Genetic ancestry and diagnostic yield of exome sequencing in a diverse population

Yusuph Mavura; Nuriye Sahin-Hodoglugil; Ugur Hodoglugil; Mark Kvale; Pierre-Marie Martin; Jessica Van Ziffle; W Patrick Devine; Sara L Ackerman; Barbara A Koenig; Pui-Yan Kwok; Mary E Norton; Anne Slavotinek; Neil Risch

doi:10.1038/s41525-023-00385-6

Genetic ancestry and diagnostic yield of exome sequencing in a diverse population

NPJ Genom Med. 2024 Jan 3;9(1):1. doi: 10.1038/s41525-023-00385-6.

Authors

Yusuph Mavura^{1

2}, Nuriye Sahin-Hodoglugil³, Ugur Hodoglugil³, Mark Kvale³, Pierre-Marie Martin³, Jessica Van Ziffle^{3

4}, W Patrick Devine^{3

4}, Sara L Ackerman^{5

6}, Barbara A Koenig^{3

7}, Pui-Yan Kwok^{3

8}, Mary E Norton^{3

9}, Anne Slavotinek^{3

10}, Neil Risch^{11

12}

Affiliations

¹ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Yusuph.Mavura@ucsf.edu.
² Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. Yusuph.Mavura@ucsf.edu.
³ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁵ Institute for Health & Aging, School of Nursing, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Social & Behavioral Sciences, School of Nursing, University of California San Francisco, San Francisco, CA, USA.
⁷ Program in Bioethics, University of California San Francisco, San Francisco, CA, USA.
⁸ Cardiovascular Research Institute and Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
⁹ Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Neil.Risch@ucsf.edu.
¹² Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. Neil.Risch@ucsf.edu.

Abstract

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

Abstract

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