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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. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.

Abstract

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

3. Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

Author

Frost, F.G., Morimoto, M., Sharma, Prashant, Ruaud, L., Belnap, N., Calame, D.G., Uchiyama, Y., Matsumoto, N., Oud, M.M., Ferreira, E.A., Narayanan, V., Rangasamy, S., Huentelman, M., Emrick, L.T., Sato-Shirai, I., Kumada, S., Wolf, N.I., Steinbach, P.J., Huang, Y., Pusey, B.N., Passemard, S., Levy, J., Drunat, S., Vincent, M., Guet, A., Agolini, E., Novelli, A., Digilio, M.C., Rosenfeld, J.A., Murphy, J.L., Lupski, J.R., Vezina, G., Macnamara, E.F., Adams, D.R., Acosta, M.T., Tifft, C.J., Gahl, W.A., Malicdan, M.C., Frost, F.G., Morimoto, M., Sharma, Prashant, Ruaud, L., Belnap, N., Calame, D.G., Uchiyama, Y., Matsumoto, N., Oud, M.M., Ferreira, E.A., Narayanan, V., Rangasamy, S., Huentelman, M., Emrick, L.T., Sato-Shirai, I., Kumada, S., Wolf, N.I., Steinbach, P.J., Huang, Y., Pusey, B.N., Passemard, S., Levy, J., Drunat, S., Vincent, M., Guet, A., Agolini, E., Novelli, A., Digilio, M.C., Rosenfeld, J.A., Murphy, J.L., Lupski, J.R., Vezina, G., Macnamara, E.F., Adams, D.R., Acosta, M.T., Tifft, C.J., Gahl, W.A., and Malicdan, M.C.

Abstract

Item does not contain fulltext, The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

Published
2023

4. 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

5. Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects

Author

AlAbdi, L., Desbois, M., Rusnac, D.V., Sulaiman, R.A., Rosenfeld, J.A., Lalani, S., Murdock, D.R., Burrage, L.C., Undiagnosed Diseases Network, Billie Au, P.Y., Towner, S., Wilson, W.G., Wong, L., Brunet, T., Strobl-Wildemann, G., Burton, J.E., Hoganson, G., McWalter, K., Begtrup, A., Zarate, Y.A., Christensen, E.L., Opperman, K.J., Giles, A.C., Helaby, R., Kania, A., Zheng, N., Grill, B., and Alkuraya, F.S.

Subjects
Neurology (clinical), Mycbp2, Phr1, Corpus Callosum, Epilepsy, Habituation, Neurodevelopmental Disorder
Abstract

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Published
2021

6. 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

7. Erratum: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome (J. Exp. Med. (2020) 217:6 Doi:10.1084/jem.20191804)

Author

Charbonnier, L.-M., Boisson, B., Couderc, L.-J., Abel, L., Rosain, J., Burrage, L.C., Chen, Y.-H., Schmitz-Abe, K., Butte, M.J., de Bruyne, M., Renkilaraj, M.R.L.M., Fieschi, C., Haerynck, F., Chatila, T.A., Casanova, J.-L., Laurence, A., Béziat, V., Materna, M., Aschenbrenner, D., Puel, A., Gartner, L., Murdock, D.R., Vladikine, N., Kohn, L.A., Staal, J., Roels, L., Dai, H., Avettand-Fenoel, V., Tavernier, S.J., Esther, C.R., Jr., Dogu, F., Catherinot, É., Tcherakian, C., Tangye, S.G., Boutboul, D., Keles, S., Grimbacher, B., Amourette, J., Seeleuthner, Y., Gauvain, C., Uhlig, H.H., Worley, L., Vogel, T.P., Ikinciogullari, A., Ouachée-Chardin, M., Jeljeli, M., Milner, J.D., Haskologlu, S., Rosenfeld, J.A., Migaud, M., Lambrecht, B.N., Network, U.D., Freeman, A.F., Lebras, M.-N., Beyaert, R., Ma, C.S., Ciznar, P., Claes, K., Nammour, J., and van Braeckel, E.

Abstract

The authors regret that in the original version of Table S1, the column for patient 12 was mistakenly duplicated in the column for patient 8. The online Table S1 PDF has been corrected. The error appears only in PDFs downloaded before June 4, 2020.

Published
2020
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8. Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

Author

Granadillo, Jorge Luis, P.A. Stegmann, Alexander, Guo, Hui, Xia, K., Angle, Brad, Bontempo, Kelly, Pfundt, R.P., Rosenfeld, J.A., Shinawi, M., Granadillo, Jorge Luis, P.A. Stegmann, Alexander, Guo, Hui, Xia, K., Angle, Brad, Bontempo, Kelly, Pfundt, R.P., Rosenfeld, J.A., and Shinawi, M.

Abstract

Contains fulltext : 226271.pdf (Publisher’s version ) (Closed access)

Published
2020

9. 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

10. 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

11. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author

Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., Jolly, L.A., Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., and Jolly, L.A.

Abstract

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access), BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hi

Published
2020

12. A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

Author

Mederer, T., Schmitteckert, S., Volz, J., Martinez, C., Roth, R., Thumberger, T., Eckstein, V., Scheuerer, J., Thoni, C., Lasitschka, F., Carstensen, L, Gunther, P., Holland-Cunz, S. (Stefan), Hofstra, R.M.W. (Robert), Brosens, E. (Erwin), Rosenfeld, J.A. (Jill), Schaaf, C.P., Schriemer, D, Ceccherini, I. (Isabella), Rusmini, M., Tilghman, J., Luzon-Toro, B., Torroglosa, A., Borrego, S. (Salud), Tang, C.S.M., Garcia-Barcelo, M, Tam, P., Paramasivam, N., Bewerunge-Hudler, M., Dalla Torre, C, Gretz, N. (Norbert), Rappold, G. (Gudrun), Romero, P. (Pedro), Niesler, B., Mederer, T., Schmitteckert, S., Volz, J., Martinez, C., Roth, R., Thumberger, T., Eckstein, V., Scheuerer, J., Thoni, C., Lasitschka, F., Carstensen, L, Gunther, P., Holland-Cunz, S. (Stefan), Hofstra, R.M.W. (Robert), Brosens, E. (Erwin), Rosenfeld, J.A. (Jill), Schaaf, C.P., Schriemer, D, Ceccherini, I. (Isabella), Rusmini, M., Tilghman, J., Luzon-Toro, B., Torroglosa, A., Borrego, S. (Salud), Tang, C.S.M., Garcia-Barcelo, M, Tam, P., Paramasivam, N., Bewerunge-Hudler, M., Dalla Torre, C, Gretz, N. (Norbert), Rappold, G. (Gudrun), Romero, P. (Pedro), and Niesler, B.

Abstract

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database

Published
2020
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13. Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.

