Search

Your search keyword '"Dobyns, William B."' showing total 1,251 results
Start Over Author "Dobyns, William B."
1,251 results on '"Dobyns, William B."'

203. Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.

Author

Pirozzi, Filomena, Lee, Benson, Horsley, Nicole, Burkardt, Deepika D., Dobyns, William B., Graham, John M., Dentici, Maria L., Cesario, Claudia, Schallner, Jens, Porrmann, Joseph, Di Donato, Nataliya, Sanchez‐Lara, Pedro A., and Mirzaa, Ghayda M.

Abstract

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2‐CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) syndrome. Megalencephaly‐associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation‐resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop‐gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2‐related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

204. The spectrum of brain malformations and disruptions in twins.

Author

Park, Kaylee B., Chapman, Teresa, Aldinger, Kimberly A., Mirzaa, Ghayda M., Zeiger, Jordan, Beck, Anita, Glass, Ian A., Hevner, Robert F., Jansen, Anna C., Marshall, Desiree A., Oegema, Renske, Parrini, Elena, Saneto, Russell P., Curry, Cynthia J., Hall, Judith G., Guerrini, Renzo, Leventer, Richard J., and Dobyns, William B.

Abstract

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co‐twins with abnormal brain imaging and compared them to population‐based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia‐ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy–Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p =.0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p <.0001. Recurrent association with twin–twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

209. Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females

Author

D’Agostino, Maria Daniela, Bernasconi, Andrea, Das, Soma, Bastos, Alexandre, Valerio, Rosa M., Palmini, André, da Costa, Jaderson Costa, Scheffer, Ingrid E., Berkovic, Samuel, Guerrini, Renzo, Dravet, Charlotte, Ono, Jiro, Gigli, GianLuigi, Federico, Antonio, Booth, Fran, Bernardi, Bruno, Volpi, Lilia, Tassinari, Carlo Alberto, Guggenheim, Mary Anne, Ledbetter, David H., Gleeson, Joseph G., Lopes-Cendes, Iscia, Vossler, David G., Malaspina, Elisabetta, Franzoni, Emilio, Sartori, Roberto J., Mitchell, Michael H., Mercho, Suha, Dubeau, François, Andermann, Frederick, Dobyns, William B., and Andermann, Eva

Published
2002

210. Lissencephaly: a human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13

Author

Dobyns, William B., Reiner, Orly, Carrozzo, Romeo, and Ledbetter, David H.

Subjects
Brain -- Abnormalities, Chromosome deletion -- Health aspects
Abstract

Classical lissencephaly may frequently be caused by missing portions of the lissencephaly critical region of chromosome 17. Lissencephaly is a malformation in which the convolutions of the cerebral cortex of the brain are not normally developed and the brain is usually small. The lissencephaly critical region contains the lissencephaly gene. Researchers reviewed published and unpublished genetic studies of 90 lissencephaly patients. Twenty-five patients had Miller-Dieker syndrome (MDS) and 65 had isolated lissencephaly sequence (ILS). Twenty-one of the patients with ILS had classical lissencephaly. Deletions in the lissencephaly critical region were found in 92% of the patients with MDS and 13% of those with ILS. Thirty-eight percent of the patients with classical lissencephaly had deletions in this region of chromosome 17.

Published
1993

211. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats

Author

Reiner, Orly, Carrozzo, Romeo, Ying Shen, Wehnert, Manfred, Faustinella, Fabrizia, Dobyns, William B., Caskey, C. Thomas, and Ledbetter, David H.

Subjects
Brain -- Abnormalities, G proteins -- Genetic aspects, Amino acid sequence -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A gene which is absent in Miller-Dieker syndrome patients, who suffer from lissencephaly which is a brain malformation, has been cloned and LIS-1 has been found as the disease gene. Considerable homology to beta-subunits of heterotrimetic G proteins can be inferred from amino-acid sequences. The LIS-1 protein, which has eight WD 40 repeats of the same type, was found in G protein beta-subunits. LIS-1 may be crucial for brain development and could also be a part of a larger group of proteins which have the WD 40 repeat units in common.

