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5 results on '"Earl, R.K."'

1. ARID1B-related disorder in 87 adults: Natural history and self-sustainability

Author

van der Sluijs, P.J., Gösgens, M., Dingemans, A.J.M., Striano, P., Riva, A., Mignot, C., Faudet, A., Vasileiou, G., Walther, M., Schrier Vergano, S.A., Alders, M., Alkuraya, F.S., Alorainy, I., Alsaif, H.S., Anderlid, B., Bache, I., van Beek, I., Blanluet, M., van Bon, B.W., Brunet, T., Brunner, H., Carriero, M.L., Charles, P., Chatron, N., Coccia, E., Dubourg, C., Earl, R.K., Eichler, E.E., Faivre, L., Foulds, N., Graziano, C., Guerrot, A.M., Hashem, M.O., Heide, S., Heron, D., Hickey, S.E., Hopman, S.M.J., Kattentidt-Mouravieva, A., Kerkhof, J., Klein Wassink-Ruiter, J.S., Kurtz-Nelson, E.C., Kušíková, K., Kvarnung, M., Lecoquierre, F., Leszinski, G.S., Loberti, L., Magoulas, P.L., Mari, F., Maystadt, I., Merla, G., Milunsky, J.M., Moortgat, S., Nicolas, G., Leary, M.O.’, Odent, S., Ozmore, J.R., Parbhoo, K., Pfundt, R., Piccione, M., Pinto, A.M., Popp, B., Putoux, A., Rehm, H.L., Reis, A., Renieri, A., Rosenfeld, J.A., Rossi, M., Salzano, E., Saugier-Veber, P., Seri, M., Severi, G., Sonmez, F.M., Strobl-Wildemann, G., Stuurman, K.E., Uctepe, E., Van Esch, H., Vitetta, G., de Vries, B.B.A., Wahl, D., Wang, T., Zacher, P., Heitink, K.R., Ropers, F.G., Steenbeek, D., Rybak, T., and Santen, G.W.E.

Published
2024
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2. Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Author

Sluijs, P.J. van der, Joosten, Marieke, Alby, C., Attié-Bitach, T., Gilmore, K., Dubourg, C., Fradin, M., Wang, T., Kurtz-Nelson, E.C., Ahlers, K.P., Arts, P., Barnett, C.P., Ashfaq, M., Baban, A., Born, M. van den, Borrie, S., Busa, T., Byrne, A., Carriero, M., Cesario, C., Chong, K., Cueto-González, A.M., Dempsey, J.C., Diderich, K.E.M., Doherty, D., Farholt, S., Gerkes, E.H., Gorokhova, S., Govaerts, L.C.P., Gregersen, P.A., Hickey, S.E., Lefebvre, M., Mari, F., Martinovic, Jelena, Northrup, H., O'Leary, M., Parbhoo, K., Patrier, S., Popp, B., Santos-Simarro, F., Stoltenburg, C., Thauvin-Robinet, C., Thompson, E., Vulto-van Silfhout, A.T., Zahir, F.R., Scott, H.S., Earl, R.K., Eichler, E.E., Vora, N.L., Wilnai, Y., Giordano, J.L., Wapner, R.J., Rosenfeld, J.A., Haak, M.C., Santen, G.W.E., Sluijs, P.J. van der, Joosten, Marieke, Alby, C., Attié-Bitach, T., Gilmore, K., Dubourg, C., Fradin, M., Wang, T., Kurtz-Nelson, E.C., Ahlers, K.P., Arts, P., Barnett, C.P., Ashfaq, M., Baban, A., Born, M. van den, Borrie, S., Busa, T., Byrne, A., Carriero, M., Cesario, C., Chong, K., Cueto-González, A.M., Dempsey, J.C., Diderich, K.E.M., Doherty, D., Farholt, S., Gerkes, E.H., Gorokhova, S., Govaerts, L.C.P., Gregersen, P.A., Hickey, S.E., Lefebvre, M., Mari, F., Martinovic, Jelena, Northrup, H., O'Leary, M., Parbhoo, K., Patrier, S., Popp, B., Santos-Simarro, F., Stoltenburg, C., Thauvin-Robinet, C., Thompson, E., Vulto-van Silfhout, A.T., Zahir, F.R., Scott, H.S., Earl, R.K., Eichler, E.E., Vora, N.L., Wilnai, Y., Giordano, J.L., Wapner, R.J., Rosenfeld, J.A., Haak, M.C., and Santen, G.W.E.

Abstract

Item does not contain fulltext, PURPOSE: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. METHODS: Clinical data was collected through an extensive web-based survey. RESULTS: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). CONCLUSION: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.

Published
2022

3. 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

4. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., Tartaglia, M., Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., and Tartaglia, M.

Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access), Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

5. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., Eichler, E.E., Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., and Eichler, E.E.

Abstract

Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Published
2020

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