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

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.

PMID: 37236975
PMCID: PMC10220040
DOI: 10.1038/s41525-023-00353-0

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

Anne Slavotinek et al. NPJ Genom Med. 2023.

. 2023 May 26;8(1):10.

doi: 10.1038/s41525-023-00353-0.

Authors

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.

PMID: 37236975
PMCID: PMC10220040
DOI: 10.1038/s41525-023-00353-0

Erratum in

Author Correction: Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.
Slavotinek A, Rego S, Sahin-Hodoglugil N, Kvale M, Lianoglou B, Yip T, Hoban H, Outram S, Anguiano B, Chen F, Michelson J, Cilio RM, Curry C, Gallagher RC, Gardner M, Kuperman R, Mendelsohn B, Sherr E, Shieh J, Strober J, Tam A, Tenney J, Weiss W, Whittle A, Chin G, Faubel A, Prasad H, Mavura Y, Van Ziffle J, Devine WP, Hodoglugil U, Martin PM, Sparks TN, Koenig B, Ackerman S, Risch N, Kwok PY, Norton ME. Slavotinek A, et al. NPJ Genom Med. 2023 Oct 23;8(1):34. doi: 10.1038/s41525-023-00382-9. NPJ Genom Med. 2023. PMID: 37872195 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Distribution of ancestry in 845 patients enrolled in the Program in Prenatal and Prenatal Genomic Sequencing (P³EGS) study.**
Each chart shows the distribution of ancestry according to the arm of the study (Pediatric and Prenatal) and the sex of the participant. Ancestries depicted are American Indian, Native American (blue), Alaskan Native (Asian (orange), White/European (light blue), Middle Eastern/North African (green), Hispanic/Latino or Latina (dark blue), More than one race/ethnicity (brown), Unknown, none of the above (gray). A Pediatric patients, maternal ancestry. B Pediatric patients, paternal ancestry. C Prenatal patients, maternal ancestry. D Prenatal patients, paternal ancestry.

**Fig. 2. Diagnostic yield by sequencing approach in 845 patients enrolled in the Program in Prenatal and Prenatal Genomic Sequencing (P³EGS) study.**
The percentages of definitive positive (orange), probable positive (yellow), inconclusive (green) and negative (brown) results are shown for proband first, duo and trio sequencing approaches. There was no statistically significant difference in diagnostic yield with any sequencing approach. A Diagnostic yield with ‘proband first’ sequencing in pediatric patients. B Diagnostic yield with duo sequencing in pediatric patients. C Diagnostic yield with trio sequencing in pediatric patients. D Diagnostic yield with ‘proband first’ sequencing in prenatal patients. E Diagnostic yield with duo sequencing in prenatal patients. F Diagnostic yield with trio sequencing in prenatal patients.

See this image and copyright information in PMC

References

1. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv. Exp. Med. Biol. 2010;686:349–364. - PubMed
1. Alwan A, Modell B. Recommendations for introducing genetics services in developing countries. Nat. Rev. Genet. 2003;4:61–68. - PubMed
1. Christianson A, Modell B. Medical genetics in developing countries. Annu Rev. Genomics Hum. Genet. 2004;5:219–265. - PubMed
1. Kingsmore SF, et al. Next-generation community genetics for low- and middle-income countries. Genome Med. 2012;4:25. - PMC - PubMed
1. Srivastava S, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet. Med. 2019;21:2413–2421. - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources