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1. NL4Opt Competition: Formulating Optimization Problems Based on Their Natural Language Descriptions

Author

Ramamonjison, Rindranirina, Yu, Timothy T., Li, Raymond, Li, Haley, Carenini, Giuseppe, Ghaddar, Bissan, He, Shiqi, Mostajabdaveh, Mahdi, Banitalebi-Dehkordi, Amin, Zhou, Zirui, Zhang, Yong, Ramamonjison, Rindranirina, Yu, Timothy T., Li, Raymond, Li, Haley, Carenini, Giuseppe, Ghaddar, Bissan, He, Shiqi, Mostajabdaveh, Mahdi, Banitalebi-Dehkordi, Amin, Zhou, Zirui, and Zhang, Yong

Abstract

The Natural Language for Optimization (NL4Opt) Competition was created to investigate methods of extracting the meaning and formulation of an optimization problem based on its text description. Specifically, the goal of the competition is to increase the accessibility and usability of optimization solvers by allowing non-experts to interface with them using natural language. We separate this challenging goal into two sub-tasks: (1) recognize and label the semantic entities that correspond to the components of the optimization problem; (2) generate a meaning representation (i.e., a logical form) of the problem from its detected problem entities. The first task aims to reduce ambiguity by detecting and tagging the entities of the optimization problems. The second task creates an intermediate representation of the linear programming (LP) problem that is converted into a format that can be used by commercial solvers. In this report, we present the LP word problem dataset and shared tasks for the NeurIPS 2022 competition. Furthermore, we investigate and compare the performance of the ChatGPT large language model against the winning solutions. Through this competition, we hope to bring interest towards the development of novel machine learning applications and datasets for optimization modeling.

Published
2023

2. Spectral Bandwidth Recovery of Optical Coherence Tomography Images using Deep Learning

Author

Yu, Timothy T., Ma, Da, Cole, Jayden, Ju, Myeong Jin, Beg, Mirza F., Sarunic, Marinko V., Yu, Timothy T., Ma, Da, Cole, Jayden, Ju, Myeong Jin, Beg, Mirza F., and Sarunic, Marinko V.

Abstract

Optical coherence tomography (OCT) captures cross-sectional data and is used for the screening, monitoring, and treatment planning of retinal diseases. Technological developments to increase the speed of acquisition often results in systems with a narrower spectral bandwidth, and hence a lower axial resolution. Traditionally, image-processing-based techniques have been utilized to reconstruct subsampled OCT data and more recently, deep-learning-based methods have been explored. In this study, we simulate reduced axial scan (A-scan) resolution by Gaussian windowing in the spectral domain and investigate the use of a learning-based approach for image feature reconstruction. In anticipation of the reduced resolution that accompanies wide-field OCT systems, we build upon super-resolution techniques to explore methods to better aid clinicians in their decision-making to improve patient outcomes, by reconstructing lost features using a pixel-to-pixel approach with an altered super-resolution generative adversarial network (SRGAN) architecture.

Published
2023

3. Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems.

Author

Yu, Timothy C, Yu, Timothy C, Liu, Winnie L, Brinck, Marcia S, Davis, Jessica E, Shek, Jeremy, Bower, Grace, Einav, Tal, Insigne, Kimberly D, Phillips, Rob, Kosuri, Sriram, Urtecho, Guillaume, Yu, Timothy C, Yu, Timothy C, Liu, Winnie L, Brinck, Marcia S, Davis, Jessica E, Shek, Jeremy, Bower, Grace, Einav, Tal, Insigne, Kimberly D, Phillips, Rob, Kosuri, Sriram, and Urtecho, Guillaume

Abstract

A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8269 rationally designed, IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. We then fit a statistical mechanics model to measured expression that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three alternative promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics.

Published
2021

4. CLN7/MFSD8 may be an important factor for SARS-CoV-2 cell entry.

Author

Heinl, Elena-Sofia, Heinl, Elena-Sofia, Lorenz, Sebastian, Schmidt, Barbara, Nasser M Laqtom, Nouf, Mazzulli, Joseph R, Francelle, Laetitia, Yu, Timothy W, Greenberg, Benjamin, Storch, Stephan, Tegtmeier, Ines, Othmen, Helga, Maurer, Katja, Steinfurth, Malin, Witzgall, Ralph, Milenkovic, Vladimir, Wetzel, Christian H, Reichold, Markus, Heinl, Elena-Sofia, Heinl, Elena-Sofia, Lorenz, Sebastian, Schmidt, Barbara, Nasser M Laqtom, Nouf, Mazzulli, Joseph R, Francelle, Laetitia, Yu, Timothy W, Greenberg, Benjamin, Storch, Stephan, Tegtmeier, Ines, Othmen, Helga, Maurer, Katja, Steinfurth, Malin, Witzgall, Ralph, Milenkovic, Vladimir, Wetzel, Christian H, and Reichold, Markus