Published
1993

212. De novocoding variants in the AGO1gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Challman, Thomas D, Wain, Karen E, Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, Lanpher, Brendan C, Kemppainen, Jennifer L, Innes, Micheil, Kooy, Frank, Meuwissen, Marije, Goldenberg, Alice, Lecoquierre, Francois, Vera, Gabriella, Diderich, Karin E M, Sheidley, Beth, El Achkar, Christelle Moufawad, Park, Meredith, Hamdan, Fadi F, Michaud, Jacques L, Lewis, Ann J, Zweier, Christiane, Reis, André, Wagner, Matias, Weigand, Heike, Journel, Hubert, Keren, Boris, Passemard, Sandrine, Mignot, Cyril, van Gassen, Koen, Brilstra, Eva H, Itzikowitz, Gina, O'Heir, Emily, Allen, Jake, Donald, Kirsten A, Korf, Bruce Richard, Skelton, Tammi, Thompson, Michelle, Robin, Nathaniel H, Rudy, Natasha L, Dobyns, William B, Foss, Kimberly, Zarate, Yuri Alexander, Bosanko, Katherine A, Alembik, Yves, Durand, Benjamin, Tran Mau-them, Frederic, Ranza, Emmanuelle, Blanc, Xavier, Antonarakis, Stylianos E, McWalter, Kirsty, Torti, Erin, Millan, Francisca, Dameron, Amy, Tokita, Mari, Zimmermann, Michael T, Klee, Eric W, Piton, Amelie, and Gerard, Benedicte

Abstract

BackgroundHigh-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).MethodsThis study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1coding variants, occurring de novo for all those whose transmission could have been verified (26/28).ResultsA total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.ConclusionOur study establishes that de novo coding variants in AGO1are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Published
2022
Full Text
View/download PDF

213. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females

Author

Sheen, Volney L., Dixon, Peter H., Fox, Jeremy W., Hong, Susan E., Kinton, Lucy, Sisodiya, Sanjay M., Duncan, John S., Dubeau, Francois, Scheffer, Ingrid E., Schachter, Steven C., Wilner, Andrew, Henchy, Ruth, Crino, Peter, Kamuro, Kazuhiro, DiMario, Frances, Berg, Michel, Kuzniecky, Ruben, Cole, Andrew J., Bromfield, Edward, Biber, Michael, Schomer, Donald, Wheless, James, Silver, Kenneth, Mochida, Ganeshwaran H., Berkovic, Samuel F., Andermann, Fred, Andermann, Eva, Dobyns, William B., Wood, Nicholas W., and Walsh, Christopher A.

Published
2001

216. Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

Author

Karasozen, Yigit, primary, Osbun, Joshua W., additional, Parada, Carolina Angelica, additional, Busald, Tina, additional, Tatman, Philip, additional, Gonzalez-Cuyar, Luis F., additional, Hale, Christopher J., additional, Alcantara, Diana, additional, O’Driscoll, Mark, additional, Dobyns, William B., additional, Murray, Mitzi, additional, Kim, Louis J., additional, Byers, Peter, additional, Dorschner, Michael O., additional, and Ferreira, Manuel, additional

Published
2019
Full Text
View/download PDF

217. Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Author

Vandervore, Laura V, primary, Schot, Rachel, additional, Kasteleijn, Esmee, additional, Oegema, Renske, additional, Stouffs, Katrien, additional, Gheldof, Alexander, additional, Grochowska, Martyna M, additional, van der Sterre, Marianne L T, additional, van Unen, Leontine M A, additional, Wilke, Martina, additional, Elfferich, Peter, additional, van der Spek, Peter J, additional, Heijsman, Daphne, additional, Grandone, Anna, additional, Demmers, Jeroen A A, additional, Dekkers, Dick H W, additional, Slotman, Johan A, additional, Kremers, Gert-Jan, additional, Schaaf, Gerben J, additional, Masius, Roy G, additional, van Essen, Anton J, additional, Rump, Patrick, additional, van Haeringen, Arie, additional, Peeters, Els, additional, Altunoglu, Umut, additional, Kalayci, Tugba, additional, Poot, Raymond A, additional, Dobyns, William B, additional, Bahi-Buisson, Nadia, additional, Verheijen, Frans W, additional, Jansen, Anna C, additional, and Mancini, Grazia M S, additional

