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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

3. Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing

Author

Chen, Xiao, Harting, John, Farrow, E., Thiffault, I., Kasperaviciute, Dalia, Genomics England Res Consortium, Genomics England Research Consortium, Hoischen, A., Gilissen, C., Pastinen, T., Eberle, Michael A., Chen, Xiao, Harting, John, Farrow, E., Thiffault, I., Kasperaviciute, Dalia, Genomics England Res Consortium, Genomics England Research Consortium, Hoischen, A., Gilissen, C., Pastinen, T., and Eberle, Michael A.

Abstract

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Published
2023

4. IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Author

Bakey, Z., Cabrera, O.A., Hoefele, J., Antony, D., Wu, K.M., Stuck, M.W., Micha, D., Eguether, T., Smith, A.O., Wel, N.N. van der, Wagner, M., Strittmatter, L., Beales, P.L., Jonassen, J.A., Thiffault, I., Cadieux-Dion, M., Boyes, L., Sharif, S., Tüysüz, B., Dunstheimer, D., Niessen, H.W.M., Devine, W., Lo, C.W., Mitchison, H.M., Schmidts, M., Pazour, G.J., Bakey, Z., Cabrera, O.A., Hoefele, J., Antony, D., Wu, K.M., Stuck, M.W., Micha, D., Eguether, T., Smith, A.O., Wel, N.N. van der, Wagner, M., Strittmatter, L., Beales, P.L., Jonassen, J.A., Thiffault, I., Cadieux-Dion, M., Boyes, L., Sharif, S., Tüysüz, B., Dunstheimer, D., Niessen, H.W.M., Devine, W., Lo, C.W., Mitchison, H.M., Schmidts, M., and Pazour, G.J.

Abstract

01 juni 2023, Contains fulltext : 294338.pdf (Publisher’s version ) (Open Access), Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

Published
2023

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., 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

7. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome

Author

Tessadori, F., Duran, K., Knapp, K., Fellner, M., Smithson, S., Meireles, A. Beleza, Elting, M.W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., Ronan, A., Brunet, T., Kotzaeridou, U., Svihovec, S., Saenz, M.S., Thiffault, I., Viso, F. Del, Devine, P., Rego, S., Tenney, J., Haeringen, A. van, Ruivenkamp, C.A.L., Koene, S., Robertson, S.P., Deshpande, C., Pfundt, R.P., Verbeek, N., Kamp, J.M. van de, Weiss, J., Ruiz, A., Gabau, E., Banne, E., Pepler, A., Bottani, A., Laurent, S., Guipponi, M., Bijlsma, E., Bruel, A.L., Sorlin, A., Willis, M., Powis, Z., Smol, T., Vincent-Delorme, C., Baralle, D., Colin, E., Revencu, N., Calpena, E., Wilkie, A.O.M., Chopra, M., Cormier-Daire, V., Keren, B., Afenjar, A., Niceta, M., Terracciano, A., Specchio, N., Tartaglia, M., Rio, M. del, Barcia, G., Rondeau, S., Colson, C., Bakkers, J., Mace, P.D., Bicknell, L.S., Haaften, G. van, Tessadori, F., Duran, K., Knapp, K., Fellner, M., Smithson, S., Meireles, A. Beleza, Elting, M.W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., Ronan, A., Brunet, T., Kotzaeridou, U., Svihovec, S., Saenz, M.S., Thiffault, I., Viso, F. Del, Devine, P., Rego, S., Tenney, J., Haeringen, A. van, Ruivenkamp, C.A.L., Koene, S., Robertson, S.P., Deshpande, C., Pfundt, R.P., Verbeek, N., Kamp, J.M. van de, Weiss, J., Ruiz, A., Gabau, E., Banne, E., Pepler, A., Bottani, A., Laurent, S., Guipponi, M., Bijlsma, E., Bruel, A.L., Sorlin, A., Willis, M., Powis, Z., Smol, T., Vincent-Delorme, C., Baralle, D., Colin, E., Revencu, N., Calpena, E., Wilkie, A.O.M., Chopra, M., Cormier-Daire, V., Keren, B., Afenjar, A., Niceta, M., Terracciano, A., Specchio, N., Tartaglia, M., Rio, M. del, Barcia, G., Rondeau, S., Colson, C., Bakkers, J., Mace, P.D., Bicknell, L.S., and Haaften, G. van

Abstract

Contains fulltext : 252023.pdf (Publisher’s version ) (Open Access), Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Published
2022

8. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., Eichler, E.E., Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., and Eichler, E.E.

