Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism
Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2012
|
| Online Access: | http://hdl.handle.net/1721.1/71762 |
| _version_ | 1810983799370022912 |
|---|---|
| author | Chahrour, Maria H. Yu, Timothy W. Lim, Elaine T. Ataman, Bulent Coulter, Michael E. Hill, R. Sean Stevens, Christine R. Schubert, Christian R. Greenberg, Michael E. Gabriel, Stacey B. Walsh, Christopher A. |
| author2 | Massachusetts Institute of Technology. Research Laboratory of Electronics |
| author_facet | Massachusetts Institute of Technology. Research Laboratory of Electronics Chahrour, Maria H. Yu, Timothy W. Lim, Elaine T. Ataman, Bulent Coulter, Michael E. Hill, R. Sean Stevens, Christine R. Schubert, Christian R. Greenberg, Michael E. Gabriel, Stacey B. Walsh, Christopher A. |
| author_sort | Chahrour, Maria H. |
| collection | MIT |
| description | Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders. |
| first_indexed | 2024-09-23T10:52:16Z |
| format | Article |
| id | mit-1721.1/71762 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:52:16Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/717622022-09-27T15:35:30Z Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism Chahrour, Maria H. Yu, Timothy W. Lim, Elaine T. Ataman, Bulent Coulter, Michael E. Hill, R. Sean Stevens, Christine R. Schubert, Christian R. Greenberg, Michael E. Gabriel, Stacey B. Walsh, Christopher A. Massachusetts Institute of Technology. Research Laboratory of Electronics Schubert, Christian R. Schubert, Christian R. Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders. National Institutes of Health (U.S.) (Grant no. T32 NS007473-11) National Institutes of Health (U.S.) (Grant no. T32 NS007484-11) 2012-07-23T18:55:57Z 2012-07-23T18:55:57Z 2012-04 2011-10 Article http://purl.org/eprint/type/JournalArticle 1553-7390 1553-7404 http://hdl.handle.net/1721.1/71762 Chahrour, Maria H. et al. “Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism.” Ed. Daniel H. Geschwind. PLoS Genetics 8.4 (2012): e1002635. en_US http://dx.doi.org/10.1371/journal.pgen.1002635 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Chahrour, Maria H. Yu, Timothy W. Lim, Elaine T. Ataman, Bulent Coulter, Michael E. Hill, R. Sean Stevens, Christine R. Schubert, Christian R. Greenberg, Michael E. Gabriel, Stacey B. Walsh, Christopher A. Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title | Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title_full | Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title_fullStr | Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title_full_unstemmed | Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title_short | Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism |
| title_sort | whole exome sequencing and homozygosity analysis implicate depolarization regulated neuronal genes in autism |
| url | http://hdl.handle.net/1721.1/71762 |
| work_keys_str_mv | AT chahrourmariah wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT yutimothyw wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT limelainet wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT atamanbulent wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT coultermichaele wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT hillrsean wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT stevenschristiner wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT schubertchristianr wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT greenbergmichaele wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT gabrielstaceyb wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism AT walshchristophera wholeexomesequencingandhomozygosityanalysisimplicatedepolarizationregulatedneuronalgenesinautism |