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Gilles Maussion, Cristiana Cruceanu, Jill A Rosenfeld, Scott C Bell, Fabrice Jollant, Jin Szatkiewicz, Ryan L Collins, Carrie Hanscom, Ilaria Kolobova, Nicolas Menjot de Champfleur, Ian Blumenthal, Colby Chiang, Vanessa Ota, Christina Hultman, Colm O'Dushlaine, Steve McCarroll, Martin Alda, Sebastien Jacquemont, Zehra Ordulu, Christian R Marshall, Melissa T Carter, Lisa G Shaffer, Pamela Sklar, Santhosh Girirajan, Cynthia C Morton, James F Gusella, Gustavo Turecki, Dimitri J Stavropoulos, Patrick F Sullivan, Stephen W Scherer, Michael E Talkowski, Carl Ernst
We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11...
October 19, 2016: American Journal of Medical Genetics. Part A
Xiang Zhan, Santhosh Girirajan, Ni Zhao, Michael C Wu, Debashis Ghosh
MOTIVATION: Copy number variants (CNVs) have been implicated in a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and schizophrenia. Recent advances in high-throughput genomic technologies have enabled rapid discovery of many genetic variants including CNVs. As a result, there is increasing interest in studying the role of CNVs in the etiology of many complex diseases. Despite the availability of an unprecedented wealth of CNV data, methods for testing association between CNVs and disease-related traits are still under-developed due to the low prevalence and complicated multi-scale features of CNVs...
August 6, 2016: Bioinformatics
Anthony R Isles, Andrés Ingason, Chelsea Lowther, James Walters, Micha Gawlick, Gerald Stöber, Elliott Rees, Joanna Martin, Rosie B Little, Harry Potter, Lyudmila Georgieva, Lucilla Pizzo, Norio Ozaki, Branko Aleksic, Itaru Kushima, Masashi Ikeda, Nakao Iwata, Douglas F Levinson, Pablo V Gejman, Jianxin Shi, Alan R Sanders, Jubao Duan, Joseph Willis, Sanjay Sisodiya, Gregory Costain, Thomas M Werge, Franziska Degenhardt, Ina Giegling, Dan Rujescu, Stefan J Hreidarsson, Evald Saemundsen, Joo Wook Ahn, Caroline Ogilvie, Santhosh D Girirajan, Hreinn Stefansson, Kari Stefansson, Michael C O'Donovan, Michael J Owen, Anne Bassett, George Kirov
Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11...
May 2016: PLoS Genetics
James R Priest, Kazutoyo Osoegawa, Nebil Mohammed, Vivek Nanda, Ramendra Kundu, Kathleen Schultz, Edward J Lammer, Santhosh Girirajan, Todd Scheetz, Daryl Waggott, Francois Haddad, Sushma Reddy, Daniel Bernstein, Trudy Burns, Jeffrey D Steimle, Xinan H Yang, Ivan P Moskowitz, Matthew Hurles, Richard P Lifton, Debbie Nickerson, Michael Bamshad, Evan E Eichler, Seema Mital, Val Sheffield, Thomas Quertermous, Bruce D Gelb, Michael Portman, Euan A Ashley
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD)...
April 2016: PLoS Genetics
Janani Iyer, Qingyu Wang, Thanh Le, Lucilla Pizzo, Sebastian Grönke, Surendra S Ambegaokar, Yuzuru Imai, Ashutosh Srivastava, Beatriz Llamusí Troisí, Graeme Mardon, Ruben Artero, George R Jackson, Adrian M Isaacs, Linda Partridge, Bingwei Lu, Justin P Kumar, Santhosh Girirajan
About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (, to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes...
2016: G3: Genes—Genomes—Genetics
Wilmar Saldarriaga, Pamela Lein, Laura Yuriko González Teshima, Carolina Isaza, Lina Rosa, Andrew Polyak, Randi Hagerman, Santhosh Girirajan, Marisol Silva, Flora Tassone
Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55-200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital...
March 2016: Neurotoxicology
Jan Schröder, Santhosh Girirajan, Anthony T Papenfuss, Paul Medvedev
The uses of the Genome Reference Consortium's human reference sequence can be roughly categorized into three related but distinct categories: as a representative species genome, as a coordinate system for identifying variants, and as an alignment reference for variation detection algorithms. However, the use of this reference sequence as simultaneously a representative species genome and as an alignment reference leads to unnecessary artifacts for structural variation detection algorithms and limits their accuracy...
2015: PloS One
Andrew Polyak, Jill A Rosenfeld, Santhosh Girirajan
BACKGROUND: Neurodevelopmental disorders such as autism and intellectual disability have a sex bias skewed towards boys; however, systematic assessment of this bias is complicated by the presence of significant genetic and phenotypic heterogeneity of these disorders. METHODS: To assess the extent and characteristics of sex bias, we analyzed the frequency of comorbid features, the magnitude of genetic load, and the existence of family history within 32,155 individuals ascertained clinically for autism or intellectual disability/developmental delay (ID/DD), including a subset of 8,373 individuals carrying rare copy-number variants (CNVs)...
2015: Genome Medicine
Andrew Polyak, Richard M Kubina, Santhosh Girirajan
While recent studies suggest a converging role for genetic factors towards risk for nosologically distinct disorders including autism, intellectual disability (ID), and epilepsy, current estimates of autism prevalence fail to take into account the impact of comorbidity of these disorders on autism diagnosis. We aimed to assess the effect of comorbidity on the diagnosis and prevalence of autism by analyzing 11 years (2000-2010) of special education enrollment data on approximately 6.2 million children per year...
