Beyond Individual Carrier Status: A Systematic Review of Couple-based Genomic Risk Stratification Using Next-generation Sequencing in Preconception Care
Aloysius Suryawan, Wiku Andonotopo, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Rizna Tyrani Rumanti, Roland Frederik Lengkey, Julia Windi Gunadi, Arief Setiawan, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, I. Nyoman Hariyasa Sanjaya, Dudy Aldiansyah, Waskita Ekamaheswara Kasumba Andanaputra
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BSTRACT
Those familiar with the burgeoning field of expanded carrier screening will recognize that it has already advanced quickly with the advent of next-generation sequencing. However, its interpretation remains firmly rooted in the individual – a concept whose applicability is often inadequate in practice, given that choices are made more commonly by couples than individuals. This systematic review was performed in order to analyze how couple-based genomic interpretation alters risk stratification in the preconception period. A systematic search through key databases yielded 1248 records, and 42 studies met prespecified eligibility criteria after rigorous screening and full-text review as advised by Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020. Across diverse study designs and populations, a common theme emerges: the clinical utility of screening does not reside simply in detecting carriers, but rather in identifying couples at risk, a distinction that is subtle in theory, but impactful in practice. Investigations of expanded panels, exome, and genome sequencing have shown high detection capability, but also highlighted ongoing uncertainties regarding residual risk and variants of uncertain significance. Notably, couple-based genomic findings were found in several reports to be a stronger driver of reproductive decisions – spanning preimplantation genetic testing to conceived planning – than individual carrier status alone. Meanwhile, as tests multiply, the need for interpretation becomes more complex and requires a counseling infrastructure sparsely distributed among healthcare systems. Combined, the evidence suggests an emerging shift: Genetic risk, at least in the context of reproduction, might be better understood as a characteristic of the couple rather than that of an individual. This reframing has implications not only for clinical workflows, but policy, ethics and the future design of screening programs.