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. AggarwalDiane 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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1454-1469
Number of pages16
JournalAmerican Journal of Human Genetics
Volume110
Issue number9
DOIs
Publication statusPublished - 2023 Sept 7

Bibliographical note

Funding Information:
We thank the families and clinicians from the Columbia University Carmen and John Thain Center for Prenatal Pediatrics, the University of North Carolina Chapel Hill Prenatal Diagnosis Program, the University of California San Francisco Prenatal Diagnostic Center, and the Simons Simplex Collection for their participation. This study was supported by resources from the National Institutes of Health (NIH): HD081256, HD099547, and MH115957 (awarded to M.E.T.); HD088742 (awarded to N.V.); UM1HG008900 (awarded to A.H.O'D-L. H.R. and M.E.T); HD105266 (awarded to R.W. and M.E.T.); K99HD108392 (awarded to C.L.); F31NS113414 (awarded to E.V.); T32HG002295 (supporting R.L.C.); and K99DE026824 (awarded to H.B.). Additional support came from the Simons Foundation Autism Research Initiative (SFARI #573206 awarded to M.E.T.). C.L. was also supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and R.L.C. was supported by the National Science Foundation (GRFP #2017240332). J.-Y.A. was supported by the National Research Foundation of Korea (2020R1C1C1003426 and 2021M3E5D9021878). Study design: B.L. H.B. D.G.M. R.W. and M.E.T. Family recruitment and sample collection: J.L.G. V.S.A. D.L. M.E.N. T.M. K.G. B.P. A.B. M.D. N.L.V. B.L. and R.W. Sample library preparation: B.B.C. and K.O'K. Computational analysis: C.L. E.V. H.Z.W. E.P.H. N.K. C.W.W. S.P.H. B.W. V.J. J.F. R.L.C. X.Z. L.D.G. C.T. N.S. J.-Y.A. S.D. B.D. D.B.G. S.J.S. D.G.M. and H.B. Manual variant curation: C.L. E.V. J.L.G. C.A.A.-T. E.E. G.L. K.G. F.V. J.C.H. A.H.O'D-L. H.L.R. N.L.V. B.L. and R.W. Verified the underlying data for these analyses: C.L. E.V. H.B. and M.E.T. Wrote the manuscript and generated the figures: C.L. E.V. H.B. and M.E.T. All authors reviewed the manuscript. C.L. and E.V. contributed equally to this study. M.E.T. and H.R. receive research funding from Microsoft Inc and/or research reagents from Illumina Inc. M.E.T. also received research funding from Levo Therapeutics and research reagents from Ionis Therapeutics for unrelated research projects.

Funding Information:
We thank the families and clinicians from the Columbia University Carmen and John Thain Center for Prenatal Pediatrics, the University of North Carolina Chapel Hill Prenatal Diagnosis Program, the University of California San Francisco Prenatal Diagnostic Center, and the Simons Simplex Collection for their participation. This study was supported by resources from the National Institutes of Health (NIH): HD081256 , HD099547 , and MH115957 (awarded to M.E.T.); HD088742 (awarded to N.V.); UM1HG008900 (awarded to A.H.O'D-L., H.R., and M.E.T); HD105266 (awarded to R.W. and M.E.T.); K99HD108392 (awarded to C.L.); F31NS113414 (awarded to E.V.); T32HG002295 (supporting R.L.C.); and K99DE026824 (awarded to H.B.). Additional support came from the Simons Foundation Autism Research Initiative (SFARI #573206 awarded to M.E.T.). C.L. was also supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and R.L.C. was supported by the National Science Foundation ( GRFP #2017240332) . J.-Y.A. was supported by the National Research Foundation of Korea ( 2020R1C1C1003426 and 2021M3E5D9021878 ).

Funding Information:
M.E.T. and H.R. receive research funding from Microsoft Inc and/or research reagents from Illumina Inc. M.E.T. also received research funding from Levo Therapeutics and research reagents from Ionis Therapeutics for unrelated research projects.

Publisher Copyright:
© 2023 American Society of Human Genetics

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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