October 2015: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Olena Korvatska, James B Leverenz, Suman Jayadev, Pamela McMillan, Irina Kurtz, Xindi Guo, Malia Rumbaugh, Mark Matsushita, Santhosh Girirajan, Michael O Dorschner, Kostantin Kiianitsa, Chang-En Yu, Zoran Brkanac, Gwenn A Garden, Wendy H Raskind, Thomas D Bird
IMPORTANCE: The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. OBJECTIVE: To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. DESIGN, SETTING, AND PARTICIPANTS: This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014...
August 2015: JAMA Neurology
Janani Iyer, Santhosh Girirajan
Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders. The sequence architecture of the human genome predisposes certain individuals to deletions and duplications within specific genomic regions. While assessment of individuals with different breakpoints has identified causal genes for certain rare CNVs, deriving gene-phenotype correlations for rare CNVs with similar breakpoints has been challenging. We present a comprehensive review of the literature related to genetic architecture that is predisposed to recurrent rearrangements, and functional evaluation of deletions, duplications and candidate genes within rare CNV intervals using mouse, zebrafish and fruit fly models...
September 2015: Briefings in Functional Genomics
Varvara Mazina, Jennifer Gerdts, Sandy Trinh, Katy Ankenman, Tracey Ward, Megan Y Dennis, Santhosh Girirajan, Evan E Eichler, Raphael Bernier
OBJECTIVE: Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings...
February 2015: Journal of Developmental and Behavioral Pediatrics: JDBP
Melanie A Jones, Sami Amr, Aerial Ferebee, Phung Huynh, Jill A Rosenfeld, Michael F Miles, Andrew G Davies, Christopher A Korey, John M Warrick, Rita Shiang, Sarah H Elsea, Santhosh Girirajan, Mike Grotewiel
Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes...
2014: Biology Open
Sarah Pendergrass, Santhosh Girirajan, Scott Selleck
A clear and predictive understanding of the etiology of autism spectrum disorders (ASD), a group of neurodevelopmental disorders characterized by varying deficits in social interaction and communication as well as repetitive behaviors, has not yet been achieved. There remains active debate about the origins of autism, and the degree to which genetic and environmental factors, and their interplay, produce the range and heterogeneity of cognitive, developmental, and behavioral features seen in children carrying a diagnosis of ASD...
2014: Pacific Symposium on Biocomputing
Santhosh Girirajan
A report on the 7(th) Wellcome Trust Genomic Disorders conference held at the Homerton College, Cambridge, UK, April 10-12, 2013.
2013: Genome Medicine
Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin, Alastair MacLennan
Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0...
January 2014: European Journal of Human Genetics: EJHG
Andrew E Timms, Michael O Dorschner, Jeremy Wechsler, Kyu Yeong Choi, Robert Kirkwood, Santhosh Girirajan, Carl Baker, Evan E Eichler, Olena Korvatska, Katherine W Roche, Marshall S Horwitz, Debby W Tsuang
IMPORTANCE: Schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment. OBJECTIVE: To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia...
June 2013: JAMA Psychiatry
Santhosh Girirajan, Rebecca L Johnson, Flora Tassone, Jorune Balciuniene, Neerja Katiyar, Keolu Fox, Carl Baker, Abhinaya Srikanth, Kian Hui Yeoh, Su Jen Khoo, Therese B Nauth, Robin Hansen, Marylyn Ritchie, Irva Hertz-Picciotto, Evan E Eichler, Isaac N Pessah, Scott B Selleck
Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray...
July 15, 2013: Human Molecular Genetics
Santhosh Girirajan, Megan Y Dennis, Carl Baker, Maika Malig, Bradley P Coe, Catarina D Campbell, Kenneth Mark, Tiffany H Vu, Can Alkan, Ze Cheng, Leslie G Biesecker, Raphael Bernier, Evan E Eichler
Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls...
February 7, 2013: American Journal of Human Genetics
Gea Beunders, Els Voorhoeve, Christelle Golzio, Luba M Pardo, Jill A Rosenfeld, Michael E Talkowski, Ingrid Simonic, Anath C Lionel, Sarah Vergult, Robert E Pyatt, Jiddeke van de Kamp, Aggie Nieuwint, Marjan M Weiss, Patrizia Rizzu, Lucilla E N I Verwer, Rosalina M L van Spaendonk, Yiping Shen, Bai-lin Wu, Tingting Yu, Yongguo Yu, Colby Chiang, James F Gusella, Amelia M Lindgren, Cynthia C Morton, Ellen van Binsbergen, Saskia Bulk, Els van Rossem, Olivier Vanakker, Ruth Armstrong, Soo-Mi Park, Lynn Greenhalgh, Una Maye, Nicholas J Neill, Kristin M Abbott, Susan Sell, Roger Ladda, Darren M Farber, Patricia I Bader, Tom Cushing, Joanne M Drautz, Laura Konczal, Patricia Nash, Emily de Los Reyes, Melissa T Carter, Elizabeth Hopkins, Christian R Marshall, Lucy R Osborne, Karen W Gripp, Devon Lamb Thrush, Sayaka Hashimoto, Julie M Gastier-Foster, Caroline Astbury, Bauke Ylstra, Hanne Meijers-Heijboer, Danielle Posthuma, Björn Menten, Geert Mortier, Stephen W Scherer, Evan E Eichler, Santhosh Girirajan, Nicholas Katsanis, Alexander J Groffen, Erik A Sistermans
Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms...
February 7, 2013: American Journal of Human Genetics
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