Publications by authors named "Stephan J Sanders"

82 Publications

A model and test for coordinated polygenic epistasis in complex traits.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095;

Interactions between genetic variants-epistasis-is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work, we develop a model for structured polygenic epistasis, called coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CE in 18 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue-trait pairs. Overall, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits.
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http://dx.doi.org/10.1073/pnas.1922305118DOI Listing
April 2021

De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families.

Am J Hum Genet 2021 Apr 5;108(4):597-607. Epub 2021 Mar 5.

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Department of Biomedical Informatics, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.012DOI Listing
April 2021

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain.

Elife 2021 Feb 11;10. Epub 2021 Feb 11.

Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States.

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.
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http://dx.doi.org/10.7554/eLife.61408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994002PMC
February 2021

Not All Autism Genes Are Created Equal: A Response to Myers et al.

Am J Hum Genet 2020 11;107(5):1000-1003

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

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http://dx.doi.org/10.1016/j.ajhg.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675033PMC
November 2020

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

N Engl J Med 2020 10 7;383(18):1746-1756. Epub 2020 Oct 7.

From the University of California, San Francisco (T.N.S., B.R.L., S.L.D., S.P., A.F., A.M.S., P.D., U.H., J.V.Z., S.J.S., T.C.M., M.E.N.), the University of California, San Diego (R.R.A., L.C.L.), the University of California, Los Angeles (I.D., K.H., A.M.), the University of California, Irvine (J.D., J.J., C.U.), and the University of California, Davis (N.M.B., N.T.F.).

Background: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.

Methods: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.

Results: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.

Conclusions: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).
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http://dx.doi.org/10.1056/NEJMoa2023643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650529PMC
October 2020

Whole-Brain Image Analysis and Anatomical Atlas 3D Generation Using MagellanMapper.

Curr Protoc Neurosci 2020 12;94(1):e104

Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California.

MagellanMapper is a software suite designed for visual inspection and end-to-end automated processing of large-volume, 3D brain imaging datasets in a memory-efficient manner. The rapidly growing number of large-volume, high-resolution datasets necessitates visualization of raw data at both macro- and microscopic levels to assess the quality of data, as well as automated processing to quantify data in an unbiased manner for comparison across a large number of samples. To facilitate these analyses, MagellanMapper provides both a graphical user interface for manual inspection and a command-line interface for automated image processing. At the macroscopic level, the graphical interface allows researchers to view full volumetric images simultaneously in each dimension and to annotate anatomical label placements. At the microscopic level, researchers can inspect regions of interest at high resolution to build ground truth data of cellular locations such as nuclei positions. Using the command-line interface, researchers can automate cell detection across volumetric images, refine anatomical atlas labels to fit underlying histology, register these atlases to sample images, and perform statistical analyses by anatomical region. MagellanMapper leverages established open-source computer vision libraries and is itself open source and freely available for download and extension. © 2020 Wiley Periodicals LLC. Basic Protocol 1: MagellanMapper installation Alternate Protocol: Alternative methods for MagellanMapper installation Basic Protocol 2: Import image files into MagellanMapper Basic Protocol 3: Region of interest visualization and annotation Basic Protocol 4: Explore an atlas along all three dimensions and register to a sample brain Basic Protocol 5: Automated 3D anatomical atlas construction Basic Protocol 6: Whole-tissue cell detection and quantification by anatomical label Support Protocol: Import a tiled microscopy image in proprietary format into MagellanMapper.
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http://dx.doi.org/10.1002/cpns.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781073PMC
December 2020

A Chromatin Accessibility Atlas of the Developing Human Telencephalon.

Cell 2020 08 30;182(3):754-769.e18. Epub 2020 Jun 30.

Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
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http://dx.doi.org/10.1016/j.cell.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415678PMC
August 2020

Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers.

Elife 2020 07 1;9. Epub 2020 Jul 1.

Department of Biochemistry and Biophysics Kavli Institute for Fundamental Neuroscience University of California, San Francisco, San Francisco, United States.

We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (, , , , ) causing a common failure of presynaptic homeostatic plasticity (PHP) in . Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, and are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of , a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.
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http://dx.doi.org/10.7554/eLife.55775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394548PMC
July 2020

Clinical impact of splicing in neurodevelopmental disorders.

Genome Med 2020 04 24;12(1):36. Epub 2020 Apr 24.

Illumina Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA, USA.

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection.
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http://dx.doi.org/10.1186/s13073-020-00737-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183108PMC
April 2020

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex.

Cell Rep 2020 04;31(1):107489

Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both "constant" and "temporal-predominant" eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
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http://dx.doi.org/10.1016/j.celrep.2020.03.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295160PMC
April 2020

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Cell 2020 02 23;180(3):568-584.e23. Epub 2020 Jan 23.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
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http://dx.doi.org/10.1016/j.cell.2019.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250485PMC
February 2020

A framework for the investigation of rare genetic disorders in neuropsychiatry.

Nat Med 2019 10 23;25(10):1477-1487. Epub 2019 Sep 23.

Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles, Los Angeles, CA, USA.

De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies.
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http://dx.doi.org/10.1038/s41591-019-0581-5DOI Listing
October 2019

The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex.

Neuron 2019 08 20;103(4):673-685.e5. Epub 2019 Jun 20.

Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein Na1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that Na1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. Na1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when Na1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for Na1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.
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http://dx.doi.org/10.1016/j.neuron.2019.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935470PMC
August 2019

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Predicting Splicing from Primary Sequence with Deep Learning.

Cell 2019 01 17;176(3):535-548.e24. Epub 2019 Jan 17.