Published
2019
Full Text
View/download PDF

220. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance

Author

Dobyns, William B., primary, Aldinger, Kimberly A., additional, Ishak, Gisele E., additional, Mirzaa, Ghayda M., additional, Timms, Andrew E., additional, Grout, Megan E., additional, Dremmen, Marjolein H.G., additional, Schot, Rachel, additional, Vandervore, Laura, additional, van Slegtenhorst, Marjon A., additional, Wilke, Martina, additional, Kasteleijn, Esmee, additional, Lee, Arthur S., additional, Barry, Brenda J., additional, Chao, Katherine R., additional, Szczałuba, Krzysztof, additional, Kobori, Joyce, additional, Hanson-Kahn, Andrea, additional, Bernstein, Jonathan A., additional, Carr, Lucinda, additional, D’Arco, Felice, additional, Miyana, Kaori, additional, Okazaki, Tetsuya, additional, Saito, Yoshiaki, additional, Sasaki, Masayuki, additional, Das, Soma, additional, Wheeler, Marsha M., additional, Bamshad, Michael J., additional, Nickerson, Deborah A., additional, Engle, Elizabeth C., additional, Verheijen, Frans W., additional, Doherty, Dan, additional, and Mancini, Grazia M.S., additional

Published
2018
Full Text
View/download PDF

223. 34 - Neurogenetics in the Genome Era

Author

McMahon, Kelly, Paciorkowski, Alex R., Walters-Sen, Lauren C., Milunsky, Jeff M., Bassuk, Alexander, Darbro, Benjamin, Diaz, Jullianne, Dobyns, William B., and Gropman, Andrea

Published
2017
Full Text
View/download PDF

226. Erratum : Correction: Human mutations in integrator complex subunits link transcriptome integrity to brain development (PLoS genetics (2017) 13 5 (e1006809))

Author

Oegema, Renske, Baillat, David, Schot, Rachel, van Unen, Leontine M., Brooks, Alice, Kia, Sima Kheradmand, Hoogeboom, A. Jeannette M., Xia, Zheng, Li, Wei, Cesaroni, Matteo, Lequin, Maarten H., van Slegtenhorst, Marjon, Dobyns, William B., de Coo, Irenaeus F.M., van den Berg, Debbie, Verheijen, Frans W., Kremer, Andreas, van der Spek, Peter J., Heijsman, Daphne, Wagner, Eric J., Fornerod, Maarten, and Mancini, Grazia M.S.

Subjects
Cancer Research, Published Erratum, Genetics, Genetics(clinical), Molecular Biology, Ecology, Evolution, Behavior and Systematics
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1006809.].

Published
2017

227. Congenital Zika Syndrome: Characterizing the Pattern of Anomalies for Pediatric Healthcare Providers

Author

Moore, Cynthia A., Staples, J. Erin, Dobyns, William B., Pessoa, André, Ventura, Camila V., da Fonseca, Eduardo Borges, Ribeiro, Erlane Marques, Ventura, Liana O., Neto, Norberto Nogueira, Arena, J. Fernando, and Rasmussen, Sonja A.

Subjects
Diagnosis, Differential, Pregnancy, Zika Virus Infection, Humans, Infant, Female, Zika Virus, Pregnancy Complications, Infectious, Nervous System Malformations, Article
Abstract

Zika virus infection can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. To inform pediatric clinicians who may be called on to evaluate and treat affected infants and children, we review the most recent evidence to better characterize congenital Zika syndrome.We reviewed published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine Zika virus infection. We conducted a comprehensive search of the English literature using Medline and EMBASE for Zika from inception through September 30, 2016. Congenital anomalies were considered in the context of the presumed pathogenetic mechanism related to the neurotropic properties of the virus. We conclude that congenital Zika syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage. Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, there are 5 features that are rarely seen with other congenital infections or are unique to congenital Zika virus infection: (1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices with subcortical calcifications; (3) macular scarring and focal pigmentary retinal mottling; (4) congenital contractures; and (5) marked early hypertonia and symptoms of extrapyramidal involvement.Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype-the congenital Zika syndrome-has emerged. Recognition of this phenotype by clinicians for infants and children can help ensure appropriate etiologic evaluation and comprehensive clinical investigation to define the range of anomalies in an affected infant as well as determine essential follow-up and ongoing care.

