Nature Medicine, Published online: 24 June 2026; doi:10.1038/s41591-026-04477-5
Talos, a new tool for the automated analysis of genomic data, demonstrates the feasibility and diagnostic utility of systematic reanalyses of data in rare diseases.
Nvidia Unveils Science Reasoning AI Suite with BioNeMo Agent Toolkit
Nvidia has announced the NVIDIA BioNeMo Agent Toolkit, which turns complex scientific workflows into agent-executable tasks, including model selection, input preparation, workflow execution, output inspection, and results explanation.
The toolkit includes NVIDIA BioNeMo and is powered by NVIDIA NIM microservices, NVIDIA Parabricks, NVIDIA NeMo, and NVIDIA Nemotron and has applications across protein structure prediction, molecular docking, generative chemistry, genomic analysis, protein design, and biomarker discovery.
“For the first time, researchers can build AI agents that understand scientific knowledge, use scientific tools, and execute scientific workflows,” said Jensen Huang, founder and CEO of Nvidia, in a press release. “This is a new way to do science—one that can dramatically accelerate discovery across biology, chemistry, genomics, and medicine.”
Nvidia has entered collaborations with research organizations, including the Arc Institute, Open Molecular Software Foundation, and the University of Washington’s Institute for Protein Design (IPD). The partnership with IPD has accelerated runtimes for the biomolecular complex prediction tool, RosettaFold3, resulting in two times faster performance than the prior generation model.
“Every tool we’ve built for protein design is only as powerful as the scientists who can efficiently access it,” said David Baker, PhD, professor of biochemistry at the University of Washington and director of the Institute for Protein Design, in a public release. “The next leap in science won’t come from a single discovery; it will come from the speed of iterative designs and agents that can repeatedly reason through the complexity of biology at a speed humans never could.”
The toolkit’s applications include virtual screening, where agents identify promising small-molecule drug candidates by generating compound designs, docking them to a target, predicting binding strength, and filtering for developability properties. The agent can then output which candidates should be prioritized to compress timelines.
In genomic analysis and target discovery, agents can identify genetic insights and biological targets from raw sequencing data. Agents can also connect real-world data to reasoning models for biomedical research, improving the efficiency and accuracy of clinical development processes, including literature review, protocol generation, clinical trial screening, and pharmacovigilance. In medical imaging analysis, agents can process, segment, synthesize, and reason over medical imaging data to support biomarker discovery.
AI-native biology companies, including Boltz, Basecamp Research, Chai Discovery, PerturbAI, Dyno, and Proxima, have collaborated with NVIDIA to develop tools to accelerate therapeutic design workflows. Diagnostics and pharmaceutical companies, including Lilly and Natera, are using BioNeMo Agent Toolkit to scale agentic workflows across discovery, translational research, and clinical insight.
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Dynamic changes of gut microbiota during progression of three Alzheimer’s disease mice models
IntroductionAlzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder characterized by cognitive impairment and irreversible neuronal degeneration, affecting approximately 55 million individuals worldwide. Despite extensive research efforts, the underlying pathogenic mechanisms of AD remain incompletely understood, and effective therapeutic strategies for preventing or delaying disease progression are still lacking. Increasing evidence suggests that the microbiota-gut-brain axis plays an important role in neurodegenerative diseases, including AD. However, the dynamic alterations of gut microbiota during AD progression across different transgenic mouse models remain poorly characterized.MethodsIn the present study, we investigated age-dependent changes in gut microbiota composition in three commonly used AD mouse models, including APP/PS1, 3xTg, and 5xFAD mice, using 16S rRNA gene sequencing. Fecal samples were collected longitudinally at 2, 4, 6, and 8 months of age to evaluate microbial diversity, community structure, and differential bacterial taxa during aging and disease progression.ResultsOur results demonstrated distinct and model-dependent alterations in gut microbiota composition across different stages of AD progression. Significant changes in microbial diversity and bacterial community structure were observed among the three AD mouse models and wild-type controls. In particular, dynamic alterations in Verrucomicrobiota, Proteobacteria, and Actinobacteriota were consistently identified during aging in AD mice. In addition, β-diversity, Linear discriminant analysis effect size (LEfSe), and correlation network analyses further revealed differential microbial signatures associated with different AD mouse models and age stages.DiscussionOverall, our findings provide additional evidence that gut microbiota composition undergoes dynamic alterations during aging in multiple AD mouse models and may be associated with AD-related progression. This study may contribute to a better understanding of microbiota-associated changes during AD development and provide a basis for future mechanistic studies targeting the microbiota-gutbrain axis in AD.
