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9 results on '"Sousa, S. B."'

1. Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype

Author

Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., Zollino M. (ORCID:0000-0003-4871-9519), Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to as episignatures have been reported in HVDAS and BAF complex disorders. Due to molecular interactions between ADNP and BAF complex, and an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS, we hypothesized the possibility of a common phenotype-specific episignature. A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants. This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures.

Published
2024

2. Severe Osteogenesis imperfecta with oligodontia: think of MESD

Author

Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., Netzer, C., Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., and Netzer, C.

Published
2020

3. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Author

Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., Zollino M. (ORCID:0000-0003-4871-9519), Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020

4. Medicinal fungi used by rural communities in Northeastern Brazil.

Author

Andrade, L. H. C., Barros, R. F. M., Lopes, J. B., and Sousa, S. B.

Subjects
MEDICINAL plants, HYMENOCHAETACEAE, AGARICACEAE, POLYPORACEAE, TRADITIONAL medicine
Abstract

The use of fungi for diversified purposes is part of the history of mankind. We sought to report what is known about fungal species used for medicinal purposes by rural populations in Northeastern Brazil. To this end, semi-structured forms were applied to 176 informants from four rural communities located in the southern region of Piauí. The fungi were deposited in the Graziela Barroso Herbarium (TEPB) of the Federal University of Piauí. The use value (UV) and relative importance (RI) of each species were calculated and similarity was estimated with the Sorensen index. Medicinal use was identified for four basidiomycete species belonging to the families Agaricaceae [Podaxis pistillaris (L.) Fr.], Hymenochaetaceae (Fomitiporia sp.) and Polyporaceae [Hexagonia hydnoides (Sw.) M. Fidalgo and Pycnoporus sanguineus (L.) Murrill]. Indicated for intestinal colic in infants, P. sanguineus was the species that presented the greatest current and potential UV and greater cultural importance. Studies on the chemical and pharmacological composition of the mentioned species were found, indicating their antibacterial, antiparasitic, antiviral, antifungal and antioxidant potential. Knowledge about these fungi has been transmitted from generation to generation, with greater similarity among individuals of the female sex and adult age. The results showed that there is ethnomycological knowledge in rural communities still to be explored in the semi-arid region of Brazil and highlighted the importance of studies about the ethnological knowledge of medicinal fungi. [ABSTRACT FROM AUTHOR]

Published
2021
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5. Phenotype and genotype in Nicolaides-Baraitser syndrome

Author

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

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

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

Published
2014

6. Coleção nuclear para o Banco Ativo de Germoplasma regional da mandioca (Manihot esculenta Crantz) da Embrapa Amazônia Ocidental

Author

SOUSA, S. B. de and Sandra Barbosa de Sousa, Coorientadora: Nelcimar R. Sousa, CPAA.

Subjects
Caracterização molecular, Mandioca, Genética
Abstract

Esta dissertação é formada por dois capítulos que visam caracterizar e contribuir para o aumento da utilização da coleção de germoplasma de mandioca da Embrapa Amazônia Ocidental, composta de 470 acessos, entre mandiocas amargas e mansas, coletados ao longo da bacia amazônica nas calhas dos rios Solimões, Purus, Madeira, Negro e Baixo Amazonas, por meio de marcadores moleculares microssatelites (SSR). No capitulo 1 foi analisada a diversidade genética em mandioca (Manihot esculenta Crantz) conservada ex-situ no Amazonas, utilizando marcadores microssatélites. No capitulo 2 foi desenhada uma coleção nuclear no banco ativo de germoplasma de mandioca na Embrapa Amazônia Ocidental. Made available in DSpace on 2019-03-11T19:47:06Z (GMT). No. of bitstreams: 1 SousaSBDissertacaoFinal.pdf: 831506 bytes, checksum: 44b79c206e7a082acc944c6f4842d71a (MD5) Previous issue date: 2014 Dissertação (Mestrado em Genética, Conservação e Biologia Evolutiva) - Instituto Nacional de Pesquisas da Amazônia, Manaus. Orientador: Charles R. Clement; Coorientadora: Nelcimar R. Sousa.