Published
2017

230. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

Author

Haldipur, Parthiv, Aldinger, Kimberly A., Bernardo, Silvia, Mei Deng, Timms, Andrew E., Overman, Lynne M., Winter, Conrad, Lisgo, Steven N., Razavi, Ferechte, Silvestri, Evelina, Manganar, Lucia, Adle-Biasette, Homa, Guilmiot, Fabien, Russo, Rosa, Kidron, Debora, Hof, Patrick R., Gerrelli, Dianne, Lindsay, Susan J., Dobyns, William B., and Glass, Ian A.

Published
2019
Full Text
View/download PDF

232. Walker-Warburg syndrome and tectocerebellar dysraphia: A novel association caused by a homozygous DAG1 mutation

Author

Leibovitz, Zvi, primary, Mandel, Hanna, additional, Falik-Zaccai, Tzipora C., additional, Ben Harouch, Shani, additional, Savitzki, David, additional, Krajden-Haratz, Karina, additional, Gindes, Liat, additional, Tamarkin, Mordechai, additional, Lev, Dorit, additional, Dobyns, William B., additional, and Lerman-Sagie, Tally, additional

Published
2018
Full Text
View/download PDF

233. Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms

Author

Berg, Anne T., primary, Chakravorty, Samya, additional, Koh, Sookyong, additional, Grinspan, Zachary M., additional, Shellhaas, Renée A., additional, Saneto, Russell P., additional, Wirrell, Elaine C., additional, Coryell, Jason, additional, Chu, Catherine J., additional, Mytinger, John R., additional, Gaillard, William D., additional, Valencia, Ignacio, additional, Knupp, Kelly G., additional, Loddenkemper, Tobias, additional, Sullivan, Joseph E., additional, Poduri, Annapurna, additional, Millichap, John J., additional, Keator, Cynthia, additional, Wusthoff, Courtney, additional, Ryan, Nicole, additional, Dobyns, William B., additional, and Hegde, Madhuri, additional

Published
2018
Full Text
View/download PDF

235. Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Author

De Mori, Roberta, primary, Romani, Marta, additional, D’Arrigo, Stefano, additional, Zaki, Maha S., additional, Lorefice, Elisa, additional, Tardivo, Silvia, additional, Biagini, Tommaso, additional, Stanley, Valentina, additional, Musaev, Damir, additional, Fluss, Joel, additional, Micalizzi, Alessia, additional, Nuovo, Sara, additional, Illi, Barbara, additional, Chiapparini, Luisa, additional, Di Marcotullio, Lucia, additional, Issa, Mahmoud Y., additional, Anello, Danila, additional, Casella, Antonella, additional, Ginevrino, Monia, additional, Leggins, Autumn Sa’na, additional, Roosing, Susanne, additional, Alfonsi, Romina, additional, Rosati, Jessica, additional, Schot, Rachel, additional, Mancini, Grazia Maria Simonetta, additional, Bertini, Enrico, additional, Dobyns, William B., additional, Mazza, Tommaso, additional, Gleeson, Joseph G., additional, and Valente, Enza Maria, additional

Published
2017
Full Text
View/download PDF

236. Defining the phenotypical spectrum associated with variants in TUBB2A

Author

Brock, Stefanie, Vanderhasselt, Tim, Vermaning, Sietske, Keymolen, Kathelijn, Régal, Luc, Romaniello, Romina, Wieczorek, Dagmar, Storm, Tim Matthias, Schaeferhoff, Karin, Hehr, Ute, Kuechler, Alma, Kra¨geloh-Mann, Ingeborg, Haack, Tobias B, Kasteleijn, Esmee, Schot, Rachel, Mancini, Grazia Maria Simonetta, Webster, Richard, Mohammad, Shekeeb, Leventer, Richard J, Mirzaa, Ghayda, Dobyns, William B, Bahi-Buisson, Nadia, Meuwissen, Marije, Jansen, Anna C, and Stouffs, Katrien

Abstract

BackgroundVariants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2Ahave been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis.MethodsIn order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2Avariants, recruited via the international network of the authors, were reviewed.ResultsWe report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2Agene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2Apatients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.ConclusionThe imaging phenotype associated with pathogenic variants in TUBB2Ais highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.

