Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines

Abstract

Purpose: Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk. Methods: For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data. Results: Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in atrisk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve. Conclusion: Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

“…Evaluation of genetic syndromes in diverse populations is essential for syndrome recognition and diagnosis (Koretzky et al, 2016; Kruszka et al, 2019). A limitation of our study is individuals self‐reported ancestry (Kaseniit et al, 2020). Genetically defined ancestry would have been more accurate, but was outside the scope of this investigation (Wang et al, 2015).…”

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)

“…Importantly, those who self-identify with a specific race/ ethnicity may be at odds with ancestry defined genetically, which is of relevance to carrier screening. 11,12 A recent report demonstrated that relying on self-identification of AJ ancestry as a criteria to screen for conditions common in the AJ population is imperfect. 13 It is important that carrier screening goes beyond commonly recognized at-risk groups and includes diverse populations.…”

Fetal screening and whole genome sequencing: where are the limits?

“…For example, a panel that detects the 23 most common CFTR pathogenic variants fails to identify nearly three-quarters of affected pregnancies in Hispanic persons compared to full sequencing of the gene with deletion and duplication analysis (8). Similarly, reduced costs of sequencing have allowed for much broader lists of genes that can be screened, no longer limiting the identification of at-risk couples to only those of certain ethnicities for small sets of conditions historically thought-often incorrectly-to be most prevalent in those ethnicities (9,10). At present, ACOG recognizes both ethnicity-based screening and expanded carrier screening (offered without regard ethnicity) as acceptable options for carrier screening.…”