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

Chelsea Lowther; Elise Valkanas; Jessica L Giordano; Harold Z Wang; Benjamin B Currall; Kathryn O'Keefe; Emma Pierce-Hoffman; Nehir E Kurtas; Christopher W Whelan; Stephanie P Hao; Ben Weisburd; Vahid Jalili; Jack Fu; Isaac Wong; Ryan L Collins; Xuefang Zhao; Christina A Austin-Tse; Emily Evangelista; Gabrielle Lemire; Vimla S Aggarwal; Diane Lucente; Laura D Gauthier; Charlotte Tolonen; Nareh Sahakian; Christine Stevens; Joon-Yong An; Shan Dong; Mary E Norton; Tippi C MacKenzie; Bernie Devlin; Kelly Gilmore; Bradford C Powell; Alicia Brandt; Francesco Vetrini; Michelle DiVito; Stephan J Sanders; Daniel G MacArthur; Jennelle C Hodge; Anne O'Donnell-Luria; Heidi L Rehm; Neeta L Vora; Brynn Levy; Harrison Brand; Ronald J Wapner; Michael E Talkowski

doi:10.1016/j.ajhg.2023.07.010

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

Am J Hum Genet. 2023 Sep 7;110(9):1454-1469. doi: 10.1016/j.ajhg.2023.07.010. Epub 2023 Aug 17.

Authors

Chelsea Lowther¹, Elise Valkanas², Jessica L Giordano³, Harold Z Wang⁴, Benjamin B Currall¹, Kathryn O'Keefe⁴, Emma Pierce-Hoffman⁵, Nehir E Kurtas¹, Christopher W Whelan⁵, Stephanie P Hao⁴, Ben Weisburd⁴, Vahid Jalili⁵, Jack Fu¹, Isaac Wong⁴, Ryan L Collins⁶, Xuefang Zhao¹, Christina A Austin-Tse⁷, Emily Evangelista⁵, Gabrielle Lemire⁵, Vimla S Aggarwal⁸, Diane Lucente⁹, Laura D Gauthier¹⁰, Charlotte Tolonen¹⁰, Nareh Sahakian¹⁰, Christine Stevens⁵, Joon-Yong An¹¹, Shan Dong¹², Mary E Norton¹³, Tippi C MacKenzie¹⁴, Bernie Devlin¹⁵, Kelly Gilmore¹⁶, Bradford C Powell¹⁷, Alicia Brandt¹⁷, Francesco Vetrini¹⁸, Michelle DiVito³, Stephan J Sanders¹², Daniel G MacArthur¹⁹, Jennelle C Hodge¹⁸, Anne O'Donnell-Luria²⁰, Heidi L Rehm⁴, Neeta L Vora¹⁶, Brynn Levy⁸, Harrison Brand¹, Ronald J Wapner³, Michael E Talkowski²¹

Affiliations

¹ Center 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.
² Center 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.
³ Department of Obstetrics & Gynecology, Columbia University Medical Center, New York, NY, USA.
⁴ Center 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.
⁵ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Center 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.
⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Program 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.
¹¹ School of Biosystem and Biomedical Science, Korea University, Seoul, South Korea.
¹² Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
¹³ Center 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.
¹⁴ Center for Maternal-Fetal Precision Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁶ Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁹ Center 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.
²⁰ Center 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.
²¹ Center 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.

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.

Keywords: genome sequencing, karyotype, microarray, exome sequencing, structural variant, autism spectrum disorder, structural anomaly, prenatal, first-tier, diagnostic.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Autism Spectrum Disorder* / diagnosis
Autism Spectrum Disorder* / genetics
Chromosome Mapping
Exome
Female
Humans
Pregnancy
Pregnancy Trimester, First
Ultrasonography, Prenatal

Abstract

Publication types

MeSH terms

Grants and funding