Abstract

The SARS-CoV-2 virus has triggered a worldwide pandemic. According to the BioGrid database, CLN7 (MFSD8) is thought to interact with several viral proteins. The aim of this work was to investigate a possible involvement of CLN7 in the infection process. Experiments on a CLN7-deficient HEK293T cell line exhibited a 90% reduced viral load compared to wild-type cells. This observation may be linked to the finding that CLN7 ko cells have a significantly reduced GM1 content in their cell membrane. GM1 is found highly enriched in lipid rafts, which are thought to play an important role in SARS-CoV-2 infection. In contrast, overexpression of CLN7 led to an increase in viral load. This study provides evidence that CLN7 is involved in SARS-CoV-2 infection. This makes it a potential pharmacological target for drug development against COVID-19. Furthermore, it provides insights into the physiological function of CLN7 where still only little is known about.

Published
2022

5. Augmenting Operations Research with Auto-Formulation of Optimization Models from Problem Descriptions

Author

Ramamonjison, Rindranirina, Li, Haley, Yu, Timothy T., He, Shiqi, Rengan, Vishnu, Banitalebi-Dehkordi, Amin, Zhou, Zirui, Zhang, Yong, Ramamonjison, Rindranirina, Li, Haley, Yu, Timothy T., He, Shiqi, Rengan, Vishnu, Banitalebi-Dehkordi, Amin, Zhou, Zirui, and Zhang, Yong

Abstract

We describe an augmented intelligence system for simplifying and enhancing the modeling experience for operations research. Using this system, the user receives a suggested formulation of an optimization problem based on its description. To facilitate this process, we build an intuitive user interface system that enables the users to validate and edit the suggestions. We investigate controlled generation techniques to obtain an automatic suggestion of formulation. Then, we evaluate their effectiveness with a newly created dataset of linear programming problems drawn from various application domains., Comment: Accepted for presentation at the EMNLP 2022 Conference (industry track)

Published
2022

6. Segmentation-guided Domain Adaptation and Data Harmonization of Multi-device Retinal Optical Coherence Tomography using Cycle-Consistent Generative Adversarial Networks

Author

Chen, Shuo, Ma, Da, Lee, Sieun, Yu, Timothy T. L., Xu, Gavin, Lu, Donghuan, Popuri, Karteek, Ju, Myeong Jin, Sarunic, Marinko V., Beg, Mirza Faisal, Chen, Shuo, Ma, Da, Lee, Sieun, Yu, Timothy T. L., Xu, Gavin, Lu, Donghuan, Popuri, Karteek, Ju, Myeong Jin, Sarunic, Marinko V., and Beg, Mirza Faisal

Abstract

Optical Coherence Tomography(OCT) is a non-invasive technique capturing cross-sectional area of the retina in micro-meter resolutions. It has been widely used as a auxiliary imaging reference to detect eye-related pathology and predict longitudinal progression of the disease characteristics. Retina layer segmentation is one of the crucial feature extraction techniques, where the variations of retinal layer thicknesses and the retinal layer deformation due to the presence of the fluid are highly correlated with multiple epidemic eye diseases like Diabetic Retinopathy(DR) and Age-related Macular Degeneration (AMD). However, these images are acquired from different devices, which have different intensity distribution, or in other words, belong to different imaging domains. This paper proposes a segmentation-guided domain-adaptation method to adapt images from multiple devices into single image domain, where the state-of-art pre-trained segmentation model is available. It avoids the time consumption of manual labelling for the upcoming new dataset and the re-training of the existing network. The semantic consistency and global feature consistency of the network will minimize the hallucination effect that many researchers reported regarding Cycle-Consistent Generative Adversarial Networks(CycleGAN) architecture., Comment: 16 pages, 10 figures

Published
2022

7. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms.