Illumina Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA, USA. Electronic address:

The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of noncoding genetic variants that cause cryptic splicing. Synonymous and intronic mutations with predicted splice-altering consequence validate at a high rate on RNA-seq and are strongly deleterious in the human population. De novo mutations with predicted splice-altering consequence are significantly enriched in patients with autism and intellectual disability compared to healthy controls and validate against RNA-seq in 21 out of 28 of these patients. We estimate that 9%-11% of pathogenic mutations in patients with rare genetic disorders are caused by this previously underappreciated class of disease variation.
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http://dx.doi.org/10.1016/j.cell.2018.12.015DOI Listing
January 2019

Integrative functional genomic analysis of human brain development and neuropsychiatric risks.

Science 2018 12;362(6420)

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including , , , , and ) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
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http://dx.doi.org/10.1126/science.aat7615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413317PMC
December 2018

Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder.

Science 2018 12;362(6420)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
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http://dx.doi.org/10.1126/science.aat6576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432922PMC
December 2018

Next-Generation Sequencing in Autism Spectrum Disorder.

Cold Spring Harb Perspect Med 2019 08 1;9(8). Epub 2019 Aug 1.

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 94158.

Autism spectrum disorder (ASD) is a common disorder that causes substantial distress. Heritability studies consistently show a strong genetic contribution, raising the hope that identifying ASD-associated genetic variants will offer insights into neurobiology and ultimately therapeutics. Next-generation sequencing (NGS) enabled the identification of disruptive variants throughout protein-coding regions of the genome. Alongside large cohorts and novel statistical methods, these NGS methods revolutionized ASD gene discovery. NGS methods have also contributed substantially to functional genetic data, such as gene expression, used to understand the neurobiological consequences of disrupting these ASD-associated genes. These functional data are also critical for annotating the noncoding genome as whole-genome sequencing (WGS) begins to provide initial insights outside of protein-coding regions. NGS methods still have a major role to play, as do similarly transformative advances in stem cell and gene-editing methods, in translating genetic discoveries into a first generation of ASD therapeutics.
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http://dx.doi.org/10.1101/cshperspect.a026872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671934PMC
August 2019

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.

Nat Genet 2018 04 26;50(5):727-736. Epub 2018 Apr 26.

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
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http://dx.doi.org/10.1038/s41588-018-0107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961723PMC
April 2018

Progress in Understanding and Treating SCN2A-Mediated Disorders.

Trends Neurosci 2018 07 23;41(7):442-456. Epub 2018 Apr 23.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.
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http://dx.doi.org/10.1016/j.tins.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015533PMC
July 2018

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.

Am J Hum Genet 2018 05 12;102(5):744-759. Epub 2018 Apr 12.

Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; l'institut du thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France. Electronic address:

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
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http://dx.doi.org/10.1016/j.ajhg.2018.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986661PMC
May 2018

Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium.

Nat Neurosci 2018 Jul;21(7):1017

Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.

In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41593-018-0102-8DOI Listing
July 2018

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

Nat Genet 2017 Nov 9;49(11):1593-1601. Epub 2017 Oct 9.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
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http://dx.doi.org/10.1038/ng.3970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675000PMC
November 2017

Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection.

Autism Res 2018 01 31;11(1):175-184. Epub 2017 Aug 31.

School of Medicine, University of California, San Francisco, 401 Parnassus Avenue, San Francisco, CA, 94143 (S.J.S., D.W., V.H.B.).

Literature indicates that some children with ASD may show behavioral improvements during fever; however, little is known about the behavioral profiles of these children. This study aims to (a) investigate the subset of children who show parent-reported behavioral improvements associated with fever and (b) compare the demographic, behavioral, and genetic characteristics of this subset of children to children whose parents report no change during fever. Parents of 2,152 children from the Simons Simplex Collection provided information about whether and in which areas their child improved during fever. Children were randomly assigned into discovery or replication samples. In discovery analyses, children who reportedly improved with fever (Improve Group) were compared to those who reportedly did not improve (No Improve Group) on demographics, medical history, ASD symptoms, adaptive skills, and presence of de novo ASD-associated mutations. Significant and marginal results from discovery analyses were tested in the replication sample. Parent reports of 17% of children indicated improvements during fever across a range of domains. Discovery and replication analyses revealed that the Improve Group had significantly lower non-verbal cognitive skills (NVIQ) and language levels and more repetitive behaviors. Groups did not differ on demographic variables, parent-report of current ASD symptoms or the presence of de novo mutations. Understanding the profiles of children who improve during episodes of fever may provide insights into innovative treatments for ASD. Autism Res 2018, 11: 175-184. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary: This study explored characteristics of children with ASD who are reported to improve during fever. Parents of 17% of children with ASD report improvements across a range of domains during fever including cognition, communication, repetitive behaviors, social interaction, and behavior. Children who are reported to improve during fever have significantly lower non-verbal cognitive skills and language levels and more repetitive behaviors. Understanding the profiles of children who improve during episodes of fever may provide insights into new treatments for ASD.
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http://dx.doi.org/10.1002/aur.1856DOI Listing
January 2018

Appreciating the Population-wide Impact of Copy Number Variants on Cognition.

Biol Psychiatry 2017 07;82(2):78-80

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2017.05.010DOI Listing
July 2017

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

Nat Genet 2017 Jul 15;49(7):978-985. Epub 2017 May 15.

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1038/ng.3863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552240PMC
July 2017

De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

Neuron 2017 May;94(3):486-499.e9

Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA. Electronic address:

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769876PMC
May 2017

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

Genome Biol 2017 03 6;18(1):36. Epub 2017 Mar 6.

Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.

Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies.

Results: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV.

Conclusions: These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.
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http://dx.doi.org/10.1186/s13059-017-1158-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338099PMC
March 2017