Published
2021
Full Text
View/download PDF

237. Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

Author

Zenner, Kaitlyn, Jensen, Dana M., Cook, Tori T., Dmyterko, Victoria, Bly, Randall A., Ganti, Sheila, Mirzaa, Ghayda M., Dobyns, William B., Perkins, Jonathan A., and Bennett, James T.

Abstract

Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM.

Published
2021
Full Text
View/download PDF

238. A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome

Author

Twigg, Stephen R.F., Hufnagel, Robert B., Miller, Kerry A., Zhou, Yan, McGowan, Simon J., Taylor, John, Craft, Jude, Taylor, Jenny C., Santoro, Stephanie L., Huang, Taosheng, Hopkin, Robert J., Brady, Angela F., Clayton-Smith, Jill, Clericuzio, Carol L., Grange, Dorothy K., Groesser, Leopold, Hafner, Christian, Horn, Denise, Temple, I. Karen, Dobyns, William B., Curry, Cynthia J., Jones, Marilyn C., and Wilkie, Andrew O.M.

Abstract

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.

Published
2016

239. A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

Author

Twigg, Stephen RF, Hufnagel, Robert B, Miller, Kerry A, Zhou, Yan, McGowan, Simon J, Taylor, John, Craft, Jude, Taylor, Jenny C, Santoro, Stephanie L, Huang, Taosheng, Hopkin, Robert J, Brady, Angela F, Clayton-Smith, Jill, Clericuzio, Carol L, Grange, Dorothy K, Groesser, Leopold, Hafner, Christian, Horn, Denise, Temple, I Karen, Dobyns, William B, Curry, Cynthia J, Jones, Marilyn C, and Wilkie, Andrew OM

Subjects
Male, Medical and Health Sciences, Craniofacial Abnormalities, Rare Diseases, Clinical Research, Report, Genetics, Humans, Genetics(clinical), Child, Preschool, Cancer, Pediatric, Genetics & Heredity, Neurosciences, Infant, Newborn, Infant, Biological Sciences, Newborn, Smoothened Receptor, Brain Disorders, Brain Cancer, Intestines, Child, Preschool, Mutation, Skin Abnormalities, Female, Syndactyly, Signal Transduction
Abstract

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.

Published
2016

240. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

Author

Huang, Lijia, Vanstone, Megan R, Hartley, Taila, Osmond, Matthew, Barrowman, Nick, Allanson, Judith, Baker, Laura, Dabir, Tabib A, Dipple, Katrina M, Dobyns, William B, Estrella, Jane, Faghfoury, Hanna, Favaro, Francine P, Goel, Himanshu, Gregersen, Pernille A, Gripp, Karen W, Grix, Art, Guion-Almeida, Maria-Leine, Harr, Margaret H, Hudson, Cindy, Hunter, Alasdair GW, Johnson, John, Joss, Shelagh K, Kimball, Amy, Kini, Usha, Kline, Antonie D, Lauzon, Julie, Lildballe, Dorte L, López-González, Vanesa, Martinezmoles, Johanna, Meldrum, Cliff, Mirzaa, Ghayda M, Morel, Chantal F, Morton, Jenny EV, Pyle, Louise C, Quintero-Rivera, Fabiola, Richer, Julie, Scheuerle, Angela E, Schönewolf-Greulich, Bitten, Shears, Deborah J, Silver, Josh, Smith, Amanda C, Temple, I Karen, UCLA Clinical Genomics Center, van de Kamp, Jiddeke M, van Dijk, Fleur S, Vandersteen, Anthony M, White, Sue M, Zackai, Elaine H, Zou, Ruobing, Care4Rare Canada Consortium, Bulman, Dennis E, Boycott, Kym M, and Lines, Matthew A