Abstract

Contains fulltext : 245103.pdf (Publisher’s version ) (Open Access), BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare va

Published
2021

9. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

10. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., Kleefstra, T., Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., and Kleefstra, T.

Abstract

Item does not contain fulltext, Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Published
2021

12. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder

Author

den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), 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), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and 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 )

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

13. Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

Author

Li, L, Ghorbani, M., Weisz-Hubshman, M., Rousseau, J., Thiffault, I., Schnur, R.E., Breen, C., Oegema, R., Weiss, M.M., Waisfisz, Q., Welner, S., Kingston, H., Hills, J.A., Boon, E.M., Basel-Salmon, L., Konen, O., Goldberg-Stern, H., Bazak, L., Tzur, S., Jin, J., Bi, X., Bruccoleri, M., McWalter, K., Cho, M.T., Scarano, M., Schaefer, G.B., Brooks, S.S., Hughes, S.S., Gassen, K.L.I. van, Hagen, J.M. van, Pandita, T.K., Agrawal, P.B., Campeau, P.M., Yang, X.J., Li, L, Ghorbani, M., Weisz-Hubshman, M., Rousseau, J., Thiffault, I., Schnur, R.E., Breen, C., Oegema, R., Weiss, M.M., Waisfisz, Q., Welner, S., Kingston, H., Hills, J.A., Boon, E.M., Basel-Salmon, L., Konen, O., Goldberg-Stern, H., Bazak, L., Tzur, S., Jin, J., Bi, X., Bruccoleri, M., McWalter, K., Cho, M.T., Scarano, M., Schaefer, G.B., Brooks, S.S., Hughes, S.S., Gassen, K.L.I. van, Hagen, J.M. van, Pandita, T.K., Agrawal, P.B., Campeau, P.M., and Yang, X.J.

Abstract

Contains fulltext : 218644.pdf (Publisher’s version ) (Closed access)

Published
2020

14. BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder

Author

Scott, T.M., Guo, H, Eichler, E.E., Rosenfeld, J.A., Pang, K., Liu, Z, Lalani, S., Bi, W., Yang, Y., Bacino, C.A., Streff, H., Lewis, A.M., Koenig, M.K., Thiffault, I., Bellomo, A., Everman, D.B., Jones, J.R., Stevenson, R.E., Bernier, R., Gilissen, C.F., Pfundt, R.P., Hiatt, S.M., Cooper, G.M., Holder, J.L., Scott, D.A., Scott, T.M., Guo, H, Eichler, E.E., Rosenfeld, J.A., Pang, K., Liu, Z, Lalani, S., Bi, W., Yang, Y., Bacino, C.A., Streff, H., Lewis, A.M., Koenig, M.K., Thiffault, I., Bellomo, A., Everman, D.B., Jones, J.R., Stevenson, R.E., Bernier, R., Gilissen, C.F., Pfundt, R.P., Hiatt, S.M., Cooper, G.M., Holder, J.L., and Scott, D.A.

Abstract

Contains fulltext : 220420.pdf (Publisher’s version ) (Closed access), The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.