Published
2014

7. Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion

Author

Guillaud Bataille, M, primary, Rhayem, Y, additional, Sousa, S B, additional, Libé, R, additional, Dambrun, M, additional, Chevalier, C, additional, Nigou, M, additional, Auzan, C, additional, North, M O, additional, Sa, J, additional, Gomes, L, additional, Salpea, P, additional, Horvath, A, additional, Stratakis, C A, additional, Hamzaoui, N, additional, Bertherat, J, additional, and Clauser, E, additional

Published
2014
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8. Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion.

Author

Bataille, M. Guillaud, Rhayem, Y., Sousa, S. B., Libe, R., Dambrun, M., Chevalier, C., Nigou, M., Auzan, C., North, M. O., Sa, J., Gomes, L., Salpea, P., Horvath, A., Stratakis, C. A., Hamzaoui, N., Bertherat, J., and Clauser, E.

Subjects
GENE rearrangement, CYCLIC-AMP-dependent protein kinase, CARNEY complex, DELETION mutation, POINT mutation (Biology), BIOLUMINESCENCE
Abstract

Background: Point mutations of the PRKAR1A gene are a genetic cause of Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD), but in 30% of the patients no mutation is detected. Objective: Set up a routine-based technique for systematic detection of large deletions or duplications of this gene and functionally characterize these mutations. Methods: Multiplex ligation-dependent probe amplification (MLPA) of the 12 exons of the PRKAR1A gene was validated and used to detect large rearrangements in 13 typical CNC and 39 confirmed or putative PPNAD without any mutations of the gene. An in-frame deletion was characterized by western blot and bioluminescence resonant energy transfer technique for its interaction with the catalytic subunit. Results: MLPA allowed identification of exons 3-6 deletion in three patients of a family with typical CNC. The truncated protein is expressed, but rapidly degraded, and does not interact with the protein kinase A catalytic subunit. Conclusions: MLPA is a powerful technique that may be used following the lack of mutations detected by direct sequencing in patients with bona fide CNC or PPNAD.We report here one such new deletion, as an example. However, these gene defects are not a frequent cause of CNC or PPNAD. [ABSTRACT FROM AUTHOR]

Published
2014
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9. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome

Author

Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, Sara El Kennani, Joaquim Sá, Karen J. Low, Cristina Dias, Markéta Havlovicová, Miroslava Hančárová, Evan E. Eichler, Françoise Devillard, Sébastien Moutton, Julien Van-Gils, Christèle Dubourg, Sylvie Odent, Bénédicte Gerard, Amélie Piton, Toshiyuki Yamamoto, Nobuhiko Okamoto, Helen Firth, Kay Metcalfe, Anna Moh, Kimberly A. Chapman, Erfan Aref-Eshghi, Jennifer Kerkhof, Annalaura Torella, Vincenzo Nigro, Laurence Perrin, Juliette Piard, Gwenaël Le Guyader, Thibaud Jouan, Christel Thauvin-Robinet, Yannis Duffourd, Jaya K. George-Abraham, Catherine A. Buchanan, Denise Williams, Usha Kini, Kate Wilson, Nicola Brunetti-Pierri, Giorgio Casari, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Sérgio B. Sousa, Raoul C.M. Hennekam, Bekim Sadikovic, Julien Thevenon, Jérôme Govin, Antonio Vitobello, Università degli studi di Napoli Federico II, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Washington [Seattle], Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bordeaux (UB), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), London Health Sciences Center (LHSC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), GSP15001, Fondazione Telethon, 209568/Z/17/Z, Wellcome Trust, Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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 Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, General Paediatrics, APH - Quality of Care, and Brunetti-Pierri, Nicola

Subjects
Foot Deformities, Foot Deformities, Congenital, [SDV]Life Sciences [q-bio], Biology, Blepharophimosis, Settore MED/03 - GENETICA MEDICA, Hypotrichosis, Chromatin remodeling, 03 medical and health sciences, Congenital, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, SMARCA2, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, BIS, Facies, medicine.disease, Phenotype, neurodevelopmental disorder, Nicolaides–Baraitser syndrome, intellectual disability, DNA methylation, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020
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