Subjects
Protein Structure, Secondary, Care4Rare Canada Consortium, RNA Splicing, Amino Acid Motifs, Molecular Sequence Data, Clinical Sciences, mandibulofacial dysostosis, Gene Expression, Penetrance, Haploinsufficiency, EFTUD2, Databases, Congenital, U5 Small Nuclear, Rare Diseases, Genetic, Models, mandibulofacial dysostosis with microcephaly, Clinical Research, Intellectual Disability, Genetics, Humans, 2.1 Biological and endogenous factors, mandibulofacial dysostosis Guion-Almeida type, microcephaly, Dental/Oral and Craniofacial Disease, Aetiology, Hearing Loss, MFDM, Pediatric, Genetics & Heredity, Prevention, Human Genome, Neurosciences, Molecular, Ribonucleoprotein, Peptide Elongation Factors, Phenotype, Mutation, Spliceosomes, Congenital Structural Anomalies, Abnormalities, UCLA Clinical Genomics Center, Multiple, Tertiary
Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Published
2016

241. Vascular abnormalities in epidermal nevus syndrome

Author

Dobyns, William B. and Garg, Bhuwan P.

Subjects
Nervous system diseases -- Development and progression, Brain -- Infarction, Birth defects -- Case studies, Health, Psychology and mental health
Abstract

Epidermal nevus syndrome is a neurocutaneous disorder that involves both multiple epidermal nevi and congenital abnormalities of some organs, including the brain. Although the clinical syndrome might superficially resemble some inherited disorders, epidermal nevus syndrome seems to be sporadic rather than familial. Brain abnormalities such as hemimegalencephaly, in which one side of the brain is excessively large, are common in cases of epidermal nevus syndrome. Neurologic symptoms resembling those of hemorrhage or infarction (tissue damage due to inadequate oxygen) are also common. The authors present the case of one patient with epidermal nevus syndrome with evidence of infarction, and review three more cases from the medical literature. The patient was noted to develop decreased use of the left arm at three months of age, and at nine months a spastic hemiparesis developed. Computed tomography revealed an infarction in the region of the right middle cerebral artery, and some associated atrophy. The patient recovered, and at three years is developing well. He did show some mild speech delay. It was not possible to identify any blood vessel abnormalities in this child. However, in the three cases reported in the medical literature, an occluded artery, an aneurysm, and an angioma could be identified. The authors suggest that when stroke-like symptoms are observed in a patient with epidermal nevus syndrome, they probably indicate a stroke. The occurrence of such events in patients with epidermal nevus syndrome most likely represents a predilection of these patients to have vascular abnormalities. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1991

242. International consensus recommendations on the diagnostic work-up for malformations of cortical development

Author

Oegema, Renske, Barakat, Tahsin Stefan, Wilke, Martina, Stouffs, Katrien, Amrom, Dina, Aronica, Eleonora, Bahi-Buisson, Nadia, Conti, Valerio, Fry, Andrew E., Geis, Tobias, Andres, David Gomez, Parrini, Elena, Pogledic, Ivana, Said, Edith, Soler, Doriette, Valor, Luis M., Zaki, Maha S., Mirzaa, Ghayda, Dobyns, William B., Reiner, Orly, Guerrini, Renzo, Pilz, Daniela T., Hehr, Ute, Leventer, Richard J., Jansen, Anna C., Mancini, Grazia M. S., and Di Donato, Nataliya

Abstract

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.

Published
2020
Full Text
View/download PDF

243. Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Author

Alcantara, Diana, primary, Timms, Andrew E, additional, Gripp, Karen, additional, Baker, Laura, additional, Park, Kaylee, additional, Collins, Sarah, additional, Cheng, Chi, additional, Stewart, Fiona, additional, Mehta, Sarju G, additional, Saggar, Anand, additional, Sztriha, László, additional, Zombor, Melinda, additional, Caluseriu, Oana, additional, Mesterman, Ronit, additional, Van Allen, Margot I, additional, Jacquinet, Adeline, additional, Ygberg, Sofia, additional, Bernstein, Jonathan A, additional, Wenger, Aaron M, additional, Guturu, Harendra, additional, Bejerano, Gill, additional, Gomez-Ospina, Natalia, additional, Lehman, Anna, additional, Alfei, Enrico, additional, Pantaleoni, Chiara, additional, Conti, Valerio, additional, Guerrini, Renzo, additional, Moog, Ute, additional, Graham Jr., John M, additional, Hevner, Robert, additional, Dobyns, William B, additional, O’Driscoll, Mark, additional, and Mirzaa, Ghayda M, additional