Author

Tuite A., Rowe L.J., Serrano Russi A.H., Russo R.S., Thabet F., Villanueva M.M., Wang R.Y., Webster R.I., Wilson D., Zalan A., Wolfe L.A., Rosenfeld J.A., Rhodes L., Freeze H.H., Ng B.G., Eklund E.A., Shiryaev S.A., Dong Y.Y., Abbott M.-A., Asteggiano C., Bamshad M.J., Barr E., Bernstein J.A., Chelakkadan S., Christodoulou J., Chung W.K., Ciliberto M.A., Cousin J., Gardiner F., Ghosh S., Graf W.D., Grunewald S., Hammond K., Hauser N.S., Hoganson G.E., Houck K.M., Kohler J.N., Morava E., Larson A.A., Liu P., Madathil S., McCormack C., Meeks N.J.L., Miller R., Monaghan K.G., Nickerson D.A., Palculict T.B., Papazoglu G.M., Pletcher B.A., Scheffer I.E., Schenone A.B., Schnur R.E., Si Y., Tuite A., Rowe L.J., Serrano Russi A.H., Russo R.S., Thabet F., Villanueva M.M., Wang R.Y., Webster R.I., Wilson D., Zalan A., Wolfe L.A., Rosenfeld J.A., Rhodes L., Freeze H.H., Ng B.G., Eklund E.A., Shiryaev S.A., Dong Y.Y., Abbott M.-A., Asteggiano C., Bamshad M.J., Barr E., Bernstein J.A., Chelakkadan S., Christodoulou J., Chung W.K., Ciliberto M.A., Cousin J., Gardiner F., Ghosh S., Graf W.D., Grunewald S., Hammond K., Hauser N.S., Hoganson G.E., Houck K.M., Kohler J.N., Morava E., Larson A.A., Liu P., Madathil S., McCormack C., Meeks N.J.L., Miller R., Monaghan K.G., Nickerson D.A., Palculict T.B., Papazoglu G.M., Pletcher B.A., Scheffer I.E., Schenone A.B., Schnur R.E., and Si Y.

Abstract

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.Copyright © 2020 SSIEM

Published
2020

14. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Author

Yan, K.Z., Rousseau, J., Littlejohn, R.O., Kiss, C., Lehman, A., Rosenfeld, J.A., Stumpel, C.T.R., Stegmann, A.P.A., Robak, L., Scaglia, F., Nguyen, T.T.M., Fu, H., Ajeawung, N.F., Camurri, M.V., Li, L., Gardham, A., Panis, B., Almannai, M., Sacoto, M.J.G., Baskin, B., Ruivenkamp, C., Xia, F., Bi, W., Cho, M.T., Potjer, T.P., Santen, G.W.E., Parker, M.J., Canham, N., McKinnon, M., Potocki, L., MacKenzie, J.J., Roeder, E.R., Campeau, P.M., Yang, X.J., DDD Study, CAUSES Study, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
0301 basic medicine, Male, Developmental Disabilities, PZP DOMAIN, HBO1 ACETYLTRANSFERASE, Histones, Mice, Intellectual disability, Global developmental delay, Child, Genetics (clinical), Histone Acetyltransferases, Genetics, Mice, Knockout, ZINC-FINGER PROTEIN, Nuclear Proteins, Acetylation, Syndrome, Chromatin, DNA-Binding Proteins, Histone, Muscle Hypotonia, Female, EXPRESSION, Adolescent, Biology, KAT6B, Article, 03 medical and health sciences, Histone H3, Intellectual Disability, medicine, Animals, Humans, HEMATOPOIETIC STEM-CELLS, Epigenetics, Histone H3 acetylation, Alleles, Adaptor Proteins, Signal Transducing, CAUSE GENITOPATELLAR SYNDROME, Lysine, PHD FINGER, medicine.disease, Bromodomain, Mice, Inbred C57BL, 030104 developmental biology, DE-NOVO MUTATIONS, Face, Mutation, biology.protein, Carrier Proteins, CAENORHABDITIS-ELEGANS
Abstract

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Syrhptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.

Published
2017

15. Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability

Author

Marom, R., Jain, M., Burrage, L.C., Song, I.W., Graham, B.H., Brown, C.W., Stevens, S.J.C., Stegmann, A.P.A., Gunter, A.T., Kaplan, J.D., Gavrilova, R.H., Shinawi, M., Rosenfeld, J.A., Bae, Y., Tran, A.A., Chen, Y, Lu, J.T., Gibbs, R.A., Eng, C., Yang, Y, Rousseau, J., Vries, B.B.A. de, Campeau, P.M., Lee, B., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
Male, Heterozygote, speech delay, Adolescent, Chromosomal Proteins, Non-Histone, Micrognathism, Mutation, Missense, Article, CHROMATIN-REMODELING COMPLEX, Humans, Exome, BAF complex, Child, HAPLOINSUFFICIENCY CAUSES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COFFIN-SIRIS SYNDROME, DNA Helicases, Nuclear Proteins, SWI/SNF COMPLEX, Chromatin Assembly and Disassembly, BARAITSER-WINTER SYNDROME, GENE, Actins, NUCLEAR ACTIN, DNA-Binding Proteins, ACTIN-RELATED PROTEINS, intellectual disability, DE-NOVO MUTATIONS, Face, Multiprotein Complexes, ACTL6A, Female, Hand Deformities, Congenital, MENTAL-RETARDATION, Protein Binding, Transcription Factors
Abstract

Item does not contain fulltext Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Published
2017

16. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Dijck, A. van, Vulto-van Silfhout, A.T., Cappuyns, E., Werf, I.M. van der, Mancini, G.M., Tzschach, A., Bernier, R., Gozes, I., Eichler, E.E., Romano, C., Lindstrand, A., Nordgren, A., Kvarnung, M., Kleefstra, T., Vries, B.B.A. de, Kury, S., Rosenfeld, J.A., Meuwissen, M.E., Vandeweyer, G., Kooy, R.F., Bakshi, M., Wilson, M., Berman, Y., Dickson, R., Fransen, E., Helsmoortel, C., Ende, J. van den, Aa, N. van der, Wijdeven, M.J. van de, Rosenblum, J., Monteiro, F., Kok, F., Quercia, N., Bowdin, S., Dyment, D., Chitayat, D., Alkhunaizi, E., Boonen, S.E., Keren, B., Jacquette, A., Faivre, L., Bezieau, S., Isidor, B., Riess, A., Moog, U., Lynch, S.A., McVeigh, T., Elpeleg, O., Smeland, M.F., Fannemel, M., Haeringen, A. van, Maas, S.M., Veenstra-Knol, H.E., Schouten, M., Willemsen, M.H., Marcelis, C.L., Ockeloen, C., Burgt, I. van der, Feenstra, I., Smagt, J. van der, Jezela-Stanek, A., Krajewska-Walasek, M., Gonzalez-Lamuno, D., Anderlid, B.M., Malmgren, H., Nordenskjold, M., Clement, E., Hurst, J., Metcalfe, K., Mansour, S., Lachlan, K., Clayton-Smith, J., Hendon, L.G., Abdulrahman, O.A., Morrow, E., McMillan, C., Gerdts, J., Peeden, J., Vergano, S.A.S., Valentino, C., Chung, W.K., Ozmore, J.R., Bedrosian-Sermone, S., Dennis, A., Treat, K., Hughes, S.S., Safina, N., Pichon, J.B. le, McGuire, M., Infante, E., Madan-Khetarpal, S., Desai, S., Benke, P., Krokosky, A., Cristian, I., Baker, L., Gripp, K., Stessman, H.A., Eichenberger, J., Jayakar, P., Pizzino, A., Manning, M.A., Slattery, L., ADNP Consortium, Universidad de Cantabria, ADNP Consortium, Human Genetics, ANS - Complex Trait Genetics, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Pediatrics, Autism Spectrum Disorder, Autism, Intellectual disability, Cohort Studies, Epilepsy, 0302 clinical medicine, Genotype-phenotype distinction, Neurodevelopmental disorder, Neurodevelopmental Disorder, Helsmoortel-Van der Aa syndrome, Child, ADNP, Syndrome, Hypotonia, Autism spectrum disorder, Child, Preschool, Cohort, Female, Abnormalities, medicine.symptom, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Helsmoortel-Van der Aa Síndrome, medicine, Genetics, Humans, Abnormalities, Multiple, Preschool, Biology, Biological Psychiatry, Homeodomain Proteins, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, medicine.disease, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Published
2019

17. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author

Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T.T.M., Spillmann, R.C., Sullivan, J.A., Shashi, V., Jiang, Y.H., Stong, N., Fiala, E., Willing, M., Pfundt, R.P., Kleefstra, T., Cho, M.T., McLaughlin, H., Piera, M. Rosello, Orellana, C., Martinez, F., Caro-Llopis, A., Monfort, S., Roscioli, T., Nixon, C.Y., Buckley, M.F., Turner, A., Jones, W.D., Hasselt, P.M. van, Hofstede, F.C., Gassen, K.L.I. van, Brooks, A.S., Slegtenhorst, M.A. van, Lachlan, K., Sebastian, J., Madan-Khetarpal, S., Sonal, D., Sakkubai, N., Thevenon, J., Faivre, L., Maurel, A., Petrovski, S., Krantz, I.D., Tarpinian, J.M., Rosenfeld, J.A., Lee, B.H., Campeau, P.M., Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T.T.M., Spillmann, R.C., Sullivan, J.A., Shashi, V., Jiang, Y.H., Stong, N., Fiala, E., Willing, M., Pfundt, R.P., Kleefstra, T., Cho, M.T., McLaughlin, H., Piera, M. Rosello, Orellana, C., Martinez, F., Caro-Llopis, A., Monfort, S., Roscioli, T., Nixon, C.Y., Buckley, M.F., Turner, A., Jones, W.D., Hasselt, P.M. van, Hofstede, F.C., Gassen, K.L.I. van, Brooks, A.S., Slegtenhorst, M.A. van, Lachlan, K., Sebastian, J., Madan-Khetarpal, S., Sonal, D., Sakkubai, N., Thevenon, J., Faivre, L., Maurel, A., Petrovski, S., Krantz, I.D., Tarpinian, J.M., Rosenfeld, J.A., Lee, B.H., and Campeau, P.M.

Abstract

Contains fulltext : 202800.pdf (publisher's version ) (Open Access), SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Published
2019

18. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author

Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), Xia, K. (Kun), Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), and Xia, K. (Kun)

Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely genedisrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITSCLIP revealed that Csde1binding targets are enriched in autismassociated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autismrelated syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

Published
2019
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19. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author

Cheng, H., Dharmadhikari, A.V., Varland, S., Ma, N., Domingo, D., Kleyner, R., Rope, A.F., Yoon, M., Stray-Pedersen, A., Posey, J.E., Crews, S.R., Eldomery, M.K., Akdemir, Z.C., Lewis, A.M., Sutton, V.R., Rosenfeld, J.A., Conboy, E., Agre, K., Xia, F., Walkiewicz, M., Longoni, M., High, F.A., Slegtenhorst, M.A. van, Mancini, G.M.S., Finnila, C.R., Haeringen, A. van, Hollander, N. den, Ruivenkamp, C., Naidu, S., Mahida, S., Palmer, E.E., Murray, L., Lim, D., Jayakar, P., Parker, M.J., Giusto, S., Stracuzzi, E., Romano, C, Beighley, J.S., Bernier, R.A., Kury, S., Nizon, M., Corbett, M.A., Shaw, M., Gardner, A., Barnett, C., Armstrong, R., Kassahn, K.S., Dijck, A. Van, Vandeweyer, G., Kleefstra, T., Schieving, J.H., Jongmans, M.C., Vries, B.B.A. de, Pfundt, R.P., Kerr, B., Rojas, S.K., Boycott, K.M., Person, R., Willaert, R., Eichler, E.E., Kooy, R.F., Yang, Y., Wu, J.C., Lupski, J.R., Arnesen, T., Cooper, G.M., Chung, W.K., Gecz, J., Stessman, H.A.F., Meng, L., Lyon, G.J., Cheng, H., Dharmadhikari, A.V., Varland, S., Ma, N., Domingo, D., Kleyner, R., Rope, A.F., Yoon, M., Stray-Pedersen, A., Posey, J.E., Crews, S.R., Eldomery, M.K., Akdemir, Z.C., Lewis, A.M., Sutton, V.R., Rosenfeld, J.A., Conboy, E., Agre, K., Xia, F., Walkiewicz, M., Longoni, M., High, F.A., Slegtenhorst, M.A. van, Mancini, G.M.S., Finnila, C.R., Haeringen, A. van, Hollander, N. den, Ruivenkamp, C., Naidu, S., Mahida, S., Palmer, E.E., Murray, L., Lim, D., Jayakar, P., Parker, M.J., Giusto, S., Stracuzzi, E., Romano, C, Beighley, J.S., Bernier, R.A., Kury, S., Nizon, M., Corbett, M.A., Shaw, M., Gardner, A., Barnett, C., Armstrong, R., Kassahn, K.S., Dijck, A. Van, Vandeweyer, G., Kleefstra, T., Schieving, J.H., Jongmans, M.C., Vries, B.B.A. de, Pfundt, R.P., Kerr, B., Rojas, S.K., Boycott, K.M., Person, R., Willaert, R., Eichler, E.E., Kooy, R.F., Yang, Y., Wu, J.C., Lupski, J.R., Arnesen, T., Cooper, G.M., Chung, W.K., Gecz, J., Stessman, H.A.F., Meng, L., and Lyon, G.J.

Abstract

Item does not contain fulltext, N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Published
2018

20. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, ben, Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y.P., State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Bezieau, S., Odent, S., Elgersma, Y., Mercier, S., Undiagnosed Dis Network, GEM HUGO, Deciphering Dev Dis Study, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neuroscience [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Expertise Center for Neurodevelopmental Disorders [Rotterdam, the Netherlands] (ENCORE), Genomics Program and Division of Genetics [Boston, USA], Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Gene Discovery Core [Boston, MA, USA] ( The Manton Center for Orphan Disease Research), Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, GeneDx [Gaithersburg, MD, USA], Department of Medical Genetics [Skien, Norway], Telemark Hospital Trust [Skien, Norway], Department of Psychiatry [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Pharmacology [Omaha, NE, USA], Creighton University Medical School [Omaha, NE, USA], Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Medical Biochemistry [Amsterdam, the Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA), Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de Génétique [HCL, Lyon] (Centre de Référence des Anomalies du Développement), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetics and Metabolism [Little Rock, AR, USA], University of Arkansas for Medical Sciences (UAMS), Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Sheffield Children's NHS Foundation Trust, Northern Ireland Regional Genetics Centre [Belfast, UK], Belfast City Hospital-Belfast Health and Social Care Trust, Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Clinical Genetics [Leiden, the Netherlands], Leiden University Medical Center (LUMC), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, The Center for Applied Genomics [Philadelphia, PA, USA], Division of Human Genetics [Philadelphia, PA, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), Division of Clinical Genomics [Aliso Viejo, CA, USA], Ambry Genetics [Aliso Viejo, CA, USA], Division of Neurology [Philadelphia, PA, USA], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], University of Heidelberg, Medical Faculty, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Biological Sciences [Limerick, Ireland], University of Limerick (UL), Bernal Institute [Limerick, Ireland], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), 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), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, The Wellcome Trust Sanger Institute [Cambridge], Department of Medicine [Melbourne, Australia], University of Melbourne-Austin Health, Division of Newborn Medicine [Boston, MA, USA], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Neurosciences, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Univ Angers, Okina, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], Universiteit Leiden-Universiteit Leiden, Department of Pediatrics [Seattle, WA, USA], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Universität Heidelberg [Heidelberg] = Heidelberg University, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Bernardo, Elizabeth

Subjects
0301 basic medicine, Male, de novo mutations, AMPAR, medicine.disease_cause, Inbred C57BL, Mice, 0302 clinical medicine, Intellectual disability, CAMK2A, Exome, Phosphorylation, Genetics (clinical), Genetics, Neurons, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain, Phenotype, NMDAR, intellectual disability, Female, Signal transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Signal Transduction, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Journal Article, Animals, Humans, Protein kinase A, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], synaptic plasticity, medicine.disease, Mice, Inbred C57BL, CAMK2, CAMK2B, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017

21. Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Author

Stankiewicz, P., Khan, T.N., Szafranski, P., Slattery, L., Streff, H., Vetrini, F., Bernstein, J.A., Brown, C.W., Rosenfeld, J.A., Rednam, S., Scollon, S., Bergstrom, K.L., Parsons, D.W., Plon, S.E., Vieira, M.W., Quaio, C., Baratela, W.A.R., Guio, J.C.A., Armstrong, R., Mehta, S.G., Rump, P., Pfundt, R.P., Lewandowski, R., Fernandes, E.M., Shinde, D.N., Tang, S., Hoyer, J., Zweier, C., Reis, A., Bacino, C.A., Xiao, R., Breman, A.M., Smith, J.L., Katsanis, N., Bostwick, B., Popp, B., Davis, E.E., Yang, Y, Stankiewicz, P., Khan, T.N., Szafranski, P., Slattery, L., Streff, H., Vetrini, F., Bernstein, J.A., Brown, C.W., Rosenfeld, J.A., Rednam, S., Scollon, S., Bergstrom, K.L., Parsons, D.W., Plon, S.E., Vieira, M.W., Quaio, C., Baratela, W.A.R., Guio, J.C.A., Armstrong, R., Mehta, S.G., Rump, P., Pfundt, R.P., Lewandowski, R., Fernandes, E.M., Shinde, D.N., Tang, S., Hoyer, J., Zweier, C., Reis, A., Bacino, C.A., Xiao, R., Breman, A.M., Smith, J.L., Katsanis, N., Bostwick, B., Popp, B., Davis, E.E., and Yang, Y

Abstract

Contains fulltext : 182555.pdf (publisher's version ) (Closed access), Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Published
2017

22. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Author

Gabriele, M., Vulto-van Silfhout, A.T., Germain, P.L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., Steindl, K., Frengen, E., Misceo, D., Pedurupillay, C.R., Stromme, P., Rosenfeld, J.A., Shao, Y., Craigen, W.J., Schaaf, C.P., Rodriguez-Buritica, D., Farach, L., Friedman, J., Thulin, P., McLean, S.D., Nugent, K.M., Morton, J., Nicholl, J., Andrieux, J., Stray-Pedersen, A., Chambon, P., Patrier, S., Lynch, S.A., Kjaergaard, S., Torring, P.M., Brasch-Andersen, C., Ronan, A., Haeringen, A. van, Anderson, P.J., Powis, Z., Brunner, H.G., Pfundt, R.P., Schuurs-Hoeijmakers, J.H.M., Bon, B.W.M. van, Lelieveld, S.H., Gilissen, C.F., Nillesen, W.M., Vissers, L.E.L.M., Gecz, J., Koolen, D.A., Testa, G., Vries, B.B. de, Gabriele, M., Vulto-van Silfhout, A.T., Germain, P.L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., Steindl, K., Frengen, E., Misceo, D., Pedurupillay, C.R., Stromme, P., Rosenfeld, J.A., Shao, Y., Craigen, W.J., Schaaf, C.P., Rodriguez-Buritica, D., Farach, L., Friedman, J., Thulin, P., McLean, S.D., Nugent, K.M., Morton, J., Nicholl, J., Andrieux, J., Stray-Pedersen, A., Chambon, P., Patrier, S., Lynch, S.A., Kjaergaard, S., Torring, P.M., Brasch-Andersen, C., Ronan, A., Haeringen, A. van, Anderson, P.J., Powis, Z., Brunner, H.G., Pfundt, R.P., Schuurs-Hoeijmakers, J.H.M., Bon, B.W.M. van, Lelieveld, S.H., Gilissen, C.F., Nillesen, W.M., Vissers, L.E.L.M., Gecz, J., Koolen, D.A., Testa, G., and Vries, B.B. de

Abstract

Contains fulltext : 174704.pdf (publisher's version ) (Open Access), Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

Published
2017

23. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M.N., Leleu, M., Mannik, K., Passeggeri, M., Giannuzzi, G., Werf, I. van der, Waszak, S.M., Zazhytska, M., Roberts-Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Hippolyte, L., Maillard, A.M., Dijck, A. Van, Kooy, R.F., Sanlaville, D., Rosenfeld, J.A., Shaffer, L.G., Andrieux, J., Marshall, C., Scherer, S.W., Shen, Y., Gusella, J.F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E.T., Deplancke, B., Beckmann, J.S., Rougemont, J., Jacquemont, S., Reymond, A., Vulto-van Silfhout, A.T., Schouten, M.I., Pfundt, R.P., Leeuw, N. de, et al., Loviglio, M.N., Leleu, M., Mannik, K., Passeggeri, M., Giannuzzi, G., Werf, I. van der, Waszak, S.M., Zazhytska, M., Roberts-Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Hippolyte, L., Maillard, A.M., Dijck, A. Van, Kooy, R.F., Sanlaville, D., Rosenfeld, J.A., Shaffer, L.G., Andrieux, J., Marshall, C., Scherer, S.W., Shen, Y., Gusella, J.F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E.T., Deplancke, B., Beckmann, J.S., Rougemont, J., Jacquemont, S., Reymond, A., Vulto-van Silfhout, A.T., Schouten, M.I., Pfundt, R.P., Leeuw, N. de, and et al.

Abstract

Contains fulltext : 174530.pdf (publisher's version ) (Open Access), Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Published
2017

24. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., Rouleau, G.A., et al., Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., and Rouleau, G.A., et al.

Abstract

Item does not contain fulltext, Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Published
2017

25. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author

Lessel, D., Schob, C., Kury, S., Reinders, M.R.F., Harel, T., Eldomery, M.K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A.P., Gerkes, E.H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T.M., Rosenfeld, J.A., Yang, Y, Posey, J.E., Immken, L., Oundjian, N., Helbig, K.L., Meeks, N., Zegar, K., Morton, J., Schieving, J.H., Claasen, A., Huentelman, M., Narayanan, V., Ramsey, K., Brunner, H.G., Elpeleg, O., Mercier, S., Bezieau, S., Kubisch, C., Kleefstra, T., Kindler, S., Lupski, J.R., Kreienkamp, H.J., Lessel, D., Schob, C., Kury, S., Reinders, M.R.F., Harel, T., Eldomery, M.K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A.P., Gerkes, E.H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T.M., Rosenfeld, J.A., Yang, Y, Posey, J.E., Immken, L., Oundjian, N., Helbig, K.L., Meeks, N., Zegar, K., Morton, J., Schieving, J.H., Claasen, A., Huentelman, M., Narayanan, V., Ramsey, K., Brunner, H.G., Elpeleg, O., Mercier, S., Bezieau, S., Kubisch, C., Kleefstra, T., Kindler, S., Lupski, J.R., and Kreienkamp, H.J.

Abstract

Contains fulltext : 182457.pdf (publisher's version ) (Closed access), DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

Published
2017

26. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), Mercier, S. (Sandra), Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), and Mercier, S. (Sandra)

Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017
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27. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Author

D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L.G., Hippolyte, L., Hanson, E., Maillard, A.M., Faucett, W.A., Mace, A., Pain, A., Bernier, R., Chawner, S.J., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gerard, M., Goin-Kochel, R.P., Grant, E., Hunter, J.V., Isidor, B., Jacquette, A., Jonch, A.E., Keren, B., Lacombe, D., Caignec, C. Le, Martin, C.L., Mannik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M.J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J.A., Spence, S.J., Steinman, K.J., Tjernagel, J., Haelst, M. van, Shen, Y., Draganski, B., Sherr, E.H., Ledbetter, D.H., Bree, M.B. van den, Beckmann, J.S., Spiro, J.E., Reymond, A., Jacquemont, S., Chung, W.K., Vries, B.B. de, Faas, B.H.W., Koolen, D.A., Vulto-van Silfhout, A.T., Leeuw, N. de, et al., D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L.G., Hippolyte, L., Hanson, E., Maillard, A.M., Faucett, W.A., Mace, A., Pain, A., Bernier, R., Chawner, S.J., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gerard, M., Goin-Kochel, R.P., Grant, E., Hunter, J.V., Isidor, B., Jacquette, A., Jonch, A.E., Keren, B., Lacombe, D., Caignec, C. Le, Martin, C.L., Mannik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M.J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J.A., Spence, S.J., Steinman, K.J., Tjernagel, J., Haelst, M. van, Shen, Y., Draganski, B., Sherr, E.H., Ledbetter, D.H., Bree, M.B. van den, Beckmann, J.S., Spiro, J.E., Reymond, A., Jacquemont, S., Chung, W.K., Vries, B.B. de, Faas, B.H.W., Koolen, D.A., Vulto-van Silfhout, A.T., Leeuw, N. de, and et al.

Abstract

Contains fulltext : 167711.pdf (publisher's version ) (Closed access), IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was sign

Published
2016

28. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

Author

Fregeau, B., Kim, B.J., Hernandez-Garcia, A., Jordan, V.K., Cho, M.T., Schnur, R.E., Monaghan, K.G., Juusola, J., Rosenfeld, J.A., Bhoj, E., Zackai, E.H., Sacharow, S., Baranano, K., Bosch, D.G.M., Vries, B.B.A. de, Lindstrom, K., Schroeder, A., James, P., Kulch, P., Lalani, S.R., Haelst, M.M. van, Gassen, K.L. van, Binsbergen, E. van, Barkovich, A.J., Scott, D.A., Sherr, E.H., Fregeau, B., Kim, B.J., Hernandez-Garcia, A., Jordan, V.K., Cho, M.T., Schnur, R.E., Monaghan, K.G., Juusola, J., Rosenfeld, J.A., Bhoj, E., Zackai, E.H., Sacharow, S., Baranano, K., Bosch, D.G.M., Vries, B.B.A. de, Lindstrom, K., Schroeder, A., James, P., Kulch, P., Lalani, S.R., Haelst, M.M. van, Gassen, K.L. van, Binsbergen, E. van, Barkovich, A.J., Scott, D.A., and Sherr, E.H.

Abstract

Item does not contain fulltext, Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.

Published
2016

29. MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

Author

Eldomery, M.K., Akdemir, Z.C., Vogtle, F.N., Charng, W.L., Mulica, P., Rosenfeld, J.A., Gambin, T., Gu, S., Burrage, L.C., Shamsi, A. Al, Penney, S., Jhangiani, S.N., Zimmerman, H.H., Muzny, D.M., Wang, X., Tang, J., Medikonda, R., Ramachandran, P.V., Wong, L.J., Boerwinkle, E., Gibbs, R.A., Eng, C.M., Lalani, S.R., Hertecant, J., Rodenburg, R.J.T., Abdul-Rahman, O.A., Yang, Y, Xia, F., Wang, M.C., Lupski, J.R., Meisinger, C., Sutton, V.R., Eldomery, M.K., Akdemir, Z.C., Vogtle, F.N., Charng, W.L., Mulica, P., Rosenfeld, J.A., Gambin, T., Gu, S., Burrage, L.C., Shamsi, A. Al, Penney, S., Jhangiani, S.N., Zimmerman, H.H., Muzny, D.M., Wang, X., Tang, J., Medikonda, R., Ramachandran, P.V., Wong, L.J., Boerwinkle, E., Gibbs, R.A., Eng, C.M., Lalani, S.R., Hertecant, J., Rodenburg, R.J.T., Abdul-Rahman, O.A., Yang, Y, Xia, F., Wang, M.C., Lupski, J.R., Meisinger, C., and Sutton, V.R.

Abstract

Contains fulltext : 170911.pdf (publisher's version ) (Open Access), BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. CONCLUSIONS: Our findings reveal for the first time the role of th

Published
2016

30. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Author

Chen, C.A., Bosch, D.G.M., Cho, M.T., Rosenfeld, J.A., Shinawi, M., Lewis, R.A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K.G., Elmslie, F., Douglas, G., Boonstra, F.N., Millan, F., Cremers, F.P.M., McKnight, D., Richard, G., Juusola, J., Kendall, F., Ramsey, K., Anyane-Yeboa, K., Malkin, E., Chung, W.K., Niyazov, D., Pascual, J.M., Walkiewicz, M., Veluchamy, V., Li, C., Hisama, F.M., Vries, B.B. de, Schaaf, C., Chen, C.A., Bosch, D.G.M., Cho, M.T., Rosenfeld, J.A., Shinawi, M., Lewis, R.A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K.G., Elmslie, F., Douglas, G., Boonstra, F.N., Millan, F., Cremers, F.P.M., McKnight, D., Richard, G., Juusola, J., Kendall, F., Ramsey, K., Anyane-Yeboa, K., Malkin, E., Chung, W.K., Niyazov, D., Pascual, J.M., Walkiewicz, M., Veluchamy, V., Li, C., Hisama, F.M., Vries, B.B. de, and Schaaf, C.

Abstract

Item does not contain fulltext, PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Published
2016

31. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

Author

Delaneau O., Marchini J., McVeanh G.A., Donnelly P., Lunter G., Marchini J.L., Myers, S., Gupta-Hinch, A., Iqbal, Z., Mathieson I., Rimmer, A., Xifara, D.K., Kerasidou, A., Churchhouse, C., Altshuler, D.M., Gabriel, S.B., Lander, E.S., Gupta, N., Daly, M.J., DePristo, M.A., Banks, E., Bhatia G., Carneiro, M.O., Del Angel G., Genovese G., Handsaker, R.E., Hartl, C., McCarroll, S.A., Nemesh J.C., Poplin, R.E., Schaffner, S.F., Shakir, K., Sabeti P.C., Grossman, S.R., Tabrizi, S., Tariyal, R., Li H., Reich, D., Durbin, R.M., Hurles, M.E., Balasubramaniam, S., Burton J., Danecek P., Keane, T.M., Kolb-Kokocinski, A., McCarthy, S., Stalker J., Quail, M., Ayub Q., Chen, Y., Coffey, A.J., Colonna V., Huang, N., Jostins L., Scally, A., Walter, K., Xue, Y., Zhang, Y., Blackburne, B., Lindsay, S.J., Ning, Z., Frankish, A., Harrow J., Chris, T.-S., Abecasis G.R., Kang H.M., Anderson P., Blackwell, T., Busonero F., Fuchsberger, C., Jun G., Maschio, A., Porcu, E., Sidore, C., Tan, A., Trost, M.K., Bentley, D.R., Grocock, R., Humphray, S., James, T., Kingsbury, Z., Bauer, M., Cheetham, R.K., Cox, T., Eberle, M., Murray L., Shaw, R., Chakravarti, A., Clark, A.G., Keinan, A., Rodriguez-Flores J.L., De LaVega F.M., Degenhardt J., Eichler, E.E., Flicek P., Clarke L., Leinonen, R., Smith, R.E., Zheng-Bradley X., Beal, K., Cunningham F., Herrero J., McLaren W.M., Ritchie G.R.S., Barker J., Kelman G., Kulesha, E., Radhakrishnan, R., Roa, A., Smirnov, D., Streeter I., Toneva I., Gibbs, R.A., Dinh H., Kovar, C., Lee, S., Lewis L., Muzny, D., Reid J., Wang, M., Yu F., Bainbridge, M., Challis, D., Evani, U.S., Lu J., Nagaswamy, U., Sabo, A., Wang, Y., Yu J., Fowler G., Hale W., Kalra, D., Green, E.D., Knoppers, B.M., Korbel J.O., Rausch, T., Sttz, A.M., Lee, C., Griffin L., Hsieh, C.-H., Mills, R.E., Von Grotthuss, M., Zhang, C., Shi X., Lehrach H., Sudbrak, R., Amstislavskiy V.S., Lienhard, M., Mertes F., Sultan, M., Timmermann, B., Yaspo, M.L., Herwig, S.R., Mardis, E.R., Wilson, R.K., Fulton L., Fulton, R., Weinstock G.M., Chinwalla, A., Ding L., Dooling, D., Koboldt, D.C., McLellan, M.D., Wallis J.W., Wendl, M.C., Zhang Q., Marth G.T., Garrison, E.P., Kural, D., Lee W.-P., Leong W.F., Ward, A.N., Wu J., Zhang, M., Nickerson, D.A., Alkan, C., Hormozdiari F., Ko, A., Sudmant P.H., Schmidt J.P., Davies, C.J., Gollub J., Webster, T., Wong, B., Zhan, Y., Sherry, S.T., Xiao, C., Church, D., Ananiev V., Belaia, Z., Beloslyudtsev, D., Bouk, N., Chen, C., Cohen, R., Cook, C., Garner J., Hefferon, T., Kimelman, M., Liu, C., Lopez J., Meric P., Ostapchuk, Y., Phan L., Ponomarov, S., Schneider V., Shekhtman, E., Sirotkin, K., Slotta, D., Zhang H., Wang J., Fang X., Guo X., Jian, M., Jiang H., Jin X., Li G., Li J., Li, Y., Liu X., Lu, Y., Ma X., Tai, S., Tang, M., Wang, B., Wang G., Wu H., Wu, R., Yin, Y., Zhang W., Zhao J., Zhao, M., Zheng X., Lachlan H., Fang L., Li Q., Li, Z., Lin H., Liu, B., Luo, R., Shao H., Xie, Y., Ye, C., Yu, C., Zheng H., Zhu H., Cai H., Cao H., Su, Y., Tian, Z., Yang H., Yang L., Zhu J., Cai, Z., Albrecht, M.W., Borodina, T.A., Auton, A., Yoon, S.C., Lihm J., Makarov V., Jin H., Kim W., Kim, K.C., Gottipati, S., Jones, D., Cooper, D.N., Ball, E.V., Stenson P.D., Barnes, B., Kahn, S., Ye, K., Batzer, M.A., Konkel, M.K., Walker J.A., MacArthur, D.G., Lek, M., Shriver, M.D., Bustamante, C.D., Gravel, S., Kenny, E.E., Kidd J.M., Lacroute P., Maples, B.K., Moreno-Estrada, A., Zakharia F., Henn, B., Sandoval, K., Byrnes J.K., Halperin, E., Baran, Y., Craig, D.W., Christoforides, A., Izatt, T., Kurdoglu, A.A., Sinari, S.A., Homer, N., Squire, K., Sebat J., Bafna V., Burchard, E.G., Hernandez, R.D., Gignoux, C.R., Haussler, D., Katzman, S.J., Kent W.J., Howie, B., Ruiz-Linares, A., Dermitzakis, E.T., Lappalainen, T., Devine, S.E., Maroo, A., Tallon L.J., Rosenfeld J.A., Michelson L.P., Angius, A., Cucca F., Sanna, S., Bigham, A., Jones, C., Reinier F., Lyons, R., Schlessinger, D., Awadalla P., Hodgkinson, A., Oleksyk, T.K., Martinez-Cruzado J.C., Fu, Y., Xiong, M., Jorde L., Witherspoon, D., Xing J., Browning, B.L., Hajirasouliha I., Chen, K., Albers, C.A., Gerstein, M.B., Abyzov, A., Chen J., Habegger L., Harmanci, A.O., Mu X.J., Sisu, C., Balasubramanian, S., Jin, M., Khurana, E., Clarke, D., Michaelson J.J., OSullivan, C., Barnes, K.C., Gharani, N., Toji L.H., Gerry, N., Kaye J.S., Kent, A., Mathias, R., Ossorio P.N., Parker, M., Rotimi, C.N., Royal, C.D., Tishkoff, S., Via, M., Bodmer W., Bedoya G., Yang G., You, C.J., Garcia-Montero, A., Orfao, A., Dutil J., Brooks L.D., Felsenfeld, A.L., McEwen J.E., Clemm, N.C., Guyer, M.S., Peterson J.L., Duncanson, A., Dunn, M., Peltonen L., and 1000 Genomes Project Consortium

Subjects
haplotype, genetic association, genotype, General Physics and Astronomy, Genome-wide association study, genetic analysis, gene sequence, Biology, gene frequency, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, polymorphism, Gene Frequency, single nucleotide polymorphism, Humans, chromosome, human, 1000 Genomes Project, indel mutation, genome, Alleles, Genetic association, Genetics, Whole genome sequencing, Multidisciplinary, accuracy, Genome, Human, Haplotype, allele, article, reference database, General Chemistry, Microarray Analysis, chromosome 20, Haplotypes, Human genome, microarray analysis, Imputation (genetics), Algorithms, SNP array, Genome-Wide Association Study
Abstract

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved.

Published
2014

33. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

Author

Burrage, L.C., Charng, W.L., Eldomery, M.K., Willer, J.R., Davis, E.E., Lugtenberg, D., Zhu, W., Leduc, M.S., Akdemir, Z.C., Azamian, M., Zapata, G., Hernandez, P.P., Schoots, J., Munnik, S.A. de, Roepman, R., Pearring, J.N., Jhangiani, S., Katsanis, N., Vissers, L.E.L.M., Brunner, H.G., Beaudet, A.L., Rosenfeld, J.A., Muzny, D.M., Gibbs, R.A., Eng, C.M., Xia, F., Lalani, S.R., Lupski, J.R., Bongers, E.M.H.F., Yang, Y, Burrage, L.C., Charng, W.L., Eldomery, M.K., Willer, J.R., Davis, E.E., Lugtenberg, D., Zhu, W., Leduc, M.S., Akdemir, Z.C., Azamian, M., Zapata, G., Hernandez, P.P., Schoots, J., Munnik, S.A. de, Roepman, R., Pearring, J.N., Jhangiani, S., Katsanis, N., Vissers, L.E.L.M., Brunner, H.G., Beaudet, A.L., Rosenfeld, J.A., Muzny, D.M., Gibbs, R.A., Eng, C.M., Xia, F., Lalani, S.R., Lupski, J.R., Bongers, E.M.H.F., and Yang, Y

Abstract

Item does not contain fulltext, Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6( *)) and c.35_38delTCAA (p.Ile12Lysfs( *)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

Published
2015

34. Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, R., Corbett, M.A., Bon, B.W.M. van, Gardner, A., Woenig, J.A., Jolly, L.A., Douglas, E., Friend, K., Tan, C., Esch, H. Van, Holvoet, M., Raynaud, M., Field, M., Leffler, M., Budny, B., Wisniewska, M., Badura-Stronka, M., Latos-Bielenska, A., Batanian, J., Rosenfeld, J.A., Basel-Vanagaite, L., Jensen, C., Bienek, M., Froyen, G., Ullmann, R., Hu, H, Love, M.I., Haas, S.A., Stankiewicz, P., Cheung, S.W., Baxendale, A., Nicholl, J., Thompson, E.M., Haan, E., Kalscheuer, V.M., Gecz, J., Kumar, R., Corbett, M.A., Bon, B.W.M. van, Gardner, A., Woenig, J.A., Jolly, L.A., Douglas, E., Friend, K., Tan, C., Esch, H. Van, Holvoet, M., Raynaud, M., Field, M., Leffler, M., Budny, B., Wisniewska, M., Badura-Stronka, M., Latos-Bielenska, A., Batanian, J., Rosenfeld, J.A., Basel-Vanagaite, L., Jensen, C., Bienek, M., Froyen, G., Ullmann, R., Hu, H, Love, M.I., Haas, S.A., Stankiewicz, P., Cheung, S.W., Baxendale, A., Nicholl, J., Thompson, E.M., Haan, E., Kalscheuer, V.M., and Gecz, J.

Abstract

Item does not contain fulltext, Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

Published
2015

35. Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly

Author

Rosenfeld, J.A., Kim, K.H., Angle, B., Troxell, R., Gorski, J.L., Westemeyer, M., Frydman, M., Senturias, Y., Earl, D., Torchia, B., Schultz, R.A., Ellison, J.W., Tsuchiya, K., Zimmerman, S., Smolarek, T.A., Ballif, B.C., and Shaffer, L.G.

Subjects
Original Article
Abstract

Microduplications of the Sotos syndrome region containing NSD1 on 5q35 have recently been proposed to cause a syndrome of microcephaly, short stature and developmental delay. To further characterize this emerging syndrome, we report the clinical details of 12 individuals from 8 families found to have interstitial duplications involving NSD1, ranging in size from 370 kb to 3.7 Mb. All individuals are microcephalic, and height and childhood weight range from below average to severely restricted. Mild-to-moderate learning disabilities and/or developmental delay are present in all individuals, including carrier family members of probands; dysmorphic features and digital anomalies are present in a majority. Craniosynostosis is present in the individual with the largest duplication, though the duplication does not include MSX2, mutations of which can cause craniosynostosis, on 5q35.2. A comparison of the smallest duplication in our cohort that includes the entire NSD1 gene to the individual with the largest duplication that only partially overlaps NSD1 suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the abnormal growth parameters seen in these patients. NSD1 duplications may therefore be added to a growing list of copy number variations for which deletion and duplication of specific genes have contrasting effects on body development.

Published
2013

36. Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Author

Traylor, R.N., Dobyns, W.B., Rosenfeld, J.A., Wheeler, P., Spence, J.E., Bandholz, A.M., Bawle, E.V., Carmany, E.P., Powell, C.M., Hudson, B., Schultz, R.A., Shaffer, L.G., and Ballif, B.C.

Subjects
Original Article
Abstract

TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1's role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.

Published
2012

37. Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Author

Mullegama, S.V., Rosenfeld, J.A., Orellana, C., Bon, B.W.M. van, Halbach, S., Repnikova, E.A., Brick, L., Li, C., Dupuis, L., Rosello, M., Aradhya, S., Stavropoulos, D.J., Manickam, K., Mitchell, E., Hodge, J.C., Talkowski, M.E., Gusella, J.F., Keller, K., Zonana, J., Schwartz, S., Pyatt, R.E., Waggoner, D.J., Shaffer, L.G., Lin, A.E., Vries, B. de, Mendoza-Londono, R., Elsea, S.H., Mullegama, S.V., Rosenfeld, J.A., Orellana, C., Bon, B.W.M. van, Halbach, S., Repnikova, E.A., Brick, L., Li, C., Dupuis, L., Rosello, M., Aradhya, S., Stavropoulos, D.J., Manickam, K., Mitchell, E., Hodge, J.C., Talkowski, M.E., Gusella, J.F., Keller, K., Zonana, J., Schwartz, S., Pyatt, R.E., Waggoner, D.J., Shaffer, L.G., Lin, A.E., Vries, B. de, Mendoza-Londono, R., and Elsea, S.H.

Abstract

Item does not contain fulltext, Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.

Published
2014

38. Refining analyses of copy number variation identifies specific genes associated with developmental delay.

Author

Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, Eichler, E.E., Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, and Eichler, E.E.

Abstract

Contains fulltext : 136682.pdf (publisher's version ) (Closed access)

Published
2014

39. Disruptive CHD8 mutations define a subtype of autism early in development.

Author

Bernier, R., Golzio, C., Xiong, B., Stessman, H.A., Coe, B.P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Silfhout, A.T. van, Schuurs-Hoeijmakers, J.H.M., Fichera, M., Bosco, P., Buono, S., Alberti, A., Failla, P., Peeters, H., Steyaert, J., Vissers, L.E.L.M., Francescatto, L., Mefford, H.C., Rosenfeld, J.A., Bakken, T., O'Roak, B.J., Pawlus, M., Moon, R., Shendure, J., Amaral, D.G., Lein, E., Rankin, J., Romano, C, Vries, L.B.A. de, Katsanis, N., Eichler, E.E., Bernier, R., Golzio, C., Xiong, B., Stessman, H.A., Coe, B.P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Silfhout, A.T. van, Schuurs-Hoeijmakers, J.H.M., Fichera, M., Bosco, P., Buono, S., Alberti, A., Failla, P., Peeters, H., Steyaert, J., Vissers, L.E.L.M., Francescatto, L., Mefford, H.C., Rosenfeld, J.A., Bakken, T., O'Roak, B.J., Pawlus, M., Moon, R., Shendure, J., Amaral, D.G., Lein, E., Rankin, J., Romano, C, Vries, L.B.A. de, Katsanis, N., and Eichler, E.E.

Abstract

Item does not contain fulltext

Published
2014

40. A systematic survey of loss-of-function variants in human protein-coding genes

Author

MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., Tyler-Smith, C., MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., and Tyler-Smith, C.

Abstract

Item does not contain fulltext, Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

Published
2012

41. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Author

Riviere, J.B., van Bon, B.W., Hoischen, A., Kholmanskikh, S.S., O'Roak, B.J., Gilissen, C.F.H.A., Gijsen, S., Sullivan, C.T., Christian, S.L., Abdul-Rahman, O.A., Atkin, J.F., Chassaing, N., Drouin-Garraud, V., Fry, A.E., Fryns, J.P., Gripp, K.W., Kempers, M., Kleefstra, T., Mancini, G.M.S., Nowaczyk, M.J., van Ravenswaaij-Arts, C.M., Roscioli, T., Marble, M., Rosenfeld, J.A., Siu, V.M., Vries, L.B.A. de, Shendure, J., Verloes, A., Veltman, J.A., Brunner, H.G., Ross, M.E., Pilz, D.T., Dobyns, W.B., Riviere, J.B., van Bon, B.W., Hoischen, A., Kholmanskikh, S.S., O'Roak, B.J., Gilissen, C.F.H.A., Gijsen, S., Sullivan, C.T., Christian, S.L., Abdul-Rahman, O.A., Atkin, J.F., Chassaing, N., Drouin-Garraud, V., Fry, A.E., Fryns, J.P., Gripp, K.W., Kempers, M., Kleefstra, T., Mancini, G.M.S., Nowaczyk, M.J., van Ravenswaaij-Arts, C.M., Roscioli, T., Marble, M., Rosenfeld, J.A., Siu, V.M., Vries, L.B.A. de, Shendure, J., Verloes, A., Veltman, J.A., Brunner, H.G., Ross, M.E., Pilz, D.T., and Dobyns, W.B.

Abstract

Item does not contain fulltext, Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

Published
2012

42. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder

Author

Talkowski, M.E., Mullegama, S.V., Rosenfeld, J.A., Bon, B.W. van, Shen, Y., Repnikova, E.A., Gastier-Foster, J., Thrush, D.L., Kathiresan, S., Ruderfer, D.M., Chiang, C., Hanscom, C., Ernst, C., Lindgren, A.M., Morton, C.C., An, Y., Astbury, C., Brueton, L.A., Lichtenbelt, K.D., Ades, L.C., Fichera, M., Romano, C, Innis, J.W., Williams, C.A., Bartholomew, D., Allen, M.I. van, Parikh, A., Zhang, L., Wu, B.L., Pyatt, R.E., Schwartz, S., Shaffer, L.G., Vries, L.B.A. de, Gusella, J.F., Elsea, S.H., Talkowski, M.E., Mullegama, S.V., Rosenfeld, J.A., Bon, B.W. van, Shen, Y., Repnikova, E.A., Gastier-Foster, J., Thrush, D.L., Kathiresan, S., Ruderfer, D.M., Chiang, C., Hanscom, C., Ernst, C., Lindgren, A.M., Morton, C.C., An, Y., Astbury, C., Brueton, L.A., Lichtenbelt, K.D., Ades, L.C., Fichera, M., Romano, C, Innis, J.W., Williams, C.A., Bartholomew, D., Allen, M.I. van, Parikh, A., Zhang, L., Wu, B.L., Pyatt, R.E., Schwartz, S., Shaffer, L.G., Vries, L.B.A. de, Gusella, J.F., and Elsea, S.H.

Abstract

Item does not contain fulltext, Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.

Published
2011

43. Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Author

Traylor, R.N., primary, Dobyns, W.B., additional, Rosenfeld, J.A., additional, Wheeler, P., additional, Spence, J.E., additional, Bandholz, A.M., additional, Bawle, E.V., additional, Carmany, E.P., additional, Powell, C.M., additional, Hudson, B., additional, Schultz, R.A., additional, Shaffer, L.G., additional, and Ballif, B.C., additional

Published
2012
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44. Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly

Author

Rosenfeld, J.A., primary, Kim, K.H., additional, Angle, B., additional, Troxell, R., additional, Gorski, J.L., additional, Westemeyer, M., additional, Frydman, M., additional, Senturias, Y., additional, Earl, D., additional, Torchia, B., additional, Schultz, R.A., additional, Ellison, J.W., additional, Tsuchiya, K., additional, Zimmerman, S., additional, Smolarek, T.A., additional, Ballif, B.C., additional, and Shaffer, L.G., additional

Published
2012
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46. Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

Author

Theisen, A., primary, Rosenfeld, J.A., additional, Shane, K., additional, McBride, K.L., additional, Atkin, J.F., additional, Gaba, C., additional, Hoo, J., additional, Kurczynski, T.W., additional, Schnur, R.E., additional, Coffey, L.B., additional, Zackai, E.H., additional, Schimmenti, L., additional, Friedman, N., additional, Zabukovec, M., additional, Ball, S., additional, Pagon, R., additional, Lucas, A., additional, Brasington, C.K., additional, Spence, J.E., additional, Sparks, S., additional, Banks, V., additional, Smith, W., additional, Friedberg, T., additional, Wyatt, P.R., additional, Aust, M., additional, Tervo, R., additional, Crowley, A., additional, Skidmore, D., additional, Lamb, A.N., additional, Ravnan, B., additional, Sahoo, T., additional, Schultz, R., additional, Torchia, B.S., additional, Sgro, M., additional, Chitayat, D., additional, and Shaffer, L.G., additional

Published
2010
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47. 20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder.

Author

Williams, P.G., Wetherbee, J.J., Rosenfeld, J.A., and Hersh, J.H.

Abstract

Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2011
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48. The Contraceptive Handbook: A Guide to Safe and Effective Choices

Author

Rosenfeld, J.A.

Subjects
The Contraceptive Handbook: A Guide to Safe and Effective Choices (Book) -- Book reviews, Books -- Book reviews
Abstract

This concisely written, well-organized book is, as it states, "a detailed guide to the methods of birth control currently available in the United States" (p 3). It is intended for [...]

Published
1993

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. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics

Subjects
0301 basic medicine, Male, Microcephaly, Autism Spectrum Disorder, Obesity/genetics, Settore MED/03 - GENETICA MEDICA, Body Mass Index, Microcephaly/genetics, Gene duplication, Chromosome Duplication, ddc:576.5, Copy-number variation, Child, In Situ Hybridization, In Situ Hybridization, Fluorescence, Genetics, medicine.diagnostic_test, Chromosome Mapping, Middle Aged, Phenotype, Chromatin, Chemistry, Psychiatry and Mental Health, Child, Preschool, Female, Original Article, Chromosomes, Human, Pair 16/genetics, Megalencephaly/genetics, Chromosome Deletion, Autistic Disorder/genetics, Molecular Biology, Cellular and Molecular Neuroscience, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, DNA Copy Number Variations, Locus (genetics), DNA Copy Number Variations/genetics, Biology, Aged, Autistic Disorder, Chromosomes, Human, Pair 16, Humans, Infant, Intellectual Disability, Megalencephaly, Obesity, Chromosomes, Fluorescence, Chromatin/metabolism, 03 medical and health sciences, medicine, Preschool, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, medicine.disease, Intellectual Disability/genetics, Autism Spectrum Disorder/genetics, 030104 developmental biology, Human medicine, Chromosome Mapping/methods, Fluorescence in situ hybridization
Abstract

Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Published
2015

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