Stephan Sanders, PhD

Assistant Professor

Psychiatry

[email protected]

415-502-2505

Genomic and bioinformatic approaches to discovering the etiology of neurodevelopmental disorders in humans, especially autism spectrum disorder

Dr Sanders trained as a pediatric physician at Nottingham and London in the UK before undertaking a PhD and postdoctoral research position at Yale. His research focuses on using genomics and bioinformatics to understand the etiology of human disease, especially autism spectrum disorder (ASD).

Using SNP genotyping arrays on samples in the Simons Simplex Collection he clarified the important role of de novo copy number variation (CNVs) in ASD including the discovery of duplications at 7q11.23, of note since deletions at this same locus cause Williams-Beuren syndrome which is associated with increased sociability. In the same sample cohort he used exome sequencing to show that de novo loss of function (LoF) mutations are associated with ASD and to establish a statistical framework for identifying the specific genes involved in ASD pathology based on these de novo events. This statistical method was used to identify the gene SCN2A and has since identified multiple ASD genes with high confidence.

Most recently recently he has worked with a group of collaborators to investigate what these ASD genes can tell us about ASD neuropathology. By integrating spatiotemporal gene expression data from the human brain (BrainSpan) and the results of exome sequencing they built and interrogated spatiotemporal co-expression networks to identify points of convergence in gene expression. This approach has highlighted the role of layer 5/6 glutamatergic neurons in the frontal cortex in mid-fetal development in the causation of ASD.

Current Projects

Whole genome sequencing of autism spectrum disorder (ASD) families
Discovery of sexually dimorphic features that could explain the female protective effect in ASD
Gene discovery in ASD
Functional analysis of SCN2A mutations in ASD

Lab Members

Joon An
Shan Dong
Clif Duhn
Michael Gilson
Sindy Law
Grace Schwartz
Donna Werling

Lab Website

Publications:

CROSS-DISORDER RARE VARIANT ANALYSIS OF AUTISM AND ADHD.

THE ALLELIC ARCHITECTURE OF RARE VARIATION IN AUTISM AND OTHER NEURODEVELOPMENTAL CONDITIONS.

Nr2f1 enhancers have distinct functions in controlling Nr2f1 expression during cortical development.

Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements.

The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.

LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder.

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Examining Sex Differences in Autism Heritability.

Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

CWAS-Plus: estimating category-wide association of rare noncoding variation from whole-genome sequencing data with cell-type-specific functional data.

Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.

A comprehensive AI model development framework for consistent Gleason grading.

Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements.

Sex-Differential Gene Expression in Developing Human Cortex and Its Intersection With Autism Risk Pathways.

Massively parallel reporter assays and mouse transgenic assays provide complementary information about neuronal enhancer activity.

CWAS-Plus: Estimating category-wide association of rare noncoding variation from whole-genome sequencing data with cell-type-specific functional data.

De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Leveraging electronic health records and knowledge networks for Alzheimer's disease prediction and sex-specific biological insights.

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Prenatal delivery of a therapeutic antisense oligonucleotide achieves broad biodistribution in the brain and ameliorates Angelman Syndrome phenotype in mice.

Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.

The Human Phenotype Ontology in 2024: phenotypes around the world.

Artificial intelligence-assisted quantification and assessment of whole slide images for pediatric kidney disease diagnosis.

Predictive Modeling Leveraging Electronic Health Records Identifies Early Predictors of Alzheimer’s Disease.

A Cre-dependent massively parallel reporter assay allows for cell-type specific assessment of the functional effects of non-coding elements in vivo.

AlphaMissense is better correlated with functional assays of missense impact than earlier prediction algorithms.

Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior.

CHARACTERIZING ASSOCIATIONS BETWEEN DISRUPTIVE DE NOVO RARE VARIANT BURDENS AND PHENOTYPIC COMBINATIONS IN OVER 3,000 AUTISTIC CHILDREN: TOWARDS BUILDING A PUBLIC CLINICAL GENETIC RESOURCE.

T63. CROSS-DISORDER ANALYSIS OF AUTISM AND ADHD USING RARE VARIANTS: INSIGHTS FROM DANISH IPSYCH EXOMES.

Neuropsychiatric biomarker discovery: go big or go home.

Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.

Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.

KCNT2-related disorders: phenotypes, functional and pharmacological properties.

Characterization of De Novo Promoter Variants in Autism Spectrum Disorder with Massively Parallel Reporter Assays.

In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review.

Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development.

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

The female protective effect against autism spectrum disorder.

Enhancing Clinical Information Display to Improve Patient Encounters: Human-Centered Design and Evaluation of the Parkinson Disease-BRIDGE Platform.

A Biomedical Open Knowledge Network Harnesses the Power of AI to Understand Deep Human Biology.

A biomedical open knowledge network harnesses the power of AI to understand deep human biology.

Detection of subtle white matter lesions in MRI through texture feature extraction and boundary delineation using an embedded clustering strategy.

High-throughput characterization of the role of non-B DNA motifs on promoter function.

Assessing the utility of electronic measures as a proxy for cognitive ability.

Building a Precision Medicine Delivery Platform for Clinics: The University of California, San Francisco, BRIDGE Experience.

