Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population

Anne Slavotinek; Shannon Rego; Nuriye Sahin-Hodoglugil; Mark Kvale; Billie Lianoglou; Tiffany Yip; Hannah Hoban; Simon Outram; Beatrice Anguiano; Flavia Chen; Jeremy Michelson; Roberta M Cilio; Cynthia Curry; Renata C Gallagher; Marisa Gardner; Rachel Kuperman; Bryce Mendelsohn; Elliott Sherr; Joseph Shieh; Jonathan Strober; Allison Tam; Jessica Tenney; William Weiss; Amy Whittle; Garrett Chin; Amanda Faubel; Hannah Prasad; Yusuph Mavura; Jessica Van Ziffle; W Patrick Devine; Ugur Hodoglugil; Pierre-Marie Martin; Teresa N Sparks; Barbara Koenig; Sara Ackerman; Neil Risch; Pui-Yan Kwok; Mary E Norton

doi:10.1038/s41525-023-00353-0

Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population

NPJ Genom Med. 2023 May 26;8(1):10. doi: 10.1038/s41525-023-00353-0.

Authors

Anne Slavotinek^{1

2}, Shannon Rego^{3

4}, Nuriye Sahin-Hodoglugil⁴, Mark Kvale^{4

5}, Billie Lianoglou⁶, Tiffany Yip^{3

4}, Hannah Hoban³, Simon Outram⁷, Beatrice Anguiano^{4

7}, Flavia Chen⁴, Jeremy Michelson⁸, Roberta M Cilio⁹, Cynthia Curry¹⁰, Renata C Gallagher^{3

4}, Marisa Gardner¹¹, Rachel Kuperman^{11

12}, Bryce Mendelsohn¹³, Elliott Sherr¹⁴, Joseph Shieh^{3

4}, Jonathan Strober¹⁴, Allison Tam³, Jessica Tenney³, William Weiss¹⁵, Amy Whittle¹⁶, Garrett Chin⁴, Amanda Faubel⁶, Hannah Prasad⁴, Yusuph Mavura^{4

5}, Jessica Van Ziffle¹⁷, W Patrick Devine¹⁷, Ugur Hodoglugil¹⁸, Pierre-Marie Martin⁴, Teresa N Sparks^{4

19}, Barbara Koenig^{4

20}, Sara Ackerman^{7

21}, Neil Risch^{4

5}, Pui-Yan Kwok²², Mary E Norton^{4

19}

Affiliations

¹ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. anne.slavotinek@cchmc.org.
² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. anne.slavotinek@cchmc.org.
³ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
⁴ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁷ Institute for Health & Aging, School of Nursing, University of California San Francisco, San Francisco, CA, USA.
⁸ Institute of Human Nutrition, Columbia University Medical Center, New York, NY, USA.
⁹ Division of Pediatric Neurology, Department of Pediatrics, University of Louvain, Brussels, Belgium.
¹⁰ Genetic Medicine, University of California, San Francisco, Fresno, CA, USA.
¹¹ Department of Neurology, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
¹² Eysz, Inc, Piedmont, CA, USA.
¹³ Division of Genetics, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.
¹⁴ Division of Child Neurology, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Division of Child Neurology, Zuckerberg San Francisco General Hospital, San Francisco, San Francisco, CA, USA.
¹⁶ Division of Pediatrics, Zuckerberg San Francisco General Hospital, San Francisco, San Francisco, CA, USA.
¹⁷ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Genomic Medicine Laboratory, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, San Francisco, USA.
²⁰ Program in Bioethics, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Social & Behavioral Sciences, School of Nursing, University of California San Francisco, San Francisco, CA, USA.
²² Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.

Abstract

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

Abstract

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