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1. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., Vasileiou G., Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., and Vasileiou G.

Abstract

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non -truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.(c) 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2023

2. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

Author

Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., Vasileiou, G., Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., and Vasileiou, G.

Abstract

Contains fulltext : 299984.pdf (Publisher’s version ) (Open Access), PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., 01 november 2023

Published
2023

3. Pädaudiologische Versorgung bei Langer-Giedion-Syndrom

Author

Läßig, AK, Große, L, Martin, E, Holthöfer, L, Bartsch, O, Koutsimpelas, D, Bohnert, A, Läßig, AK, Große, L, Martin, E, Holthöfer, L, Bartsch, O, Koutsimpelas, D, and Bohnert, A

Abstract

Hintergrund: Die Prävalenz einer höhergradigen Mikrotie in der westlichen Bevölkerung wird mit 0,76-2,35 Fälle pro 10.000 Geburten angegeben, davon sind ca. 20-30% syndromaler Genese. Bei zusätzlicher kongenitaler Gehörgangsatresie wird bei einseitigem Vorliegen oft an ein Goldenhar-Syndrom oder bei beidseitiger Fehlbildung an ein Franceschetti-Syndrom gedacht. Bei zusätzlichen Dysmorphiezeichen, insbesondere dem Vorliegen von Spaltbildungen des Gaumens und Skelettfehlbildungen, sollte eine humangenetische Untersuchung zur Ursachenklärung angestrebt werden.Material und Methoden: Wir berichten über einen bei Erstvorstellung 7,7 Jahre alten Jungen syrischer nicht konsanguiner Eltern, der uns bei klinischem Verdacht auf Franceschetti-Syndrom zur pädaudiologischen Diagnostik und Optimierung der technischen Versorgung der Schwerhörigkeit vorgestellt wurde. Die Schwangerschaft und Geburt seien in Syrien unauffällig verlaufen. Das 7. Kind der Eltern wies deutliche Dysmorphiezeichen auf: Ohrmuscheldysplasie III°, vollständige Gehörgangsatresie bds., Z.n. operativem Verschluss einer Gaumenspalte im 2. Lebensjahr, dreieckige Gesichtsform mit spitzem, ausgeprägtem Unterkiefer, langes breites, akzentuiertes Philtrum, schmales Oberlippenrot, kräftige Nase mit breitem Nasenrücken, Epicanthus links, nach außen abfallende Lidachsen, lange gebogene Wimpern, sehr bauschige Augenbrauen, Zahnfehlstellungen, multiple Exostosen v.a. am proximalen rechten Oberarm, linken Schulterblatt, distalen linken Unterarm, mehreren Rippen, distalen Femur, deutliche Mikrocephalgie (<1. P.), proportionierter Minderwuchs und Dystrophie, prämature Pubarche, nicht altersgerechte Sprachentwicklung bei sukzessivem Zweispracherwerb Arabisch/Deutsch, Intelligenzminderung. Anamnestisch wurde auch berichtet, dass die motorische Entwicklung verzögert war (Sitzen: 24 Monate, Laufen: 3 Jahre, erste Worte: mit 3 Jahren). Es bestand im Alter von ca. 2-3 Jahren eine Knochenleitungshörgeräteversorgung über Softband, d

Published
2021

4. A case of an Angelman-syndrome caused by an intragenic duplication of UBE3A uncovered by adaptive nanopore sequencing.

Author

Holthöfer L, Diederich S, Haug V, Lehmann L, Hewel C, Paul NW, Schweiger S, Gerber S, and Linke M

Subjects
Humans, Female, Male, Exons genetics, Pedigree, Genomic Imprinting genetics, Angelman Syndrome genetics, Angelman Syndrome diagnosis, Ubiquitin-Protein Ligases genetics, Nanopore Sequencing methods, DNA Methylation genetics, Gene Duplication genetics
Abstract

Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM&#95;000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders., (© 2024. The Author(s).)

Published
2024
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5. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

Author

Bosch E, Popp B, Güse E, Skinner C, van der Sluijs PJ, Maystadt I, Pinto AM, Renieri A, Bruno LP, Granata S, Marcelis C, Baysal Ö, Hartwich D, Holthöfer L, Isidor B, Cogne B, Wieczorek D, Capra V, Scala M, De Marco P, Ognibene M, Jamra RA, Platzer K, Carter LB, Kuismin O, van Haeringen A, Maroofian R, Valenzuela I, Cuscó I, Martinez-Agosto JA, Rabani AM, Mefford HC, Pereira EM, Close C, Anyane-Yeboa K, Wagner M, Hannibal MC, Zacher P, Thiffault I, Beunders G, Umair M, Bhola PT, McGinnis E, Millichap J, van de Kamp JM, Prijoles EJ, Dobson A, Shillington A, Graham BH, Garcia EJ, Galindo MK, Ropers FG, Nibbeling EAR, Hubbard G, Karimov C, Goj G, Bend R, Rath J, Morrow MM, Millan F, Salpietro V, Torella A, Nigro V, Kurki M, Stevenson RE, Santen GWE, Zweier M, Campeau PM, Severino M, Reis A, Accogli A, and Vasileiou G

Subjects
Humans, Face, Facies, Phenotype, DNA-Binding Proteins genetics, Transcription Factors genetics, Abnormalities, Multiple genetics, Micrognathism genetics, Intellectual Disability genetics, Intellectual Disability complications, Neurodevelopmental Disorders
Abstract

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort., Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays., Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD., Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., Competing Interests: Conflict of Interest Renee Bend and Julie Rath are employees of PreventionGenetics, part of Exact Sciences. Michelle M. Morrow and Francisca Millan are employees of GeneDx, LLC. All other authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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