Author

Yabumoto, Megan, Yabumoto, Megan, Kianmahd, Jessica, Singh, Meghna, Palafox, Maria F, Wei, Angela, Elliott, Kathryn, Goodloe, Dana H, Dean, S Joy, Gooch, Catherine, Murray, Brianna K, Swartz, Erin, Schrier Vergano, Samantha A, Towne, Meghan C, Nugent, Kimberly, Roeder, Elizabeth R, Kresge, Christina, Pletcher, Beth A, Grand, Katheryn, Graham, John M, Gates, Ryan, Gomez-Ospina, Natalia, Ramanathan, Subhadra, Clark, Robin Dawn, Glaser, Kimberly, Benke, Paul J, Cohen, Julie S, Fatemi, Ali, Mu, Weiyi, Baranano, Kristin W, Madden, Jill A, Gubbels, Cynthia S, Yu, Timothy W, Agrawal, Pankaj B, Chambers, Mary-Kathryn, Phornphutkul, Chanika, Pugh, John A, Tauber, Kate A, Azova, Svetlana, Smith, Jessica R, O'Donnell-Luria, Anne, Medsker, Hannah, Srivastava, Siddharth, Krakow, Deborah, Schweitzer, Daniela N, Arboleda, Valerie A, Yabumoto, Megan, Yabumoto, Megan, Kianmahd, Jessica, Singh, Meghna, Palafox, Maria F, Wei, Angela, Elliott, Kathryn, Goodloe, Dana H, Dean, S Joy, Gooch, Catherine, Murray, Brianna K, Swartz, Erin, Schrier Vergano, Samantha A, Towne, Meghan C, Nugent, Kimberly, Roeder, Elizabeth R, Kresge, Christina, Pletcher, Beth A, Grand, Katheryn, Graham, John M, Gates, Ryan, Gomez-Ospina, Natalia, Ramanathan, Subhadra, Clark, Robin Dawn, Glaser, Kimberly, Benke, Paul J, Cohen, Julie S, Fatemi, Ali, Mu, Weiyi, Baranano, Kristin W, Madden, Jill A, Gubbels, Cynthia S, Yu, Timothy W, Agrawal, Pankaj B, Chambers, Mary-Kathryn, Phornphutkul, Chanika, Pugh, John A, Tauber, Kate A, Azova, Svetlana, Smith, Jessica R, O'Donnell-Luria, Anne, Medsker, Hannah, Srivastava, Siddharth, Krakow, Deborah, Schweitzer, Daniela N, and Arboleda, Valerie A

Abstract

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Published
2021

8. Domain Adaptation via CycleGAN for Retina Segmentation in Optical Coherence Tomography

Author

Chen, Ricky, Yu, Timothy T., Xu, Gavin, Ma, Da, Sarunic, Marinko V., Beg, Mirza Faisal, Chen, Ricky, Yu, Timothy T., Xu, Gavin, Ma, Da, Sarunic, Marinko V., and Beg, Mirza Faisal

Abstract

With the FDA approval of Artificial Intelligence (AI) for point-of-care clinical diagnoses, model generalizability is of the utmost importance as clinical decision-making must be domain-agnostic. A method of tackling the problem is to increase the dataset to include images from a multitude of domains; while this technique is ideal, the security requirements of medical data is a major limitation. Additionally, researchers with developed tools benefit from the addition of open-sourced data, but are limited by the difference in domains. Herewith, we investigated the implementation of a Cycle-Consistent Generative Adversarial Networks (CycleGAN) for the domain adaptation of Optical Coherence Tomography (OCT) volumes. This study was done in collaboration with the Biomedical Optics Research Group and Functional & Anatomical Imaging & Shape Analysis Lab at Simon Fraser University. In this study, we investigated a learning-based approach of adapting the domain of a publicly available dataset, UK Biobank dataset (UKB). To evaluate the performance of domain adaptation, we utilized pre-existing retinal layer segmentation tools developed on a different set of RETOUCH OCT data. This study provides insight on state-of-the-art tools for domain adaptation compared to traditional processing techniques as well as a pipeline for adapting publicly available retinal data to the domains previously used by our collaborators., Comment: 10 pages, 6 figures, 1 table

Published
2021

9. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, Yu, Timothy W, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, and Yu, Timothy W

Published
2021

10. Practice facilitation to promote evidence-based screening and management of unhealthy alcohol use in primary care: a practice-level randomized controlled trial

Author

Huffstetler, Alison N., Kuzel, Anton J., Sabo, Roy T., Richards, Alicia, Brooks, E. M., Lail Kashiri, Paulette, Villalobos, Gabriela, Arias, Albert J., Svikis, Dace, Bortz, Beth A., Edwards, Ashley, Epling, John W., Cohen, Deborah J., Parchman, Michael L., Winter, Jonathan, Wessler, Patricia, Yu, Timothy J., Krist, Alex H., Huffstetler, Alison N., Kuzel, Anton J., Sabo, Roy T., Richards, Alicia, Brooks, E. M., Lail Kashiri, Paulette, Villalobos, Gabriela, Arias, Albert J., Svikis, Dace, Bortz, Beth A., Edwards, Ashley, Epling, John W., Cohen, Deborah J., Parchman, Michael L., Winter, Jonathan, Wessler, Patricia, Yu, Timothy J., and Krist, Alex H.

Abstract

Background Unhealthy alcohol use is the third leading cause of preventable death in the United States. Evidence demonstrates that screening for unhealthy alcohol use and providing persons engaged in risky drinking with brief behavioral and counseling interventions improves health outcomes, collectively termed screening and brief interventions. Medication assisted therapy (MAT) is another effective method for treatment of moderate or severe alcohol use disorder. Yet, primary care clinicians are not regularly screening for or treating unhealthy alcohol use. Methods and analysis We are initiating a clinic-level randomized controlled trial aimed to evaluate how primary care clinicians can impact unhealthy alcohol use through screening, counseling, and MAT. One hundred and 25 primary care practices in the Virginia Ambulatory Care Outcomes Research Network (ACORN) will be engaged; each will receive practice facilitation to promote screening, counseling, and MAT either at the beginning of the trial or at a 6-month control period start date. For each practice, the intervention includes provision of a practice facilitator, learning collaboratives with three practice champions, and clinic-wide information sessions. Clinics will be enrolled for 6–12 months. After completion of the intervention, we will conduct a mixed methods analysis to identify changes in screening rates, increase in provision of brief counseling and interventions as well as MAT, and the reduction of alcohol intake for patients after practices receive practice facilitation. Discussion This study offers a systematic process for dissemination and implementation of the evidence-based practice of screening, counseling, and treatment for unhealthy alcohol use. Practices will be asked to implement a process for screening, counseling, and treatment based on their practice characteristics, patient population, and workflow. We propose practice facilitation as a robust and feasible intervention to assist in making cha

Published
2020
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11. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.

Author

Kanca, Oguz, Kanca, Oguz, Andrews, Jonathan C, Lee, Pei-Tseng, Patel, Chirag, Braddock, Stephen R, Slavotinek, Anne M, Cohen, Julie S, Gubbels, Cynthia S, Aldinger, Kimberly A, Williams, Judy, Indaram, Maanasa, Fatemi, Ali, Yu, Timothy W, Agrawal, Pankaj B, Vezina, Gilbert, Simons, Cas, Crawford, Joanna, Lau, C Christopher, Undiagnosed Diseases Network, Chung, Wendy K, Markello, Thomas C, Dobyns, William B, Adams, David R, Gahl, William A, Wangler, Michael F, Yamamoto, Shinya, Bellen, Hugo J, Malicdan, May Christine V, Kanca, Oguz, Kanca, Oguz, Andrews, Jonathan C, Lee, Pei-Tseng, Patel, Chirag, Braddock, Stephen R, Slavotinek, Anne M, Cohen, Julie S, Gubbels, Cynthia S, Aldinger, Kimberly A, Williams, Judy, Indaram, Maanasa, Fatemi, Ali, Yu, Timothy W, Agrawal, Pankaj B, Vezina, Gilbert, Simons, Cas, Crawford, Joanna, Lau, C Christopher, Undiagnosed Diseases Network, Chung, Wendy K, Markello, Thomas C, Dobyns, William B, Adams, David R, Gahl, William A, Wangler, Michael F, Yamamoto, Shinya, Bellen, Hugo J, and Malicdan, May Christine V

Abstract

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Published
2019

12. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

Author

Marsh, Ashley PL, Marsh, Ashley PL, Edwards, Timothy J, Galea, Charles, Cooper, Helen M, Engle, Elizabeth C, Jamuar, Saumya S, Méneret, Aurélie, Moutard, Marie-Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer-Smith, Megan, Trouillard, Oriane, Billette de Villemeur, Thierry, Walsh, Christopher A, Yu, Timothy W, IRC5 Consortium, Heron, Delphine, Sherr, Elliott H, Richards, Linda J, Depienne, Christel, Leventer, Richard J, Lockhart, Paul J, Marsh, Ashley PL, Marsh, Ashley PL, Edwards, Timothy J, Galea, Charles, Cooper, Helen M, Engle, Elizabeth C, Jamuar, Saumya S, Méneret, Aurélie, Moutard, Marie-Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer-Smith, Megan, Trouillard, Oriane, Billette de Villemeur, Thierry, Walsh, Christopher A, Yu, Timothy W, IRC5 Consortium, Heron, Delphine, Sherr, Elliott H, Richards, Linda J, Depienne, Christel, Leventer, Richard J, and Lockhart, Paul J

