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Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study

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Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. / Rauch, Anita; Wieczorek, Dagmar; Graf, Elisabeth; Wieland, Thomas; Endele, Sabine; Schwarzmayr, Thomas; Albrecht, Beate; Bartholdi, Deborah; Beygo, Jasmin; Di Donato, Nataliya; Dufke, Andreas; Cremer, Kirsten; Hempel, Maja; Horn, Denise; Hoyer, Juliane; Joset, Pascal; Röpke, Albrecht; Moog, Ute; Riess, Angelika; Thiel, Christian T; Tzschach, Andreas; Wiesener, Antje; Wohlleber, Eva; Zweier, Christiane; Ekici, Arif B; Zink, Alexander M; Rump, Andreas; Meisinger, Christa; Grallert, Harald; Sticht, Heinrich; Schenck, Annette; Engels, Hartmut; Rappold, Gudrun; Schröck, Evelin; Wieacker, Peter; Riess, Olaf; Meitinger, Thomas; Reis, André; Strom, Tim M.

In: LANCET, Vol. 380, No. 9854, 10.11.2012, p. 1674-82.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rauch, A, Wieczorek, D, Graf, E, Wieland, T, Endele, S, Schwarzmayr, T, Albrecht, B, Bartholdi, D, Beygo, J, Di Donato, N, Dufke, A, Cremer, K, Hempel, M, Horn, D, Hoyer, J, Joset, P, Röpke, A, Moog, U, Riess, A, Thiel, CT, Tzschach, A, Wiesener, A, Wohlleber, E, Zweier, C, Ekici, AB, Zink, AM, Rump, A, Meisinger, C, Grallert, H, Sticht, H, Schenck, A, Engels, H, Rappold, G, Schröck, E, Wieacker, P, Riess, O, Meitinger, T, Reis, A & Strom, TM 2012, 'Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study', LANCET, vol. 380, no. 9854, pp. 1674-82. https://doi.org/10.1016/S0140-6736(12)61480-9

APA

Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., Hempel, M., Horn, D., Hoyer, J., Joset, P., Röpke, A., Moog, U., Riess, A., ... Strom, T. M. (2012). Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. LANCET, 380(9854), 1674-82. https://doi.org/10.1016/S0140-6736(12)61480-9

Vancouver

Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. LANCET. 2012 Nov 10;380(9854):1674-82. https://doi.org/10.1016/S0140-6736(12)61480-9

Bibtex

@article{8a44ab19495f424985131ec9e5fb9865,
title = "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study",
abstract = "BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity.INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.",
keywords = "Case-Control Studies, Child, Exome, Female, Humans, Intellectual Disability, Male, Mutation",
author = "Anita Rauch and Dagmar Wieczorek and Elisabeth Graf and Thomas Wieland and Sabine Endele and Thomas Schwarzmayr and Beate Albrecht and Deborah Bartholdi and Jasmin Beygo and {Di Donato}, Nataliya and Andreas Dufke and Kirsten Cremer and Maja Hempel and Denise Horn and Juliane Hoyer and Pascal Joset and Albrecht R{\"o}pke and Ute Moog and Angelika Riess and Thiel, {Christian T} and Andreas Tzschach and Antje Wiesener and Eva Wohlleber and Christiane Zweier and Ekici, {Arif B} and Zink, {Alexander M} and Andreas Rump and Christa Meisinger and Harald Grallert and Heinrich Sticht and Annette Schenck and Hartmut Engels and Gudrun Rappold and Evelin Schr{\"o}ck and Peter Wieacker and Olaf Riess and Thomas Meitinger and Andr{\'e} Reis and Strom, {Tim M}",
note = "Copyright {\textcopyright} 2012 Elsevier Ltd. All rights reserved.",
year = "2012",
month = nov,
day = "10",
doi = "10.1016/S0140-6736(12)61480-9",
language = "English",
volume = "380",
pages = "1674--82",
journal = "LANCET",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9854",

}

RIS

TY - JOUR

T1 - Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study

AU - Rauch, Anita

AU - Wieczorek, Dagmar

AU - Graf, Elisabeth

AU - Wieland, Thomas

AU - Endele, Sabine

AU - Schwarzmayr, Thomas

AU - Albrecht, Beate

AU - Bartholdi, Deborah

AU - Beygo, Jasmin

AU - Di Donato, Nataliya

AU - Dufke, Andreas

AU - Cremer, Kirsten

AU - Hempel, Maja

AU - Horn, Denise

AU - Hoyer, Juliane

AU - Joset, Pascal

AU - Röpke, Albrecht

AU - Moog, Ute

AU - Riess, Angelika

AU - Thiel, Christian T

AU - Tzschach, Andreas

AU - Wiesener, Antje

AU - Wohlleber, Eva

AU - Zweier, Christiane

AU - Ekici, Arif B

AU - Zink, Alexander M

AU - Rump, Andreas

AU - Meisinger, Christa

AU - Grallert, Harald

AU - Sticht, Heinrich

AU - Schenck, Annette

AU - Engels, Hartmut

AU - Rappold, Gudrun

AU - Schröck, Evelin

AU - Wieacker, Peter

AU - Riess, Olaf

AU - Meitinger, Thomas

AU - Reis, André

AU - Strom, Tim M

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2012/11/10

Y1 - 2012/11/10

N2 - BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity.INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.

AB - BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity.INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.

KW - Case-Control Studies

KW - Child

KW - Exome

KW - Female

KW - Humans

KW - Intellectual Disability

KW - Male

KW - Mutation

U2 - 10.1016/S0140-6736(12)61480-9

DO - 10.1016/S0140-6736(12)61480-9

M3 - SCORING: Journal article

C2 - 23020937

VL - 380

SP - 1674

EP - 1682

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 9854

ER -