Published
2017
Full Text
View/download PDF

244. Early-Life Epilepsies and the Emerging Role of Genetic Testing

Author

Berg, Anne T., primary, Coryell, Jason, additional, Saneto, Russell P., additional, Grinspan, Zachary M., additional, Alexander, John J., additional, Kekis, Mariana, additional, Sullivan, Joseph E., additional, Wirrell, Elaine C., additional, Shellhaas, Renée A., additional, Mytinger, John R., additional, Gaillard, William D., additional, Kossoff, Eric H., additional, Valencia, Ignacio, additional, Knupp, Kelly G., additional, Wusthoff, Courtney, additional, Keator, Cynthia, additional, Dobyns, William B., additional, Ryan, Nicole, additional, Loddenkemper, Tobias, additional, Chu, Catherine J., additional, Novotny, Edward J., additional, and Koh, Sookyong, additional

Published
2017
Full Text
View/download PDF

245. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy

Author

Syrbe, Steffen, primary, Harms, Frederike L, additional, Parrini, Elena, additional, Montomoli, Martino, additional, Mütze, Ulrike, additional, Helbig, Katherine L, additional, Polster, Tilman, additional, Albrecht, Beate, additional, Bernbeck, Ulrich, additional, van Binsbergen, Ellen, additional, Biskup, Saskia, additional, Burglen, Lydie, additional, Denecke, Jonas, additional, Heron, Bénédicte, additional, Heyne, Henrike O, additional, Hoffmann, Georg F, additional, Hornemann, Frauke, additional, Matsushige, Takeshi, additional, Matsuura, Ryuki, additional, Kato, Mitsuhiro, additional, Korenke, G Christoph, additional, Kuechler, Alma, additional, Lämmer, Constanze, additional, Merkenschlager, Andreas, additional, Mignot, Cyril, additional, Ruf, Susanne, additional, Nakashima, Mitsuko, additional, Saitsu, Hirotomo, additional, Stamberger, Hannah, additional, Pisano, Tiziana, additional, Tohyama, Jun, additional, Weckhuysen, Sarah, additional, Werckx, Wendy, additional, Wickert, Julia, additional, Mari, Francesco, additional, Verbeek, Nienke E, additional, Møller, Rikke S, additional, Koeleman, Bobby, additional, Matsumoto, Naomichi, additional, Dobyns, William B, additional, Battaglia, Domenica, additional, Lemke, Johannes R, additional, Kutsche, Kerstin, additional, and Guerrini, Renzo, additional

Published
2017
Full Text
View/download PDF

246. Correction: Human mutations in integrator complex subunits link transcriptome integrity to brain development

Author

Oegema, Renske, primary, Baillat, David, additional, Schot, Rachel, additional, van Unen, Leontine M., additional, Brooks, Alice, additional, Kia, Sima Kheradmand, additional, Hoogeboom, A. Jeannette M., additional, Xia, Zheng, additional, Li, Wei, additional, Cesaroni, Matteo, additional, Lequin, Maarten H., additional, van Slegtenhorst, Marjon, additional, Dobyns, William B., additional, de Coo, Irenaeus F. M., additional, van den Berg, Debbie, additional, Verheijen, Frans W., additional, Kremer, Andreas, additional, van der Spek, Peter J., additional, Heijsman, Daphne, additional, Wagner, Eric J., additional, Fornerod, Maarten, additional, and Mancini, Grazia M. S., additional

