Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

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• 作者：Timothy W. Yu¹ ; ² ; ³ ; ⁴ ; ⁵ ; ⁶ ; ⁷ ; ³² ; ^{timothy.yu@childrens.harvard.edu} ; Maria H. Chahrour¹ ; ² ; ³ ; ⁴ ; ⁵ ; ⁷ ; ³² ; Michael E. Coulter¹ ; ² ; ³ ; ⁵ ; Sarn Jiralerspong⁸ ; Kazuko Okamura-Ikeda⁹ ; Bulent Ataman¹⁰ ; Klaus Schmitz-Abe¹ ; ² ; ⁵ ; David A. Harmin¹⁰ ; Mazhar Adli¹¹ ; Athar N. Malik¹⁰ ; Alissa M. D&rsquo ; Gama⁵ ; Elaine T. Lim¹² ; Stephan J. Sanders¹³ ; Ganesh H. Mochida¹ ; ² ; ³ ; ⁵ ; ⁶ ; Jennifer N. Partlow¹ ; ² ; ³ ; Christine M. Sunu¹ ; ² ; ³ ; Jillian M. Felie¹ ; ² ; ³ ; Jacqueline Rodriguez¹ ; ² ; ³ ; Ramzi H. Nasir⁵ ; ¹⁴ ; Janice Ware⁵ ; ¹⁴ ; Robert M. Joseph⁴ ; ¹⁵ ; R. Sean Hill¹ ; ² ; ³ ; ⁵ ; Benjamin Y. Kwan¹⁶ ; Muna Al-Saffar¹ ; ² ; ¹⁷ ; Nahit M. Mukaddes¹⁸ ; Asif Hashmi¹⁹ ; Soher Balkhy²⁰ ; Generoso G. Gascon⁶ ; ¹⁸ ; ²¹ ; Fuki M. Hisama²² ; Elaine LeClair⁵ ; ¹⁴ ; Annapurna Poduri⁵ ; ²³ ; Ozgur Oner²⁴ ; Samira Al-Saad²⁵ ; Sadika A. Al-Awadi²⁶ ; Laila Bastaki²⁶ ; Tawfeg Ben-Omran²⁷ ; ²⁸ ; Ahmad S. Teebi²⁷ ; ²⁸ ; Lihadh Al-Gazali¹⁷ ; Valsamma Eapen²⁹ ; Christine R. Stevens⁷ ; Leonard Rappaport⁴ ; ⁵ ; ¹⁴ ; Stacey B. Gabriel⁷ ; Kyriacos Markianos¹ ; ² ; ⁵ ; Matthew W. State¹³ ; Michael E. Greenberg¹⁰ ; Hisaaki Taniguchi⁹ ; Nancy E. Braverman⁸ ; Eric M. Morrow⁴ ; ³⁰ ; ³¹ ; Christopher A. Walsh¹ ; ² ; ³ ; ⁴ ; ⁵ ; ⁷ ; ^{christopher.walsh@childrens.harvard.edu}
• 刊名：Neuron
• 出版年：2013
• 出版时间：23 January, 2013
• 年：2013
• 卷：77
• 期：2
• 页码：259-273
• 全文大小：1533 K

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Summary

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.