Abstract

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Published
2018

13. Newborn Sequencing in Genomic Medicine and Public Health.

Author

Berg, Jonathan S, Berg, Jonathan S, Agrawal, Pankaj B, Bailey, Donald B, Beggs, Alan H, Brenner, Steven E, Brower, Amy M, Cakici, Julie A, Ceyhan-Birsoy, Ozge, Chan, Kee, Chen, Flavia, Currier, Robert J, Dukhovny, Dmitry, Green, Robert C, Harris-Wai, Julie, Holm, Ingrid A, Iglesias, Brenda, Joseph, Galen, Kingsmore, Stephen F, Koenig, Barbara A, Kwok, Pui-Yan, Lantos, John, Leeder, Steven J, Lewis, Megan A, McGuire, Amy L, Milko, Laura V, Mooney, Sean D, Parad, Richard B, Pereira, Stacey, Petrikin, Joshua, Powell, Bradford C, Powell, Cynthia M, Puck, Jennifer M, Rehm, Heidi L, Risch, Neil, Roche, Myra, Shieh, Joseph T, Veeraraghavan, Narayanan, Watson, Michael S, Willig, Laurel, Yu, Timothy W, Urv, Tiina, Wise, Anastasia L, Berg, Jonathan S, Berg, Jonathan S, Agrawal, Pankaj B, Bailey, Donald B, Beggs, Alan H, Brenner, Steven E, Brower, Amy M, Cakici, Julie A, Ceyhan-Birsoy, Ozge, Chan, Kee, Chen, Flavia, Currier, Robert J, Dukhovny, Dmitry, Green, Robert C, Harris-Wai, Julie, Holm, Ingrid A, Iglesias, Brenda, Joseph, Galen, Kingsmore, Stephen F, Koenig, Barbara A, Kwok, Pui-Yan, Lantos, John, Leeder, Steven J, Lewis, Megan A, McGuire, Amy L, Milko, Laura V, Mooney, Sean D, Parad, Richard B, Pereira, Stacey, Petrikin, Joshua, Powell, Bradford C, Powell, Cynthia M, Puck, Jennifer M, Rehm, Heidi L, Risch, Neil, Roche, Myra, Shieh, Joseph T, Veeraraghavan, Narayanan, Watson, Michael S, Willig, Laurel, Yu, Timothy W, Urv, Tiina, and Wise, Anastasia L

Abstract

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Published
2017

14. Biallelic mutations in human DCC cause developmental split-brain syndrome.

Author

Jamuar, Saumya, Jamuar, Saumya, Schmitz-Abe, Klaus, DGama, Alissa, Drottar, Marie, Chan, Wai-Man, Peeva, Maya, Servattalab, Sarah, Lam, Anh-Thu, Delgado, Mauricio, Clegg, Nancy, Zayed, Zayed, Dogar, Mohammad, Alorainy, Ibrahim, Jamea, Abdullah, Abu-Amero, Khaled, Griebel, May, Ward, Wendy, Lein, Ed, Markianos, Kyriacos, Robson, Caroline, Grant, P, Bosley, Thomas, Engle, Elizabeth, Walsh, Christopher, Yu, Timothy, Barkovich, Anthony, Jamuar, Saumya, Jamuar, Saumya, Schmitz-Abe, Klaus, DGama, Alissa, Drottar, Marie, Chan, Wai-Man, Peeva, Maya, Servattalab, Sarah, Lam, Anh-Thu, Delgado, Mauricio, Clegg, Nancy, Zayed, Zayed, Dogar, Mohammad, Alorainy, Ibrahim, Jamea, Abdullah, Abu-Amero, Khaled, Griebel, May, Ward, Wendy, Lein, Ed, Markianos, Kyriacos, Robson, Caroline, Grant, P, Bosley, Thomas, Engle, Elizabeth, Walsh, Christopher, Yu, Timothy, and Barkovich, Anthony

Abstract

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor deleted in colorectal carcinoma (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