Published
2017
Full Text
View/download PDF

247. Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish

Author

Van De Weghe, Julie C., primary, Rusterholz, Tamara D.S., additional, Latour, Brooke, additional, Grout, Megan E., additional, Aldinger, Kimberly A., additional, Shaheen, Ranad, additional, Dempsey, Jennifer C., additional, Maddirevula, Sateesh, additional, Cheng, Yong-Han H., additional, Phelps, Ian G., additional, Gesemann, Matthias, additional, Goel, Himanshu, additional, Birk, Ohad S., additional, Alanzi, Talal, additional, Rawashdeh, Rifaat, additional, Khan, Arif O., additional, Bamshad, Michael J., additional, Nickerson, Deborah A., additional, Neuhauss, Stephan C.F., additional, Dobyns, William B., additional, Alkuraya, Fowzan S., additional, Roepman, Ronald, additional, Bachmann-Gagescu, Ruxandra, additional, and Doherty, Dan, additional

Published
2017
Full Text
View/download PDF

248. Neuroimaging findings in Mowat–Wilson syndrome: a study of 54 patients

Author

Garavelli, Livia, primary, Ivanovski, Ivan, additional, Caraffi, Stefano Giuseppe, additional, Santodirocco, Daniela, additional, Pollazzon, Marzia, additional, Cordelli, Duccio Maria, additional, Abdalla, Ebtesam, additional, Accorsi, Patrizia, additional, Adam, Margaret P., additional, Baldo, Chiara, additional, Bayat, Allan, additional, Belligni, Elga, additional, Bonvicini, Federico, additional, Breckpot, Jeroen, additional, Callewaert, Bert, additional, Cocchi, Guido, additional, Cuturilo, Goran, additional, Devriendt, Koenraad, additional, Dinulos, Mary Beth, additional, Djuric, Olivera, additional, Epifanio, Roberta, additional, Faravelli, Francesca, additional, Formisano, Debora, additional, Giordano, Lucio, additional, Grasso, Marina, additional, Grønborg, Sabine, additional, Iodice, Alessandro, additional, Iughetti, Lorenzo, additional, Lacombe, Didier, additional, Maggi, Massimo, additional, Malbora, Baris, additional, Mammi, Isabella, additional, Moutton, Sebastien, additional, Møller, Rikke, additional, Muschke, Petra, additional, Napoli, Manuela, additional, Pantaleoni, Chiara, additional, Pascarella, Rosario, additional, Pellicciari, Alessandro, additional, Poch-Olive, Maria Luisa, additional, Raviglione, Federico, additional, Rivieri, Francesca, additional, Russo, Carmela, additional, Savasta, Salvatore, additional, Scarano, Gioacchino, additional, Selicorni, Angelo, additional, Silengo, Margherita, additional, Sorge, Giovanni, additional, Tarani, Luigi, additional, Tone, Luis Gonzaga, additional, Toutain, Annick, additional, Trimouille, Aurelien, additional, Te Valera, Elvis rci, additional, Vergano, Samantha Schrier, additional, Zanotta, Nicoletta, additional, Zollino, Marcella, additional, Dobyns, William B, additional, and Paciorkowski, Alex R, additional

Published
2017
Full Text
View/download PDF

249. Human mutations in integrator complex subunits link transcriptome integrity to brain development

Author

Oegema, Renske, primary, Baillat, David, additional, Schot, Rachel, additional, van Unen, Leontine M., additional, Brooks, Alice, additional, Kia, Sima Kheradmand, additional, Hoogeboom, A. Jeannette M., additional, Xia, Zheng, additional, Li, Wei, additional, Cesaroni, Matteo, additional, Lequin, Maarten H., additional, van Slegtenhorst, Marjon, additional, Dobyns, William B., additional, de Coo, Irenaeus F. M., additional, Verheijen, Frans W., additional, Kremer, Andreas, additional, van der Spek, Peter J., additional, Heijsman, Daphne, additional, Wagner, Eric J., additional, Fornerod, Maarten, additional, and Mancini, Grazia M. S., additional

Published
2017
Full Text
View/download PDF

250. Lissencephaly: Expanded imaging and clinical classification

Author

Di Donato, Nataliya, primary, Chiari, Sara, additional, Mirzaa, Ghayda M., additional, Aldinger, Kimberly, additional, Parrini, Elena, additional, Olds, Carissa, additional, Barkovich, A. James, additional, Guerrini, Renzo, additional, and Dobyns, William B., additional

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results