Merck, Protillion Launch AI Drug Discovery Collaboration with Up-to-$510M in Milestone Payments
Merck & Co. will partner with Protillion Biosciences to discover multiple new therapy candidates through a collaboration that could generate up to $510 million in milestone payments for the artificial intelligence-based drug design company whose “lab-in-the-loop” approach combines AI with a continuous feedback loop of experimental wet-lab data.
The collaboration, launched through a multi-target discovery collaboration and license agreement, is designed to combine Merck’s global expertise in discovering novel therapeutics with Protillion’s Prot-MaP
on-chip antibody discovery platform.
Prot-MaP, short for Protein Display on a Massively Parallel Array, is designed to facilitate AI-based optimization of therapeutic antibodies through the quantitative analysis of protein libraries with unprecedented speed, scale, and precision, characterizing millions of variants per run and avoiding the common pitfalls of model overfitting.
The result, according to Protillion, is the identification of optimized biologics with sophisticated therapeutic profiles such as pH-dependent sweeping and multi-target specificity—profiles that are difficult to achieve with traditional methods.
Protillion says Prot-MaP is intended to enable the engineering of novel biologics by generating megascale, just-in-time quantitative antibody binding datasets for protein design AI. The platform enables the generation of tens of millions of clusters of immobilized proteins directly on an Illumina DNA sequencing flow cell through efficient tethered in situ transcription and translation.
Prot-MaP was invented by the company’s CEO and co-founder, Curtis Layton, and co-founder Will Greenleaf, PhD, a professor of genetics at Stanford University School of Medicine and a member of Protillion’s Scientific Advisory Board. After receiving his PhD in computational biology from Duke University, Layton studied with Greenleaf as a postdoctoral fellow in the genetics department at Stanford Medicine.
Layton developed Prot-MaP while working in Greenleaf’s lab, then organized Protillion in 2019 to commercialize the technology. Layton’s work pioneered a new approach to high-throughput interrogation of biochemical systems, tackling ultra-high-impact technology approaches for drug discovery by uniting fields that included protein engineering, next-generation sequencing technology, molecular biology, in vitro transcription and translation, computational biology, software development, and various engineering disciplines.
Days rather than months
“Prot-MaP is a technology platform that allows us to test millions of protein interactions simultaneously, generating an unprecedented amount of data in a matter of days rather than months. For example, we can rapidly evaluate large libraries of therapeutic protein candidates to see how they bind to different targets and how they behave under different biological conditions,” Robert Hollingsworth, PhD, Protillion’s CSO, told GEN.
“We then combine that data with proprietary AI and machine learning tools to understand what drives the best-performing proteins and quickly design improved candidates. This gives us the ability to engineer antibodies with highly specific characteristics, such as stronger and more precise target binding, the ability to engage multiple targets, or the ability to activate only under certain physiological conditions,” Hollingsworth explained. “In practical terms, Prot-MaP helps us discover and optimize better drug candidates faster, with a level of insight and precision that has not previously been possible at this scale.”
Prot-MaP allows Protillion to test up to one million protein variants simultaneously in a single experiment and generate results in as little as 48 hours.
“Because we operate multiple proprietary platforms in parallel, we can rapidly scale that capability and generate enormous amounts of experimental data on demand,” Hollingsworth explained.
What makes Prot-MaP unique, he continued, is not just its scale, but its combination of scale, speed, and AI.
“The platform is designed to seamlessly connect high-throughput protein testing with proprietary machine learning models, allowing us to quickly identify promising drug candidates, understand what makes them work, and design improved versions,” Hollingsworth said. “This enables us to tackle everything from discovering entirely new therapeutic molecules to optimizing existing candidates for multiple desired characteristics. In practical terms, Prot-MaP helps us find and develop better biologic medicines faster and more efficiently than traditional approaches.
Opposite approach
How does Prot-MaP overcome the complexity of protein molecules, which has long been a hurdle in protein and biologics design?
“Many companies start with AI and then look for data. We took the opposite approach,” Hollingsworth said.
Rather than relying primarily on computer predictions of protein structure, he elaborated, Protillion can apply Prot-MaP to directly generate large-scale functional data and identify the best therapeutic candidates based on real-world experimental results.
“What makes this especially powerful is the sheer scale of the data we can generate. While much of the industry has focused on applying AI to relatively limited biological datasets, we believe that the biggest challenge in drug discovery is obtaining enough high-quality data to truly understand the complexity of protein function. Prot-MaP was built to solve that problem,” Hollingsworth said.