Published
2017

15. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Author

Weiner, Daniel J., Wigdor, Emilie M., Ripke, Stephan, Walters, Raymond K., Kosmicki, Jack A., Grove, Jakob, Samocha, Kaitlin E., Goldstein, Jacqueline I., Okbay, Aysu, Bybjerg-Grauholm, Jonas, Werge, Thomas, Hougaard, David M., Taylor, Jacob, Skuse, David, Devlin, Bernie, Anney, Richard, Sanders, Stephan J., Bishop, Somer, Mortensen, Preben Bo, Børglum, Anders D., Smith, George Davey, Daly, Mark J., Robinson, Elise B., Bækvad-Hansen, Marie, Dumont, Ashley, Hansen, Christine, Hansen, Thomas F., Howrigan, Daniel, Mattheisen, Manuel, Moran, Jennifer, Mors, Ole, Nordentoft, Merete, Nørgaard-Pedersen, Bent, Poterba, Timothy, Poulsen, Jesper, Stevens, Christine, Anttila, Verneri, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Wassink, Thomas H., Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group, Weiner, Daniel J., Wigdor, Emilie M., Ripke, Stephan, Walters, Raymond K., Kosmicki, Jack A., Grove, Jakob, Samocha, Kaitlin E., Goldstein, Jacqueline I., Okbay, Aysu, Bybjerg-Grauholm, Jonas, Werge, Thomas, Hougaard, David M., Taylor, Jacob, Skuse, David, Devlin, Bernie, Anney, Richard, Sanders, Stephan J., Bishop, Somer, Mortensen, Preben Bo, Børglum, Anders D., Smith, George Davey, Daly, Mark J., Robinson, Elise B., Bækvad-Hansen, Marie, Dumont, Ashley, Hansen, Christine, Hansen, Thomas F., Howrigan, Daniel, Mattheisen, Manuel, Moran, Jennifer, Mors, Ole, Nordentoft, Merete, Nørgaard-Pedersen, Bent, Poterba, Timothy, Poulsen, Jesper, Stevens, Christine, Anttila, Verneri, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Wassink, Thomas H., Psychiatric Genomics Consortium Autism Group, and iPSYCH-Broad Autism Group

Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

Published
2017
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16. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author

Anney, Richard J.L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thomas, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A.S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogé, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnström, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, McMahon, William M., McGrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceição, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B.S., Casey, Jillian, Cantor, Rita M., Café, Cátia, Bybjerg-Grauholm, Jonas, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Børglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hakonarson, Hakon, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Anney, Richard J.L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thomas, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A.S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogé, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnström, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, McMahon, William M., McGrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceição, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B.S., Casey, Jillian, Cantor, Rita M., Café, Cátia, Bybjerg-Grauholm, Jonas, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Børglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hakonarson, Hakon, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, and Daly, Mark J.

Abstract

Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci whic

Published
2017

17. Using whole-exome sequencing to identify inherited causes of autism.

Author

Yu, Timothy W, Yu, Timothy W, Chahrour, Maria H, Coulter, Michael E, Jiralerspong, Sarn, Okamura-Ikeda, Kazuko, Ataman, Bulent, Schmitz-Abe, Klaus, Harmin, David A, Adli, Mazhar, Malik, Athar N, D'Gama, Alissa M, Lim, Elaine T, Sanders, Stephan J, Mochida, Ganesh H, Partlow, Jennifer N, Sunu, Christine M, Felie, Jillian M, Rodriguez, Jacqueline, Nasir, Ramzi H, Ware, Janice, Joseph, Robert M, Hill, R Sean, Kwan, Benjamin Y, Al-Saffar, Muna, Mukaddes, Nahit M, Hashmi, Asif, Balkhy, Soher, Gascon, Generoso G, Hisama, Fuki M, LeClair, Elaine, Poduri, Annapurna, Oner, Ozgur, Al-Saad, Samira, Al-Awadi, Sadika A, Bastaki, Laila, Ben-Omran, Tawfeg, Teebi, Ahmad S, Al-Gazali, Lihadh, Eapen, Valsamma, Stevens, Christine R, Rappaport, Leonard, Gabriel, Stacey B, Markianos, Kyriacos, State, Matthew W, Greenberg, Michael E, Taniguchi, Hisaaki, Braverman, Nancy E, Morrow, Eric M, Walsh, Christopher A, Yu, Timothy W, Yu, Timothy W, Chahrour, Maria H, Coulter, Michael E, Jiralerspong, Sarn, Okamura-Ikeda, Kazuko, Ataman, Bulent, Schmitz-Abe, Klaus, Harmin, David A, Adli, Mazhar, Malik, Athar N, D'Gama, Alissa M, Lim, Elaine T, Sanders, Stephan J, Mochida, Ganesh H, Partlow, Jennifer N, Sunu, Christine M, Felie, Jillian M, Rodriguez, Jacqueline, Nasir, Ramzi H, Ware, Janice, Joseph, Robert M, Hill, R Sean, Kwan, Benjamin Y, Al-Saffar, Muna, Mukaddes, Nahit M, Hashmi, Asif, Balkhy, Soher, Gascon, Generoso G, Hisama, Fuki M, LeClair, Elaine, Poduri, Annapurna, Oner, Ozgur, Al-Saad, Samira, Al-Awadi, Sadika A, Bastaki, Laila, Ben-Omran, Tawfeg, Teebi, Ahmad S, Al-Gazali, Lihadh, Eapen, Valsamma, Stevens, Christine R, Rappaport, Leonard, Gabriel, Stacey B, Markianos, Kyriacos, State, Matthew W, Greenberg, Michael E, Taniguchi, Hisaaki, Braverman, Nancy E, Morrow, Eric M, and Walsh, Christopher A

Abstract

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.

