Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

Kandamurugu Manickam; Monica R McClain; Laurie A Demmer; Sawona Biswas; Hutton M Kearney; Jennifer Malinowski; Lauren J Massingham; Danny Miller; Timothy W Yu; Fuki M Hisama; ACMG Board of Directors

doi:10.1038/s41436-021-01242-6

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1.

Authors

Kandamurugu Manickam^{1

2}, Monica R McClain³, Laurie A Demmer⁴, Sawona Biswas⁵, Hutton M Kearney⁶, Jennifer Malinowski⁷, Lauren J Massingham^{8

9}, Danny Miller¹⁰, Timothy W Yu^{11

12}, Fuki M Hisama¹³; ACMG Board of Directors

Affiliations

¹ Division of Genetic and Genomic Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
² The Ohio State University College of Medicine, Columbus, OH, USA.
³ Scientific and Strategic Affairs, Evidera | PPD, Waltham, MA, USA.
⁴ Division of Medical Genetics, Department of Pediatrics, Atrium Health's Levine Children's Hospital, Charlotte, NC, USA.
⁵ Division of Adult Genetics, Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁶ Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁷ Write Inscite, LLC, South Salem, NY, USA.
⁸ Division of Medical Genetics, Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.
⁹ Alpert School of Medicine at Brown University, Providence, RI, USA.
¹⁰ MEPAN Foundation, Corte Madera, CA, USA.
¹¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
¹² Harvard Medical School, Boston, MA, USA.
¹³ Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

PMID: 34211152
DOI: 10.1038/s41436-021-01242-6

Abstract

Purpose: To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years.

Methods: The Pediatric Exome/Genome Sequencing Evidence-Based Guideline Work Group (n = 10) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework based on the recent American College of Medical Genetics and Genomics (ACMG) systematic review, and an Ontario Health Technology Assessment to develop and present evidence summaries and health-care recommendations. The document underwent extensive internal and external peer review, and public comment, before approval by the ACMG Board of Directors.

Results: The literature supports the clinical utility and desirable effects of ES/GS on active and long-term clinical management of patients with CA/DD/ID, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective when ordered early in the diagnostic evaluation.

Conclusion: We strongly recommend that ES/GS be considered as a first- or second-tier test for patients with CA/DD/ID.

MeSH terms

Child
Exome / genetics
Exome Sequencing
Genetics, Medical*
Genomics
Humans
Infant
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Practice Guidelines as Topic
United States