Published
2020

15. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Author

Yan, K. (Kezhi), Rousseau, J. (Justine), Machol, K. (Keren), Cross, L.A. (Laura A.), Agre, K.E. (Katherine E.), Gibson, C.F. (Cynthia Forster), Goverde, A. (Anne), Engleman, K.L. (Kendra L.), Verdin, H. (Hanna), De Baere, E. (Elfride), Potocki, L. (Lorraine), Zhou, D. (Dihong), Cadieux-Dion, M. (Maxime), Bellus, G.A. (Gary A.), Wagner, M.D. (Monisa D.), Hale, R.J. (Rebecca J.), Esber, N. (Natacha), Riley, A.F. (Alan F.), Solomon, B.D. (Benjamin D.), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Eyal, R. (Roy), Hainlen, M.K. (Meagan K.), Mendelsohn, B.A. (Bryce A.), Porter, H.M. (Hillary M.), Lanpher, B.C. (Brendan C.), Lewis, A.M. (Andrea M.), Savatt, J. (Juliann), Thiffault, I. (Isabelle), Callewaert, L., Campeau, P.M. (Philippe M), Yang, X.-J. (Xiang-Jiao), Yan, K. (Kezhi), Rousseau, J. (Justine), Machol, K. (Keren), Cross, L.A. (Laura A.), Agre, K.E. (Katherine E.), Gibson, C.F. (Cynthia Forster), Goverde, A. (Anne), Engleman, K.L. (Kendra L.), Verdin, H. (Hanna), De Baere, E. (Elfride), Potocki, L. (Lorraine), Zhou, D. (Dihong), Cadieux-Dion, M. (Maxime), Bellus, G.A. (Gary A.), Wagner, M.D. (Monisa D.), Hale, R.J. (Rebecca J.), Esber, N. (Natacha), Riley, A.F. (Alan F.), Solomon, B.D. (Benjamin D.), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Eyal, R. (Roy), Hainlen, M.K. (Meagan K.), Mendelsohn, B.A. (Bryce A.), Porter, H.M. (Hillary M.), Lanpher, B.C. (Brendan C.), Lewis, A.M. (Andrea M.), Savatt, J. (Juliann), Thiffault, I. (Isabelle), Callewaert, L., Campeau, P.M. (Philippe M), and Yang, X.-J. (Xiang-Jiao)

Abstract

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylatio

Published
2020
Full Text
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16. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Author

Yan, KZ, Rousseau, J, Machol, K, Cross, LA, Agre, KE, Gibson, CF, Goverde, Anne, Engleman, KL, Verdin, H, De Baere, E, Potocki, L, Zhou, DH, Cadieux-Dion, M, Bellus, GA, Wagner, MD, Hale, RJ, Esber, N, Riley, AF, Solomon, BD, Cho, M T, McWalter, K, Eyal, R, Hainlen, MK, Mendelsohn, BA, Porter, HM, Lanpher, BC, Lewis, AM, Savatt, J, Thiffault, I, Callewaert, B, Campeau, PM, Yang, XJ, Yan, KZ, Rousseau, J, Machol, K, Cross, LA, Agre, KE, Gibson, CF, Goverde, Anne, Engleman, KL, Verdin, H, De Baere, E, Potocki, L, Zhou, DH, Cadieux-Dion, M, Bellus, GA, Wagner, MD, Hale, RJ, Esber, N, Riley, AF, Solomon, BD, Cho, M T, McWalter, K, Eyal, R, Hainlen, MK, Mendelsohn, BA, Porter, HM, Lanpher, BC, Lewis, AM, Savatt, J, Thiffault, I, Callewaert, B, Campeau, PM, and Yang, XJ

Published
2020

17. The founder mutation MSH2*1906G [right arrow] C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population

Author

Foulkes, W.D., Thiffault, I., Gruber, S.B., Horwitz, M., Hamel, N., Lee, C., Shia, J., Markowitz, A., Figer, A., Friedman, E., Farber, D., Greenwood, C.M. T., Bonner, J.D., Nafa, K., Walsh, T., Marcus, V., Tomsho, L., Gebert, J., Macrae, F.A., Gaff, C.L., Bressac-de Paillerets, B., Gregersen, P.K., Weitzel, J.N., Gordon, P.H., MacNamara, E., King, M.-C., Hampel, H., de la Chapelle, A., Boyd, J., Offit, K., Rennert, G., Chong, G., and Ellis, N.A.