By generating millions of protein measurements in parallel, Protillion says, it can create the kind of rich, large-scale datasets needed to train more powerful and predictive machine learning models. Those models, in turn, help design and optimize better therapeutic candidates faster and with greater precision.
“Prot-MaP combines high-throughput experimentation with AI. The platform allows us to rapidly generate the data, and the AI helps us learn from it—creating a cycle that accelerates the discovery of next-generation biologic medicines,” Hollingsworth said.
Speaking with GEN, Layton said Protillion and Merck have charted a course for the start of their drug discovery collaboration.
“Our first two programs focus on inflammatory diseases, where we see significant unmet medical need and strong opportunities for differentiation,” he said.
Immune-mediated inflammatory disorders are Merck’s specialty within its therapeutic area of focus in immunology. Merck focuses on several other therapeutic areas, which include oncology, vaccines, infectious diseases, cardiometabolic and respiratory diseases, neuroscience, and ophthalmology.
“However, the Prot-MaP platform’s capabilities extend far beyond inflammation, enabling the discovery and development of novel biologics across a broad range of therapeutic areas,” Layton added. “As we continue to advance the platform, we expect to expand into additional disease areas where its unique capabilities can have the greatest impact.”
Tech-focused pipeline collaborations
Merck has launched several tech-focused pipeline collaborations in recent months aimed at replenishing its cancer and immunology pipelines, with the goal of developing new therapies that can recoup the billions of dollars in sales the pharma giant will lose as patent exclusivity expires in the United States and elsewhere for its aging blockbusters, including cancer immunotherapy Keytruda® (pembrolizumab) and Gardasil® 9 (Human Papillomavirus 9-valent Vaccine, Recombinant).
In March, Merck inked an up-to-$2.2 billion collaboration with Quotient Therapeutics to apply Quotient’s somatic genomics platform to discover novel drug targets in inflammatory bowel disease (IBD). Also that month, Merck launched a partnership with Infinimmune to apply its Anthrobody® discovery platform and GLIMPSE antibody language model to identify and develop antibody candidates against multiple undisclosed Merck-designated targets. Merck agreed to pay Infinimmune an undisclosed upfront payment and up to $838 million in milestone payments.
Merck has also launched several tech-focused partnerships, with partners that include:
- Google Cloud—An up-to-$1 billion collaboration announced in April to deploy an agentic platform across Merck’s R&D, manufacturing, commercial, and corporate functions. Google Cloud engineers are working alongside Merck teams to deploy Google Cloud’s most sophisticated AI, including Gemini Enterprise.
- Tempus AI—An expanded, multi-year collaboration of undisclosed value announced in March, aimed at accelerating discovery and development of precision medicine biomarkers, and supporting Merck’s oncology and potentially broader therapeutic portfolios.
- Mayo Clinic—An R&D agreement of undisclosed value to apply AI, advanced analytics, and multimodal clinical data to support drug discovery and development. The agreement integrates Mayo Clinic’s Platform architecture, as well as clinical and genomic datasets, with Merck’s ambition of harnessing AI-enabled virtual cell technologies to enhance disease understanding, improve target identification, and drive early development decisions.
In its latest collaboration, Merck has agreed to pay Protillion an undisclosed upfront payment, plus up to $510 million in payments tied to achieving research, development, and commercial milestones toward the successful development of an unspecified number of therapies.
“Compelling opportunity”
“Powerful emerging technologies offer the potential to transform the speed and precision with which we characterize protein landscapes and identify novel therapeutic candidates,” Juan Alvarez, PhD, vice president, discovery biologics at Merck Research Laboratories, said in a statement. “Protillion’s platform offers a compelling opportunity, and we look forward to working with the team to advance these programs.”
Illumina’s venture capital arm, Illumina Ventures, is among investors in Protillion, having joined ARCH Venture Partners in 2022 to co-lead an $18 million financing in 2022.
Based in Carlsbad, CA, Protillion has grown rapidly to a workforce of 30 people. In March, Protillion hired Robert Hollingsworth, PhD, a drug development executive with more than 30 years’ experience in biopharma, as CSO through a placement by executive search firm CollectiveMinds. Before joining Protillion, Hollingsworth was CSO at Shoreline Therapeutics, and earlier held positions in companies that included Pfizer (as vp and CSO of cancer vaccines and immunotherapeutics), Pharmacia & Upjohn (since absorbed into Pfizer), GlaxoSmithKline (GSK), and MedImmune (acquired by AstraZeneca).
