ArticleAmerican journal of human genetics2023
Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.
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Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33citing papers in PubMed
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33 citing papers in PubMed, 52 citations in OpenAlex.
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- Characterization of rare genomic structural variants across 2,981 genomes reveals significant involvements in recessive conditions.Science China. Life sciences · 2026Article
- Uncultured Amniocytes Enable Rapid and Clinically Informative Prenatal RNA Sequencing for Genetic Diagnosis.International journal of molecular sciences · 2026Article
- Genetic architecture of patients with autism spectrum disorder - data analysis based on the literature review.BMC medical genomics · 2026Review
- Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- The Expanding Role of Gene Sequencing in Shaping Fetal Therapies: Clinical and Ethical Considerations.Prenatal diagnosis · 2026Review
- Autism Information Progression and the Impact of Misinformation on Autism Knowledge, Awareness and Stigmatization.Behavioral sciences (Basel, Switzerland) · 2026Article
- Expanding beyond the exome: identifying pediatric patients best suited for genome sequencing.Journal of community genetics · 2026Article
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- Progress and opportunity in developmental neurobiology and youth mental health.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- Modeling the long-range effect of an inversion downstream of EFNB1 concludes a 43-year molecular diagnostic odyssey for craniofrontonasal syndrome.European journal of human genetics : EJHG · 2025Article
- CRISPR-engineered deletion ofbioRxiv : the preprint server for biology · 2025Article
- Genetic Counseling Utilization and Experience Among Caregivers of Children With ASD in the United States.Journal of autism and developmental disorders · 2025Article
- Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.Genome medicine · 2025Article
- International Society for Prenatal Diagnosis 2024 Debate 3-Cytogenetics Is a Dinosaur and Should Be Replaced by Molecular Technologies.Prenatal diagnosis · 2025Review
- Diversity and consequences of structural variation in the human genome.Nature reviews. Genetics · 2025Review
- Clinical utility of genome sequencing in autism: illustrative examples from a genomic research study.Journal of medical genetics · 2025Article
- Exome sequencing uncovers promising candidate genes for foetal structural malformations.The Indian journal of medical research · 2025Article
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Authors and funding
45 authors at 9 institutions in 3 countries.
Chelsea LowtherCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Elise ValkanasCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
Jessica L GiordanoDepartment of Obstetrics & Gynecology, Columbia University Medical Center, New York, NY, USA.
Harold Z WangCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Benjamin B CurrallCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Kathryn O'KeefeCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Emma Pierce-HoffmanProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nehir E KurtasCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Christopher W WhelanProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stephanie P HaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ben WeisburdCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Vahid JaliliProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jack FuCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Isaac WongCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ryan L CollinsCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
Xuefang ZhaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Christina A Austin-TseCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA.
Emily EvangelistaProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Gabrielle LemireProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Vimla S AggarwalDepartment of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Diane LucenteCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Laura D GauthierProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Charlotte TolonenProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nareh SahakianProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Christine StevensProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Joon-Yong AnSchool of Biosystem and Biomedical Science, Korea University, Seoul, South Korea.
Shan DongDepartment of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Mary E NortonCenter for Maternal-Fetal Precision Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA.
Tippi C MacKenzieCenter for Maternal-Fetal Precision Medicine, University of California, San Francisco, San Francisco, CA, USA.
Bernie DevlinDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kelly GilmoreDepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Bradford C PowellDepartment of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Alicia BrandtDepartment of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Francesco VetriniDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Michelle DiVitoDepartment of Obstetrics & Gynecology, Columbia University Medical Center, New York, NY, USA.
Stephan J SandersDepartment of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Daniel G MacArthurCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Centre for Population Genomics, Garvan Institute of Medical Research, and University of New South Wales Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Jennelle C HodgeDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Anne O'Donnell-LuriaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Heidi L RehmCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Neeta L VoraDepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Brynn LevyDepartment of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Harrison BrandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Ronald J WapnerDepartment of Obstetrics & Gynecology, Columbia University Medical Center, New York, NY, USA.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. Electronic address: mtalkowski@mgh.harvard.edu.
Broad Institute · USColumbia University Irving Medical Center · USUniversity of California, San Francisco · USUniversity of North Carolina at Chapel Hill · USIndiana University School of MedicineHarvard University · USKorea University · KRMassachusetts General Hospital · USUniversity of Pittsburgh · US
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MTraining Program in Bioinformatics and Integrative GenomicsT32HG002295 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Peter J Park · 2001 to 2026
$15.8MClinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2MScalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4MThe Genomic Architecture of Pregnancy LossR01HD105266 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E, WAPNER, RONALD · 2021 to 2024
$3.1MScalable tools and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR56MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2018 to 2018
$870kEarly Genomic DiagnosisK23HD088742 · NICHD · UNIV OF NORTH CAROLINA CHAPEL HILL · PI VORA, NEETA L · 2017 to 2020
$685kExploring the genetic architecture of structural birth defectsR03HD099547 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2019 to 2020
$336kIntegrative Genomic Applications to Understand the Etiology of Unsolved Craniofacial AnomaliesK99DE026824 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI BRAND, HARRISON · 2017 to 2018
$324kDisruption of three-dimensional genome organization as a noncoding mechanism of disease in human developmental disordersK99HD108392 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI LOWTHER, CHELSEA · 2022 to 2023
$272kCharacterizing a spectrum of mosaic variation in the population and across neurological disordersF31NS113414 · NINDS · HARVARD MEDICAL SCHOOL · PI VALKANAS, ELISE · 2019 to 2021
$111kNHGRI NIH HHS T32 HG002295NHGRI NIH HHS UM1 HG008900NICHD NIH HHS K23 HD088742NICHD NIH HHS K99 HD108392NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD105266NICHD NIH HHS R03 HD099547NIDCR NIH HHS K99 DE026824NIMH NIH HHS R01 MH115957NIMH NIH HHS R56 MH115957NINDS NIH HHS F31 NS113414
Abstract
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
Indexed as
Autism Spectrum DisorderChromosome MappingExomeFemaleHumansPregnancyPregnancy Trimester, FirstUltrasonography, Prenatalgenome sequencing, karyotype, microarray, exome sequencing, structural variant, autism spectrum disorder, structural anomaly, prenatal, first-tier, diagnostic
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