The Genomic Infinity Loop

The loop of Henle is a model of biologic efficiency: Its counter-current architecture concentrates solutes and conserves water through a self-reinforcing system. In recent years, an analogous self-reinforcing structure has emerged in genomic medicine, where clinical data, sequencing, interpretation, and reanalysis form a dynamic, iterative cycle. In the United Kingdom, two flagship initiatives—the National Institute of Health Research (NIHR) BioResource and the 100,000 Genomes Project—exemplify this genomic infinity loop and have helped embed whole genome sequencing (WGS) within routine care while catalyzing research. What began as research infrastructure has evolved into a national system enabling bidirectional flow between discovery and diagnosis, phenotype and genotype, and bench and bedside—a system that, like the nephron, gains power through iteration.

In the mid-2000s, the development of massively parallel, or Next Generation DNA Sequencing (NGS) dramatically reduced the cost and time required to sequence a human genome: from approximately $100 million in 2001 to <$5000 by the early 2010s. In parallel with, and subsequently catalyzed by, these advances, the identification of genes responsible for Mendelian kidney diseases—initially through classical linkage studies—accelerated rapidly. Among nephrologists, the importance of inherited kidney diseases (beyond Alport syndrome and autosomal dominant polycystic kidney disease) was already well recognized, but this era of gene discovery defined numerous further distinct genetic kidney diseases and expanded the role of molecular genetics in nephrology by revealing the wide burden of genetic kidney disease.

Recognizing the transformative potential of genomics across clinical specialties, the UK Government established the Human Genomics Strategy Group in 2010. Its key 2012 report, Building on Our Inheritance,¹ together with the Department for Business, Innovation and Skills's Strategy for UK Life Sciences,² laid the groundwork for national-scale genomic initiatives.

Two major programs emerged from this strategic vision. The first, the NIHR BioResource for Rare Diseases, aimed to support research-based genomic sequencing and recall-by-genotype. It recruited approximately 10,000 patients with rare diseases through specialist centers and existing research networks.³ The second was the 100,000 Genomes Project, which was delivered by Genomics England Limited (GEL), a company wholly owned by the Department of Health and tasked with “delivering the benefits of genomic healthcare to everyone.” Its goal was to integrate WGS into routine National Health Service (NHS) care across rare diseases, cancer, and infectious disease.⁴ The vision was to establish both the infrastructure and evidence base for nationwide genomic medicine.

In nephrology, the NIHR BioResource included steroid-resistant nephrotic syndrome and primary membranoproliferative GN/C3 glomerulopathy, with recruitment and phenotype data collection through the National Registry for Rare Kidney Disease. For the 100,000 Genomes Project, GEL established Genomics England Clinical Interpretation Partnerships (GeCIPs) to bring together specialty-specific expertise to guide eligibility criteria, phenotyping, and interpretation. The Renal GeCIP, comprising over 100 clinicians, researchers, and patient representatives, helped shape inclusion criteria for kidney disease. Initially, these were narrowly defined, but consensus within the Renal GeCIP enabled the case to be made to the GEL Scientific Advisory Board for broader inclusion. This process enabled recruitment of large numbers of patients with cystic and developmental kidney disorders across the spectrum of clinical severity, and individuals with unexplained kidney failure younger than 50 years, reflecting the likely contribution of undiagnosed monogenic conditions to kidney failure in this population. Ultimately, kidney disease—perhaps owing to the accessibility to recruiting clinicians of people receiving KRT—became the second largest recruiting rare disease domain in the project, after intellectual disability, with over 3500 participants.

Both flagship programs used the same short-read clinical grade WGS platform, structured phenotype recording using manually inputted human phenotype ontology (a standardized, hierarchically organized vocabulary for describing clinical features and phenotypic abnormalities amenable to computational analysis) terms, and automated linkage to Hospital Episode Statistics (capturing all secondary care encounters) and hospital laboratory data. WGS offers superior diagnostic yield by enabling comprehensive detection of variant types—such as structural variants, missense, and noncoding alterations—that can be missed by exome sequencing or gene panels. This integration enabled association analyses, with downstream laboratory investigations augmenting diagnostic yield and supporting the elucidation of mechanisms underlying novel gene–disease associations. This study design has been represented graphically as an “infinity loop”³ to capture the bidirectional flow between clinical data and genomic-driven discovery, as well as the potential for a genetic diagnosis to unmask previously unsuspected phenotypes or risks, e.g., cancer risk revealed by a diagnosis of WT1-associated glomerulopathy. In the 100,000 Genomes Project, the “infinity loop” design was similar, but the scope was broader and the recruitment and sample processing pipeline (operational in >75 NHS hospitals) was clinically accredited, allowing the results to be returned to participants and integrated into clinical care. Crucially, this embedded the consent processes and clinical infrastructure needed to deliver genomic medicine at scale across the NHS.