47. GENE DISCOVERY FROM EXOME SEQUENCING IN AUTISM AND COMPARISON TO DEVELOPMENTAL DELAY AND SCHIZOPHRENIA.

THE FEMALE PROTECTIVE EFFECT AGAINST AUTISM SPECTRUM DISORDER.

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain.

Patterns of delay in early gross motor and expressive language milestone attainment in probands with genetic conditions versus idiopathic ASD from SFARI registries.

Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells.

Exome sequencing of fetuses with congenital diaphragmatic hernia supports a causal role for NR2F2, PTPN11, and WT1 variants.

Extrathymic Aire-expressing cells support maternal-fetal tolerance.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

Prenatal exposure to paternal smoking and likelihood for autism spectrum disorder.

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

16p11.2.

7q11.23 Duplications.

Multiplex-Simplex Comparisons.

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

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

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

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

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

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

Whole-Exome Sequencing in Fetuses with Congenital Diaphragmatic Hernias: Known and Novel Genetic Mutation.

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

A Chromatin Accessibility Atlas of the Developing Human Telencephalon.

Clinical impact of splicing in neurodevelopmental disorders.

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

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice.

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

83: HyDROPS study: Exome sequencing identifies genetic disorders causing non-immune hydrops fetalis.

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

Next-Generation Sequencing in Autism Spectrum Disorder.

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

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

Predicting Splicing from Primary Sequence with Deep Learning.

31DISCOVERY AND CHARACTERIZATION OF 102 GENES ASSOCIATED WITH AUTISM FROM EXOME SEQUENCING OF 37,269 INDIVIDUALS.

9 LIMITED CONTRIBUTION OF RARE, NONCODING VARIATION TO AUTISM SPECTRUM DISORDER FROM SEQUENCING OF 2,076 GENOMES IN QUARTET FAMILIES.

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

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

Automating Installation of the Integrating Biology and the Bedside (i2b2) Platform.

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

Progress in Understanding and Treating SCN2A-Mediated Disorders.

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

Whole genome sequencing in psychiatric disorders: the WGSPD consortium.

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

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

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

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

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

De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

706 Wnt/ß-Catenin Pathway Contributions to Dendritic Spine and Glutamatergic Synapse Formation Responsive to Lithium-Mediated GSK3 Inhibition.

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder.

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

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.

Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/ß-catenin signaling.

S.33.03 Phenotype-genotype associations in the Simons Simplex Collection for autism spectrum disorder.

Intergenerational Neuroimaging of Human Brain Circuitry.

Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Frequency and Complexity of De Novo Structural Mutation in Autism.

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population.

Attention Finally Being Paid to Girls at Risk of Autism.

Gene coexpression modules in human cognition.

Chapter 1 The Newly Emerging View of the Genome.

Chapter 29 Autism Spectrum Disorder Genes to Pathways to Circuits.

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

First glimpses of the neurobiology of autism spectrum disorder.

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

Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation.

Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority.

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.

Loss of d-catenin function in severe autism.

The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

A MARKOV RANDOM FIELD-BASED APPROACH TO CHARACTERIZING HUMAN BRAIN DEVELOPMENT USING SPATIAL-TEMPORAL TRANSCRIPTOME DATA.

No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.

Genotype to phenotype relationships in autism spectrum disorders.

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

Synaptic, transcriptional and chromatin genes disrupted in autism.

The contribution of de novo coding mutations to autism spectrum disorder.

De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.

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

Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci.

A framework for the interpretation of de novo mutation in human disease.

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Most genetic risk for autism resides with common variation.

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

Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics.

Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.

Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Gender differences in heterosexual college students' conceptualizations and indicators of sexual consent: implications for contemporary sexual assault prevention education.

Intellectual disability is associated with increased runs of homozygosity in simplex autism.

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

High rate of disease-related copy number variations in childhood onset schizophrenia.

De novo mutations in histone-modifying genes in congenital heart disease.

Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

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

16p11.2.

7q11.23 Duplications.

Multiplex-Simplex Comparisons.

Copy-number disorders are a common cause of congenital kidney malformations.

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

Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders.

Cytomegalovirus reactivation following autologous peripheral blood stem cell transplantation for multiple myeloma in the era of novel chemotherapeutics and tandem transplantation.

A complex chromosomal rearrangement involving chromosomes 2, 5, and X in autism spectrum disorder.

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.

Physiological and psychological illness symptoms at high altitude and their relationship with acute mountain sickness: a prospective cohort study.

De novo mutations revealed by whole-exome sequencing are strongly associated with autism.

A balanced t(10;15) translocation in a male patient with developmental language disorder.

Searching for Potocki-Lupski syndrome phenotype: a patient with language impairment and no autism.

Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.

Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia.

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Sexual behavior in the United States: results from a national probability sample of men and women ages 14-94.

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

L-histidine decarboxylase and Tourette's syndrome.

Standardizing the next generation of bioinformatics software development with BioHDF (HDF5).

Body composition at high altitude: a randomized placebo-controlled trial of dietary carbohydrate supplementation.

Condom use as a dependent variable: a brief commentary about classification of inconsistent users.

Hereditary hyperferritinaemia-cataract syndrome and differential diagnosis of hereditary haemochromatosis.

Appositions between cocaine and amphetamine-related transcript- and gonadotropin releasing hormone-immunoreactive neurons in the hypothalamus of the Siberian hamster.