Subjects
Colorectal cancer -- Genetic aspects, Genetic disorders -- Research, Familial diseases -- Research, Gene mutations -- Health aspects, Ashkenazim -- Genetic aspects, Ashkenazim -- Diseases, Biological sciences
Published
2002

18. Phenotypic spectrum associated with SPECC1L pathogenic variants:new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes

Author

Verloes, A., Haye, D., Toutain, A., Bonneau, D., Nielsen, I. Kibaek, Lund, I. Bay, Bogaard, P., Leenskjold, S., Karaer, K., Wild, K. T., Grand, K. L., Astiazaran, M. C., Gonzalez-Nieto, L. A., Carvalho, A., Lehalle, D., Amudhavalli, S. M., Repnikova, E., Saunders, C., Thiffault, I., Saadi, I., Li, D., Hakonarson, H., Vial, Y., Zackai, E., Callier, P., Drunat, S., and Bhoj, E. E.

Published
2019

23. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author

Diets, I.J., Donk, R. van der, Baltrunaite, K., Waanders, E., Reijnders, M.R.F., Dingemans, A.J., Pfundt, R.P., Vulto-van Silfhout, A.T., Wiel, L.J.M. van de, Gilissen, C.F., Thevenon, J., Perrin, L., Afenjar, A., Nava, C., Keren, B., Bartz, S., Peri, B., Beunders, G., Verbeek, N., Gassen, K. van, Thiffault, I., Cadieux-Dion, M., Huerta-Saenz, L., Wagner, M., Konstantopoulou, V., Vodopiutz, J., Griese, M., Boel, A., Callewaert, B., Brunner, H.G., Kleefstra, T., Hoogerbrugge, N., Vries, B.B. de, Hwa, V., Dauber, A., Hehir-Kwa, J.Y., Kuiper, R.P, Jongmans, M.C.J., Diets, I.J., Donk, R. van der, Baltrunaite, K., Waanders, E., Reijnders, M.R.F., Dingemans, A.J., Pfundt, R.P., Vulto-van Silfhout, A.T., Wiel, L.J.M. van de, Gilissen, C.F., Thevenon, J., Perrin, L., Afenjar, A., Nava, C., Keren, B., Bartz, S., Peri, B., Beunders, G., Verbeek, N., Gassen, K. van, Thiffault, I., Cadieux-Dion, M., Huerta-Saenz, L., Wagner, M., Konstantopoulou, V., Vodopiutz, J., Griese, M., Boel, A., Callewaert, B., Brunner, H.G., Kleefstra, T., Hoogerbrugge, N., Vries, B.B. de, Hwa, V., Dauber, A., Hehir-Kwa, J.Y., Kuiper, R.P, and Jongmans, M.C.J.

Abstract

Contains fulltext : 202646.pdf (publisher's version ) (Open Access), By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

Published
2019

24. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., Rodan, L.H., O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., and Rodan, L.H.

Abstract

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

28. KCNB1 MUTATIONS ARE CAUSING A NEURODEVELOPMENTAL DISORDER INCLUDING EPILEPSY AND AUTISM

Author

Conlin, L., Krock, B., Thiffault, I., Pendziwiat, M., Desai, S., Schonewolf-Greulich, B., Syrbe, S., de Kovel, C. G. F., Bayat, A., Naidu, S., Bergqvist, C., Rajagopalan, R., Verbeek, N., Brilstra, E. H., Jayaraman, V., Srivastava, S., Caglayan, H., Dubbs, H., Plugge, S., van den Boogaardt, M-J., Lemke, J. R., Borggraefe, I., Polster, T., Moller, R. S., Helbig, I., Kerr, B., Kessler, S., Marsh, E., Goldberg, E., Saunders, C., Rook, M., Yis, U., Koeleman, B. P. C., Gardella, E., Larsen, L. H. G., Svaneby, D., and Rokkjaer, M.

