletion in chromosome 7 bands q22.2-q22.3 associated with overgrowth and delayed bone age.

Author

Uliana V, Grosso S, Cioni M, Ariani F, Papa FT, Tamburello S, Rossi E, Katzaki E, Mucciolo M, Marozza A, Pollazzon M, Mencarelli MA, Mari F, Balestri P, and Renieri A

Subjects
Bone and Bones pathology, Cell Cycle, Child, Comparative Genomic Hybridization, Corpus Callosum pathology, Facies, Growth Disorders genetics, Heterozygote, Humans, Intellectual Disability genetics, Male, Syndrome, Chromosome Banding, Chromosome Deletion, Chromosomes, Human, Pair 7
Abstract

We report a patient with mental retardation, epilepsy, overgrowth, delayed bone age, peculiar facial features, corpus callosum hypoplasia, enlarged cisterna magna and right cerebellar hypoplasia. Array-CGH analysis revealed the presence of a de novo 3.2 Mb interstitial deletion of the long arm of chromosome 7 involving bands q22.2-q22.3. The rearrangement includes 15 genes and encompasses a genomic region that represents a site of frequent loss of heterozygosity in myeloid malignancies. Four genes are implicated in the control of cell cycle: SRPK2, MLL5, RINT1 and LHFPL3. Haploinsufficiency of these genes might therefore be associated with overgrowth and could confer susceptibility to cancers or other tumours, so that attention to this possibility would be appropriate during regular medical review. In conclusion, array-CGH analysis should be performed in patients with overgrowth where the known causes have already been excluded, because some still unclassified overgrowth syndromes may be caused by subtle genomic imbalances., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Published
2010
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