Universität zu Köln

van Doormaal, Perry T. C., Ticozzi, Nicola ORCID: 0000-0001-5963-7426, Weishaupt, Jochen H., Kenna, Kevin, Diekstra, Frank P., Verde, Federico ORCID: 0000-0002-3977-6995, Andersen, Peter M., Dekker, Annelot M., Tiloca, Cinzia, Marroquin, Nicolai, Overste, Daniel J., Pensato, Viviana ORCID: 0000-0001-9798-2669, Nuernberg, Peter, Pulit, Sara L., Schellevis, Raymond D., Calini, Daniela, Altmueller, Janine, Francioli, Laurent C., Muller, Bernard, Castellotti, Barbara, Motameny, Susanne, Ratti, Antonia, Wolf, Joachim, Gellera, Cinzia, Ludolph, Albert C., van den Berg, Leonard H., Kubisch, Christian ORCID: 0000-0003-4220-0978, Landers, John E., Veldink, Jan H., Silani, Vincenzo and Volk, Alexander E. (2017). The role of de novo mutations in the development of amyotrophic lateral sclerosis. Hum. Mutat., 38 (11). S. 1534 - 1542. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code van Doormaal, Perry T. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ticozzi, Nicola UNSPECIFIED orcid.org/0000-0001-5963-7426 UNSPECIFIED Weishaupt, Jochen H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kenna, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Diekstra, Frank P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verde, Federico UNSPECIFIED orcid.org/0000-0002-3977-6995 UNSPECIFIED Andersen, Peter M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dekker, Annelot M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiloca, Cinzia UNSPECIFIED UNSPECIFIED UNSPECIFIED Marroquin, Nicolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Overste, Daniel J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pensato, Viviana UNSPECIFIED orcid.org/0000-0001-9798-2669 UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Pulit, Sara L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schellevis, Raymond D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Calini, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Francioli, Laurent C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Muller, Bernard UNSPECIFIED UNSPECIFIED UNSPECIFIED Castellotti, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Motameny, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Ratti, Antonia UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Gellera, Cinzia UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludolph, Albert C. UNSPECIFIED UNSPECIFIED UNSPECIFIED van den Berg, Leonard H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED Landers, John E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Veldink, Jan H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Silani, Vincenzo UNSPECIFIED UNSPECIFIED UNSPECIFIED Volk, Alexander E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-213423
DOI:	10.1002/humu.23295
Journal or Publication Title:	Hum. Mutat.
Volume:	38
Number:	11
Page Range:	S. 1534 - 1542
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FAMILIAL ALS; SPORADIC ALS; VARIANTS; DISEASE; POPULATION; PATTERNS; TRIOS; RISK; AGE Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21342