For clinical reporting, a “virtual gene panel” approach was used: for each disease, syndrome, or phenotype under investigation in a participant, variants in a curated set of relevant genes were filtered and interpreted according to clinical guidelines. To facilitate this, Genomics England developed and maintains PanelApp (https://panelapp.genomicsengland.co.uk), a public, crowd-sourced, expert-reviewed platform to adjudicate genes. This structure is complemented by other efforts globally, including PanelApp Australia (https://panelapp-aus.org) and ClinGen (https://www.clinicalgenome.org). In both the NIHR BioResource and 100,000 Genomes Project, multidisciplinary teams (comprising molecular laboratories, clinical genetics, and disease specialists) adjudicated potentially reportable findings since, when an entire genome of a patient is analyzed, a very high degree of confidence is needed to action a variant clinically (i.e., is not simply an innocent bystander).

Together, these programs have driven numerous advances in rare disease genomics, with scores of publications.^3,5–8 In nephrology, examples include identifying and quantifying the association of monoallelic IFT140 variants with cystic kidney disease,^9,10 and the diagnostic yield of 17% for WGS in <50-year-olds with unexplained kidney failure.¹¹ This evidence, alongside other initiatives globally, informed the incorporation of WGS into the NHS Genomic Medicine Service, where, since 2020, it has become a funded clinical test especially in nephrology.

All patients undergoing clinical WGS within the Genomic Medicine Service are offered participation in the UK National Genomic Research Library. With consent, genomic and linked clinical data are made available to approved researchers within GEL's secure research environment. To maximize this national resource, GEL has formed eight research communities (https://www.genomicsengland.co.uk/research-network-communities) spanning bioinformatics and machine learning, statistical genetics, and therapeutic innovation. These networks replaced the previous organ-based GeCIPs and aim to stimulate collaborations across (rather than within) individual specialties, thus completing what former GEL chief executive Chris Wigley termed the “infinity loop” structure of UK genomics (Figure 1).

Figure 1.

The genomic infinity loop. Illustrates how the NHS GMS integrates clinical care (red)—including patient consent, structured phenotype capture (using HPO codes) and hospital record data, WGS, clinical interpretation by a MDT, and reporting—to deliver diagnoses, with research (blue) through the NGRL. Research use of deidentified genomic data enhances diagnostic yield (with novel findings, once established to be clinically actionable, fed back to reidentified participants through MDT review) and provides mechanistic insights that can drive the development of new therapies, which can then be evaluated in the clinic. Adapted from Chris Wigley's 2023 blog post (https://www.genomicsengland.co.uk/blog/10-highlights-10-years), with permission. GMS, Genomic Medicine Service; HPO, human phenotype ontology; MDT, multidisciplinary team; NGRL, National Genomic Research Library; NHS, National Health Service; WGS, whole genome sequencing.

Ongoing initiatives leveraging this infrastructure include the Generation Study—a pilot assessing WGS in 100,000 newborns to inform NHS policy on population genomic screening. Kidney diseases, from Alport syndrome to Wilms tumor predisposition syndrome, feature among the reportable conditions, and their (presymptomatic) early diagnosis already has implications for pediatric nephrologists, parents, and geneticists.

With the integration of genomic technologies into routine care, the NHS has entered a new era of personalized medicine that is proving especially relevant to patients with kidney diseases—for instance by informing prognostication in Alport syndrome and tolvaptan treatment decisions in autosomal dominant polycystic kidney disease. These efforts have inspired other initiatives, including Genomics Australia, Genomic Medicine France 2025, and the Saudi Genomics Program, and are well complemented by international population-scale biobanks such as UK BioBank, FinnGen, and All of Us (which are large but not enriched for patients with rare diseases). As research and clinical care become increasingly intertwined, the infrastructure, datasets, and national networks now in place offer unprecedented opportunities: to understand, diagnose, and treat rare diseases with ever greater precision and to bring trials of novel ribosome-directed, mRNA-directed, or DNA-directed therapies targeting highly specific and ultrarare patient groups into the realm of feasibility. The challenge, and opportunity, ahead lies in ensuring that these advances are equitably implemented, continually evaluated, and translated into tangible benefits for patients of all ages and across all specialties.

Supplementary Material

jasn-37-613-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F496.

Author Contributions

Conceptualization: Daniel P. Gale.

Visualization: Daniel P. Gale.

Writing – original draft: Daniel P. Gale.

Writing – review & editing: Melanie M.Y. Chan, Omid Sadeghi-Alavijeh.

Funding

D.P. Gale: St Peter’s Trust for Kidney Bladder and Prostate Research. O. Sadeghi-Alavijeh: Medical Research Council (MR/S021329/1).