Published
2013

19. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, Devlin, Bernie, Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, and Devlin, Bernie

Abstract

BackgroundPhenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.MethodsGenome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.ResultsAssociation analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.ConclusionsIn genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

20. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.

Author

Sanders, Stephan J, Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Autism Sequencing Consortium, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, State, Matthew W, Sanders, Stephan J, Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Autism Sequencing Consortium, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W

Abstract

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Published
2015

21. 20151119 Equinox Nov 19 2015

Author

Perez, Melanie; Arathoon, Katelyn; Levanti, Larry; Levine, Sandy; Clarke, Daniel; Holt, Molly; King, Terry; Yu, Timothy; Butera, Armand; Kennedy, Bill; Alami, Khadija; Madden, Chris; Martinez, Christina; Carlosn, Chris; Ashby, Natasha; Miles, David; White, Elizabeth; Goweh, Tyonna; Gaitan, Jeremy and Perez, Melanie; Arathoon, Katelyn; Levanti, Larry; Levine, Sandy; Clarke, Daniel; Holt, Molly; King, Terry; Yu, Timothy; Butera, Armand; Kennedy, Bill; Alami, Khadija; Madden, Chris; Martinez, Christina; Carlosn, Chris; Ashby, Natasha; Miles, David; White, Elizabeth; Goweh, Tyonna; Gaitan, Jeremy

Abstract

Teaneck edition; Volume 27, Issue 6; Frequency varies

Published
2015

22. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

Author

Chaste, Pauline, Chaste, Pauline, Sanders, Stephan, Mohan, Kommu, Klei, Lambertus, Song, Youeun, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Martin, Christa, Devlin, Bernie, Beaudet, Arthur, Cook, Edwin, Kim, Soo-Jeong, Chaste, Pauline, Chaste, Pauline, Sanders, Stephan, Mohan, Kommu, Klei, Lambertus, Song, Youeun, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Martin, Christa, Devlin, Bernie, Beaudet, Arthur, Cook, Edwin, and Kim, Soo-Jeong

Abstract

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Published
2014

23. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., Margulies, David M., Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., QC 20140819

Published
2014
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24. Somatic mutations in cerebral cortical malformations.

Author

Jamuar, Saumya S, Jamuar, Saumya S, Lam, Anh-Thu N, Kircher, Martin, D'Gama, Alissa M, Wang, Jian, Barry, Brenda J, Zhang, Xiaochang, Hill, Robert Sean, Partlow, Jennifer N, Rozzo, Aldo, Servattalab, Sarah, Mehta, Bhaven K, Topcu, Meral, Amrom, Dina, Andermann, Eva, Dan, Bernard, Parrini, Elena, Guerrini, Renzo, Scheffer, Ingrid E, Berkovic, Samuel F, Leventer, Richard J, Shen, Yiping, Wu, Bai Lin, Barkovich, A James, Sahin, Mustafa, Chang, Bernard S, Bamshad, Michael, Nickerson, Deborah A, Shendure, Jay, Poduri, Annapurna, Yu, Timothy W, Walsh, Christopher A, Jamuar, Saumya S, Jamuar, Saumya S, Lam, Anh-Thu N, Kircher, Martin, D'Gama, Alissa M, Wang, Jian, Barry, Brenda J, Zhang, Xiaochang, Hill, Robert Sean, Partlow, Jennifer N, Rozzo, Aldo, Servattalab, Sarah, Mehta, Bhaven K, Topcu, Meral, Amrom, Dina, Andermann, Eva, Dan, Bernard, Parrini, Elena, Guerrini, Renzo, Scheffer, Ingrid E, Berkovic, Samuel F, Leventer, Richard J, Shen, Yiping, Wu, Bai Lin, Barkovich, A James, Sahin, Mustafa, Chang, Bernard S, Bamshad, Michael, Nickerson, Deborah A, Shendure, Jay, Poduri, Annapurna, Yu, Timothy W, and Walsh, Christopher A

Abstract

BackgroundAlthough there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.MethodsUsing a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.ResultsValidated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.ConclusionsTargeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

Published
2014

25. Katanin p80 regulates human cortical development by limiting centriole and cilia number.

Author

Hu, Wen F, Hu, Wen F, Pomp, Oz, Ben-Omran, Tawfeg, Kodani, Andrew, Henke, Katrin, Mochida, Ganeshwaran H, Yu, Timothy W, Woodworth, Mollie B, Bonnard, Carine, Raj, Grace Selva, Tan, Thong Teck, Hamamy, Hanan, Masri, Amira, Shboul, Mohammad, Al Saffar, Muna, Partlow, Jennifer N, Al-Dosari, Mohammed, Alazami, Anas, Alowain, Mohammed, Alkuraya, Fowzan S, Reiter, Jeremy F, Harris, Matthew P, Reversade, Bruno, Walsh, Christopher A, Hu, Wen F, Hu, Wen F, Pomp, Oz, Ben-Omran, Tawfeg, Kodani, Andrew, Henke, Katrin, Mochida, Ganeshwaran H, Yu, Timothy W, Woodworth, Mollie B, Bonnard, Carine, Raj, Grace Selva, Tan, Thong Teck, Hamamy, Hanan, Masri, Amira, Shboul, Mohammad, Al Saffar, Muna, Partlow, Jennifer N, Al-Dosari, Mohammed, Alazami, Anas, Alowain, Mohammed, Alkuraya, Fowzan S, Reiter, Jeremy F, Harris, Matthew P, Reversade, Bruno, and Walsh, Christopher A

Abstract

Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.

Published
2014

26. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4⁺ T cells.

Author

Bertin, Samuel, Bertin, Samuel, Aoki-Nonaka, Yukari, de Jong, Petrus Rudolf, Nohara, Lilian L, Xu, Hongjian, Stanwood, Shawna R, Srikanth, Sonal, Lee, Jihyung, To, Keith, Abramson, Lior, Yu, Timothy, Han, Tiffany, Touma, Ranim, Li, Xiangli, González-Navajas, José M, Herdman, Scott, Corr, Maripat, Fu, Guo, Dong, Hui, Gwack, Yousang, Franco, Alessandra, Jefferies, Wilfred A, Raz, Eyal, Bertin, Samuel, Bertin, Samuel, Aoki-Nonaka, Yukari, de Jong, Petrus Rudolf, Nohara, Lilian L, Xu, Hongjian, Stanwood, Shawna R, Srikanth, Sonal, Lee, Jihyung, To, Keith, Abramson, Lior, Yu, Timothy, Han, Tiffany, Touma, Ranim, Li, Xiangli, González-Navajas, José M, Herdman, Scott, Corr, Maripat, Fu, Guo, Dong, Hui, Gwack, Yousang, Franco, Alessandra, Jefferies, Wilfred A, and Raz, Eyal

Abstract

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.

Published
2014

27. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, Margulies, David M., Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., Boston Children's Hospital (Manton Center for Orphan Disease Research), Harvard Medical School (Center for Biomedical Infomatics)

Published
2014

28. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, Dworzynski, Piotr, Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, and Dworzynski, Piotr

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

Published
2014

29. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait.

Author

Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Lese Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Devlin, Bernie, Cook, Edwin, Kim, Soo-Jeong, Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Lese Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Devlin, Bernie, Cook, Edwin, and Kim, Soo-Jeong

Abstract

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

Published
2013

30. Common genetic variants, acting additively, are a major source of risk for autism.

Author

Klei, Lambertus, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Melhem, Nadine, Chaste, Pauline, Sutcliffe, James, State, Matthew, Cook, Edwin, Roeder, Kathryn, Devlin, Bernie, Klei, Lambertus, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Melhem, Nadine, Chaste, Pauline, Sutcliffe, James, State, Matthew, Cook, Edwin, Roeder, Kathryn, and Devlin, Bernie

Abstract

BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wi

Published
2012

31. Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

Author

Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Chahrour, Maria H., Yu, Timothy W., Lim, Elaine T., Ataman, Bulent, Coulter, Michael E., Hill, R. Sean, Stevens, Christine R., Greenberg, Michael E., Gabriel, Stacey B., Walsh, Christopher A., Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Chahrour, Maria H., Yu, Timothy W., Lim, Elaine T., Ataman, Bulent, Coulter, Michael E., Hill, R. Sean, Stevens, Christine R., Greenberg, Michael E., Gabriel, Stacey B., and Walsh, Christopher A.

Abstract

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)

Published
2012

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