For couples experiencing recurrent pregnancy loss or difficulty conceiving, the search for answers can become an exhausting and painful journey. Many spend years moving through appointments, tests, and inconclusive results, often without a clear explanation for what they are experiencing. Genetic testing can add another layer of uncertainty, with multiple assays ordered one after another, each examining only a small part of the genome.
This reality is what initiated the founding of the HiFi Solves Sub-fertility Consortium in Asia Pacific. Through this collaboration, researchers and clinicians across Singapore, South Korea, Taiwan, and Thailand are working together to better understand the complex genetics behind recurrent pregnancy loss and unexplained infertility, with the goal of exploring whether a more comprehensive genomic approach could help reduce the long series of fragmented tests many couples undergo while searching for answers.
As global collaborations like this continue to grow, advances in long-read sequencing are making it possible to study regions of the genome that have historically been difficult to resolve, while capturing many different forms of genetic variation through a single workflow. Click below to explore the technology helping researchers build a more complete picture of human health and discover introductory resources to learn more.
Genetic insights into unexplained infertility
Difficulty conceiving affects millions of people worldwide, yet for many couples, the underlying cause remains unknown even after extensive evaluations. Subfertility, defined as any form of reduced fertility with prolonged time to conception1, affects approximately one in six people globally, while recurrent pregnancy loss affects 1 to 2% of women worldwide2.
Genetic factors are believed to contribute to up to 30% of male and female subfertility cases3⁻5, but identifying those genetic causes is often far from straightforward. Traditional testing workflows can involve multiple separate assays including karyotyping, chromosomal microarrays, Fragile X testing, and panel or exome sequencing. Each test provides only part of the picture, which can leave important variants unresolved or missed entirely.
In its first major study, the HiFi Solves Sub-fertility Consortium explored whether long-read whole genome sequencing could provide a more complete genomic view in a single assay while helping reduce the emotional, financial, and logistical strain of fragmented testing workflows.
A collaborative long-read sequencing approach
The study included 84 individuals across institutions in Singapore, South Korea, Thailand, and Taiwan who underwent PacBio HiFi whole genome sequencing. Participants included couples with unexplained difficulty conceiving lasting at least one year or recurrent pregnancy loss after standard evaluations had already ruled out known causes.
Researchers used a standardized analysis workflow across participating sites, enabling consistent analysis while securely managing data locally through a federated framework hosted by DNAstack.
Because reproductive genetics often involves contributions from both partners, the study analyzed genomic variation across couples rather than individuals alone. HiFi sequencing enabled researchers to assess multiple variant classes from a single assay, including SNVs, structural variants, copy number variants, repeat expansions, and phased variants.
Long-read sequencing insights in reproductive genetics
Even in a cohort where previous testing had already ruled out known causes, HiFi sequencing identified clinically relevant findings in approximately 1 in 10 couples. Likely diagnostic findings were identified in 4.8% of sequenced individuals, while additional variants of uncertain significance in 14.2% of individuals may help guide future research.
The study also highlighted the value of generating multiple layers of genomic insight from a single assay. In some individuals, long-read sequencing helped rule out additional rare variants without requiring further follow-up testing. In another case, HiFi comprehensive phasing enabled researchers to determine that two disease-causing variants were located on the same allele, helping provide clearer insight while reducing the need for additional investigations during an already difficult journey.
Beyond the primary reproductive phenotype, researchers also identified carrier status and actionable secondary findings through the same dataset, highlighting the broader value of a comprehensive genome approach. Importantly, comprehensive negative findings also carried value. For couples without candidate variants, more confidently ruling out known genetic causes may help inform future clinical decisions and redirect focus toward other possible explanations.
The future of reproductive genetics research
The consortium’s first publication adds to growing evidence that HiFi sequencing can help researchers study complex reproductive genetics through a more complete and connected approach. As the consortium expands recruitment across additional Asia-Pacific centers and explores broader multiomic strategies, researchers hope to continue uncovering genetic contributors that may otherwise remain unresolved through conventional testing pathways.
For couples searching for explanations, the promise of a single comprehensive genome assay is not only about efficiency. It is about the possibility of reducing uncertainty, potentially shortening long diagnostic journeys, and building a clearer understanding of conditions that are often deeply personal and emotionally challenging.
HiFi sequencing is helping drive that shift by enabling researchers to capture many forms of genomic variation in a single workflow, including regions of the genome that have historically been difficult to study. Click below to explore the technology behind these discoveries and learn how HiFi long-read sequencing is helping researchers uncover what was previously out of reach.
¹ Gnoth, C., Godehardt, E., Frank-Herrmann, P., Friol, K., Tigges, J., & Freundl, G. (2005). Definition and prevalence of subfertility and infertility. Human reproduction, 20(5), 1144-1147. https://doi.org/10.1093/humrep/deh870
² World Health Organization. (2023). Infertility prevalence estimates, 1990–2021. World Health Organization. https://www.who.int/publications/i/item/978920068315
³ El Hachem, H., Crepaux, V., May-Panloup, P., Descamps, P., Legendre, G., & Bouet, P. E. (2017). Recurrent pregnancy loss: current perspectives. International journal of women’s health, 331-345. https://doi.org/10.2147/IJWH.S100817
⁴ Veltman, J. A., & Tüttelmann, F. (2024). Why geneticists should care about male infertility. Nature Reviews Genetics, 25(12), 823-824. https://doi.org/10.1038/s41576-024-00773-3
⁵ Krausz, C., Rosta, V., Swerdloff, R. S., & Wang, C. (2022). Genetics of male infertility. Emery and rimoin’s principles and practice of medical genetics and genomics, 121-147. https://doi.org/10.1016/B978-0-12-815236-2.00010-2