Published
2017

30. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Author

Flex, E., Niceta, M., Cecchetti, S., Thiffault, I., Au, M.G., Capuano, A., Piermarini, E., Ivanova, A.A., Francis, J.W., Chillemi, G., Chandramouli, B., Carpentieri, G., Haaxma, C.A., Ciolfi, A., Pizzi, S., Douglas, G.V., Levine, K., Sferra, A., Dentici, M.L., Pfundt, R.R., Pichon, J.B. Le, Farrow, E., Baas, F., Piemonte, F., Dallapiccola, B., Graham, J.M., Saunders, C.J., Bertini, E., Kahn, R.A., Koolen, D.A., Tartaglia, M., Flex, E., Niceta, M., Cecchetti, S., Thiffault, I., Au, M.G., Capuano, A., Piermarini, E., Ivanova, A.A., Francis, J.W., Chillemi, G., Chandramouli, B., Carpentieri, G., Haaxma, C.A., Ciolfi, A., Pizzi, S., Douglas, G.V., Levine, K., Sferra, A., Dentici, M.L., Pfundt, R.R., Pichon, J.B. Le, Farrow, E., Baas, F., Piemonte, F., Dallapiccola, B., Graham, J.M., Saunders, C.J., Bertini, E., Kahn, R.A., Koolen, D.A., and Tartaglia, M.

Abstract

Item does not contain fulltext, Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the alphabeta-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective beta-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble alpha/beta-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynam

Published
2016

31. An early-onset breast and colorectal cancer-prone family: Does a specific hereditary breast and colorectal cancer syndrome exist?

Author

Thiffault, I., Pal, T., Hamel, N., Deschenes, J., Marcus, V., Odefrey, F., Watters, K., Graham, T., Meschino, W., Narod, S., Goldgar, D., Farber, D., MacNamara, E., Chong, G., and Foulkes, W.

Subjects
Human genetics -- Research, Genetic disorders -- Research, Colorectal cancer -- Genetic aspects, Breast cancer -- Genetic aspects, Biological sciences
Published
2001

32. A founder mutation in MSH2 in the Ashkenazim

Author

Foulkes, W.D., Thiffault, I, Farber, D., Gruber, S.B., Tomsho, L., Rennert, G., Horwitz, M., Walsh, T., King, M.-C., Ellis, N., Offit, K., Bressac-de Paillerets, B., Grandjouan, S., Weitzel, J., Fujimura, F., Gordon, P.H., MacNamara, E., Marcus, V., and Chong, G.

Subjects
Human genetics -- Research, Ashkenazim -- Physiological aspects, Genetic disorders -- Research, Biological sciences
Published
2001

34. Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

Author

Thiffault, I., Wolf, N.I., Forget, D., Guerrero, K., Tran, L.T., Choquet, K., Lavallee-Adam, M., Poitras, C., Brais, B., Yoon, G., Sztriha, L., Webster, R.I., Timmann, D., Warrenburg, B.P.C. van de, Seeger, J.P.H., Zimmermann, A., Mate, A., Goizet, C., Fung, E., Knaap, M.S. van der, Fribourg, S., Vanderver, A., Simons, C., Taft, R.J., Yates, J.R., 3rd, Coulombe, B., Bernard, G., Thiffault, I., Wolf, N.I., Forget, D., Guerrero, K., Tran, L.T., Choquet, K., Lavallee-Adam, M., Poitras, C., Brais, B., Yoon, G., Sztriha, L., Webster, R.I., Timmann, D., Warrenburg, B.P.C. van de, Seeger, J.P.H., Zimmermann, A., Mate, A., Goizet, C., Fung, E., Knaap, M.S. van der, Fribourg, S., Vanderver, A., Simons, C., Taft, R.J., Yates, J.R., 3rd, Coulombe, B., and Bernard, G.

Abstract

Contains fulltext : 153818.pdf (publisher's version ) (Open Access), A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.

Published
2015

35. Mitochondrial Disease Sequence Data Resource (MSeqDR): A global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities

Author

Falk, M.J. (Marni J.), Shen, L. (Lishuang), Gonzalez, M. (Michael), Leipzig, J. (Jeremy), Lott, M.T. (Marie T.), Stassen, A.P.M. (Alphons P.M.), Diroma, M.A. (Maria Angela), Navarro-Gomez, D. (Daniel), Yeske, P. (Philip), Bai, R. (Renkui), Boles, R.G. (Richard G.), Brilhante, V. (Virginia), Ralph, D. (David), DaRe, J.T. (Jeana T.), Shelton, R. (Robert), Terry, S.F. (Sharon), Zhang, Z. (Zhe), Copeland, W.C. (William C.), Oven, M. (Mannis) van, Prokisch, H. (Holger), Wallace, D.C., Attimonelli, M. (Marcella), Krotoski, D. (Danuta), Zuchner, S. (Stephan), Gai, X. (Xiaowu), Bale, S. (Sherri), Bedoyan, J. (Jirair), Behar, D.M. (Doron), Bonnen, P. (Penelope), Brooks, L. (Lisa), Calabrese, C. (Claudia), Calvo, S. (Sarah), Chinnery, P.F. (Patrick), Christodoulou, J. (John), Church, D. (Deanna), Clima, R. (Rosanna), Cohen, B.H. (Bruce H.), Cotton, R.G.H. (Richard), Coo, I.F.M. (René) de, Derbenevoa, O. (Olga), Dunnen, J.T. (Johan) den, Dimmock, D. (David), Enns, G. (Gregory), Gasparre, G. (Giuseppe), Goldstein, A. (Amy), Gonzalez, I. (Iris), Gwinn, K. (Katrina), Hahn, S. (Sihoun), Haas, R.H. (Richard H.), Hakonarson, H. (Hakon), Hirano, M. (Michio), Kerr, D. (Douglas), Li, D. (Dong), Lvova, M. (Maria), Macrae, F. (Finley), Maglott, D. (Donna), McCormick, E. (Elizabeth), Mitchell, G. (Grant), Mootha, V.K. (Vamsi K.), Okazaki, Y. (Yasushi), Pujol, A. (Aurora), Parisi, M. (Melissa), Perin, J.C. (Juan Carlos), Pierce, E.A. (Eric A.), Procaccio, V. (Vincent), Rahman, S. (Shamima), Reddi, H. (Honey), Rehm, H. (Heidi), Riggs, E. (Erin), Rodenburg, R.J.T. (Richard), Rubinstein, Y. (Yaffa), Saneto, R. (Russell), Santorsola, M. (Mariangela), Scharfe, C. (Curt), Sheldon, C. (Claire), Shoubridge, E.A. (Eric), Simone, D. (Domenico), Smeets, B. (Bert), Smeitink, J.A.M. (Jan), Stanley, C. (Christine), Suomalainen, A. (Anu), Tarnopolsky, M.A. (Mark), Thiffault, I. (Isabelle), Thorburn, D.R. (David R.), Hove, J.V. (Johan Van), Wolfe, L. (Lynne), Wong, L.-J. (Lee-Jun), Falk, M.J. (Marni J.), Shen, L. (Lishuang), Gonzalez, M. (Michael), Leipzig, J. (Jeremy), Lott, M.T. (Marie T.), Stassen, A.P.M. (Alphons P.M.), Diroma, M.A. (Maria Angela), Navarro-Gomez, D. (Daniel), Yeske, P. (Philip), Bai, R. (Renkui), Boles, R.G. (Richard G.), Brilhante, V. (Virginia), Ralph, D. (David), DaRe, J.T. (Jeana T.), Shelton, R. (Robert), Terry, S.F. (Sharon), Zhang, Z. (Zhe), Copeland, W.C. (William C.), Oven, M. (Mannis) van, Prokisch, H. (Holger), Wallace, D.C., Attimonelli, M. (Marcella), Krotoski, D. (Danuta), Zuchner, S. (Stephan), Gai, X. (Xiaowu), Bale, S. (Sherri), Bedoyan, J. (Jirair), Behar, D.M. (Doron), Bonnen, P. (Penelope), Brooks, L. (Lisa), Calabrese, C. (Claudia), Calvo, S. (Sarah), Chinnery, P.F. (Patrick), Christodoulou, J. (John), Church, D. (Deanna), Clima, R. (Rosanna), Cohen, B.H. (Bruce H.), Cotton, R.G.H. (Richard), Coo, I.F.M. (René) de, Derbenevoa, O. (Olga), Dunnen, J.T. (Johan) den, Dimmock, D. (David), Enns, G. (Gregory), Gasparre, G. (Giuseppe), Goldstein, A. (Amy), Gonzalez, I. (Iris), Gwinn, K. (Katrina), Hahn, S. (Sihoun), Haas, R.H. (Richard H.), Hakonarson, H. (Hakon), Hirano, M. (Michio), Kerr, D. (Douglas), Li, D. (Dong), Lvova, M. (Maria), Macrae, F. (Finley), Maglott, D. (Donna), McCormick, E. (Elizabeth), Mitchell, G. (Grant), Mootha, V.K. (Vamsi K.), Okazaki, Y. (Yasushi), Pujol, A. (Aurora), Parisi, M. (Melissa), Perin, J.C. (Juan Carlos), Pierce, E.A. (Eric A.), Procaccio, V. (Vincent), Rahman, S. (Shamima), Reddi, H. (Honey), Rehm, H. (Heidi), Riggs, E. (Erin), Rodenburg, R.J.T. (Richard), Rubinstein, Y. (Yaffa), Saneto, R. (Russell), Santorsola, M. (Mariangela), Scharfe, C. (Curt), Sheldon, C. (Claire), Shoubridge, E.A. (Eric), Simone, D. (Domenico), Smeets, B. (Bert), Smeitink, J.A.M. (Jan), Stanley, C. (Christine), Suomalainen, A. (Anu), Tarnopolsky, M.A. (Mark), Thiffault, I. (Isabelle), Thorburn, D.R. (David R.), Hove, J.V. (Johan Van), Wolfe, L. (Lynne), and Wong, L.-J. (Lee-Jun)

Abstract

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (. https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integr

Published
2015
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36. Diversity of ARSACS Mutations in French-Canadians

Author

Thiffault, I., primary, Dicaire, M.J., additional, Tetreault, M., additional, Huang, K.N., additional, Demers-Lamarche, J., additional, Bernard, G., additional, Duquette, A., additional, Larivière, R., additional, Gehring, K., additional, Montpetit, A., additional, McPherson, P.S., additional, Richter, A., additional, Montermini, L., additional, Mercier, J., additional, Mitchell, G.A., additional, Dupré, N., additional, Prévost, C., additional, Bouchard, J.P., additional, Mathieu, J., additional, and Brais, B., additional

Published
2013
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38. Germline truncating mutations in both MSH2 and BRCA2 in a single kindred.

Author

Thiffault, I, Hamel, N, Pal, T, McVety, S, Marcus, VA, Farber, D, Cowie, S, Deschênes, J, Meschino, W, Odefrey, F, Goldgar, D, Graham, T, Narod, S, Watters, AK, MacNamara, E, Du Sart, D, Chong, G, Foulkes, WD, Thiffault, I, Hamel, N, Pal, T, McVety, S, Marcus, VA, Farber, D, Cowie, S, Deschênes, J, Meschino, W, Odefrey, F, Goldgar, D, Graham, T, Narod, S, Watters, AK, MacNamara, E, Du Sart, D, Chong, G, and Foulkes, WD

Abstract

There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone.

Published
2004

42. Germline truncating mutations in both MSH2 and BRCA2 in a single kindred

Author

Thiffault, I, primary, Hamel, N, additional, Pal, T, additional, McVety, S, additional, Marcus, V A, additional, Farber, D, additional, Cowie, S, additional, Deschênes, J, additional, Meschino, W, additional, Odefrey, F, additional, Goldgar, D, additional, Graham, T, additional, Narod, S, additional, Watters, A K, additional, MacNamara, E, additional, Sart, D Du, additional, Chong, G, additional, and Foulkes, W D, additional

Published
2004
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43. The Founder Mutation MSH2*1906G→C Is an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Ashkenazi Jewish Population

Author

Foulkes, W.D., primary, Thiffault, I., additional, Gruber, S.B., additional, Horwitz, M., additional, Hamel, N., additional, Lee, C., additional, Shia, J., additional, Markowitz, A., additional, Figer, A., additional, Friedman, E., additional, Farber, D., additional, Greenwood, C. M.T., additional, Bonner, J.D., additional, Nafa, K., additional, Walsh, T., additional, Marcus, V., additional, Tomsho, L., additional, Gebert, J., additional, Macrae, F.A., additional, Gaff, C.L., additional, Paillerets, B. Bressac-de, additional, Gregersen, P.K., additional, Weitzel, J.N., additional, Gordon, P.H., additional, MacNamara, E., additional, King, M.-C., additional, Hampel, H., additional, de la Chapelle, A., additional, Boyd, J., additional, Offit, K., additional, Rennert, G., additional, Chong, G., additional, and Ellis, N.A., additional

Published
2002
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44. The Founder Mutation MSH2*1906G.... C Is an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Ashkenazi Jewish Population.

Author

Foulkes, W.D., Thiffault, I., Gruber, S.B., Horwitz, M., Hamel, N., Lee, C., Shia, J., Markowitz, A., Figer, A., Friedman, E., Farber, D., Greenwood, C.M.T., Bonner, J.D., Nafa, K., Walsh, T., Marcus, V., Tomsho, L., Gebert, J., and Macrae, F.A.

Subjects
*COLON cancer, *GENETIC disorders
Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2[sup *]1906G→C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P = .042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P = .033 ). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria. [ABSTRACT FROM AUTHOR]

Published
2002
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46. The HNPCC associated MSH2 1906G→C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population.

Author

Sun, S., Greenwood, C. M. T., Thiffault, I., Hamel, N., Chong, G., and Foulkes, W. D.

Subjects
COLON cancer, GENETIC mutation, CANCER patients, GENETICS, ASHKENAZIM, JEWS
Abstract

The MSH2*1906G→C mutation was recently shown to be a rare yet highly penetrant mutation leading to colorectal cancer. The mutation was only found among Ashkenazi Jewish individuals and lies on an extended haplotype that is common in that population. This study determined that the mutation probably arose between 11 and 22 generations ago, during the time when the Ashkenazim were living in eastern Europe. [ABSTRACT FROM AUTHOR]

Published
2005
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47. Dual molecular effects of dominant RORA mutations cause two variants of syndromic intellectual disability with either autistic features or cerebellar ataxia

Author

Latypova, X., Guissart, C., Khan, T. N., Rollier, P., Stamberger, H., Mcwalter, K., Cho, M. T., Kjaergaard, S., Weckhuysen, S., Lesca, G., Besnard, T., KATRIN OUNAP, Schema, L., Chiocchetti, A. G., Mcdonald, M., Bellescize, J., Vincent, M., Esch, H., Sattler, S., Forghani, I., Thiffault, I., Freitag, C. M., Barbouth, D., Cadieux-Dion, M., Saffina, N. P., Grote, L., Carre, W., Saunders, C., Pajusalu, S., Boland, A., Karlowicz, D. Hays, Deleuze, J., Wojcik, M. H., Pressman, R., Isidor, B., Vogels, A., Paesschen, W., Rivier, F., Leboucq, N., Cogne, B., Sasorith, S., Sanlaville, D., Retterer, K., Odent, S., Katsanis, N., Bezieau, S., Koenig, M., Pasquier, L., Davis, E. E., and Kury, S.

49. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

50. P.075 Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

Author

Gauquelin, L, Cayami, FK, Sztriha, L, Yoon, G, Tran, LT, Guerrero, K, Hocke, F, van Spaendonk, RM, Fung, EL, D’Arrigo, S, Vasco, G, Thiffault, I, Niyazov, DM, Person, R, Lewis, KS, Wassmer, E, Prescott, T, Fallon, P, McEntagart, M, Rankin, J, Webster, R, Philippi, H, van de Warrenburg, B, Timmann, D, Dixit, A, Searle, C, Thakur, N, Kruer, MC, Sharma, S, Vanderver, A, Tonduti, D, van der Knaap, MS, Bertini, E, Goizet, C, Fribourg, S, Wolf, NI, and Bernard, G

Abstract

Background:Biallelic variants in POLR1Care associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods:A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1Cvariants were reviewed. Results:Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1Cwere identified, including 13 new disease-causing variants. Conclusions:Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Published
2019
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