Protillion says it is continuing to expand its team and facilities, with the aim of supporting its internal pipeline and high-value strategic partnerships.
“We plan to hire six more FTEs [full-time equivalents] by the end of the year,” Layton said.
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Single-Cell RNA Sequencing Reveals Gene Activity Changes in Crohn’s Disease
Researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust (CUH), and Open Targets have created a detailed cellular study of Crohn’s disease (CD), mapping how gene activity changes across more than 50 cell types in the gut. (Founded in 2014, Open Targets is a pre-competitive, public-private partnership that uses human genetics and genomics data to systematically identify and prioritize drug targets.)
Co-led by Tim Raine, MD, PhD, consultant gastroenterologist at Cambridge University Hospitals NHS Foundation Trust, the team analyzed over a million gut cells from people with Crohn’s and from healthy controls, comparing changes in the gut lining and identifying immune cells that drive inflammation. The resulting single cell RNA-sequencing (sc-RNA-seq) resource, IBDverse, characterizes each cell type and those whose activity shifts in disease, uncovering new molecular and cellular signatures of immune activity in the gut lining.
Co-first author Monika Krzak, PhD, formerly at the Wellcome Sanger Institute and now based at the Institute of Metabolic Science, University of Cambridge, said, “Crohn’s disease is complex, variable and deeply personal to every individual living with it, which is why understanding it at the level of single cells is so important. By creating this unprecedented map of more than one million gut cells, we are giving researchers around the world a powerful new tool to uncover how inflammation begins, persists and may one day be stopped. This is the kind of open science that can accelerate discoveries and bring us closer to better treatments for patients.”
Raine added, “There is an urgent need for increased understanding of the biology of Crohn’s disease if we are to develop more effective and safe medications for people living with this condition. The patients who contributed to this research have helped us build insight into the different ways that gut function and immune function are disrupted in the disease, and with the insight comes immediate new avenues for drug development and targeted therapies.”
Reported in Nature Genetics (“Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis,”) the research revealing the cell types and molecular changes involved in Crohn’s inflammation is one of two complementary studies—the other a paper recently published in Nature—built on IBDverse to investigate different aspects of the disease.
In their newly published report the team concluded, “These findings establish a comprehensive cellular and molecular framework for CD, offering insights into disease mechanisms and therapeutic opportunities.”
Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that cause chronic inflammation of the gastrointestinal tract. Over half a million people in the U.K. are estimated to be living with IBD, which includes Crohn’s disease and ulcerative colitis.
Crohn’s is a chronic condition that causes inflammation and ulcers in the digestive tract, from the mouth to the anus, often affecting the small intestine and colon. However, the authors noted, “Although inflammation is most commonly observed in the terminal ileum, CD exhibits substantial heterogeneity in disease location, severity and behavior, both between patients and within patients, over time.”
Although inflammation is most commonly observed in the terminal ileum—the final section of the small intestine—Crohn’s is found in many locations of the body and with variation in severity both between patients and within patients over time.
While therapies targeting immune cells have improved clinical outcomes for some patients, non-response to treatment remains high, with 15% of Crohn’s patients requiring surgery within five years of diagnosis. Consequently, there is an urgent need to better understand the etiology of CD in order to broaden therapeutic opportunities,” the investigators stated.
For their newly reported study the researchers took and analyzed biopsies from 111 patients with Crohn’s and a history of current or previous terminal ileitis—inflammation of the ileum—and 232 healthy volunteers. The team performed single-cell RNA sequencing to measure gene expression in individual cells. “Single-cell RNA sequencing (scRNA-seq) technologies provide a high-throughput means to dissect complex tissues at the resolution of single cells and cell types,” they noted.
By creating a comprehensive map of cellular and molecular differences in Crohn’s compared to healthy controls, the researchers established IBDverse as a result—an online data resource of over 1,185,000 cells isolated from small intestine samples. The large IBDverse dataset will serve as an open resource for future research.
Using the data, the scientists identified genes that are abnormally expressed in Crohn’s and those where expression is specific to given cell types and cellular processes.
One of the study’s most striking findings was a ‘molecular scar’ in the gut lining. Even after visible inflammation had healed, genes that help send messages to the immune system stayed switched on in the gut’s stem cells—the cells that constantly renew the lining. This suggests that an episode of inflammation leaves a lasting mark on these cells, which may shape how the gut responds to inflammation in future. In their paper the authors noted, “We uncovered epithelial changes marked by interferon-driven upregulation of major histocompatibility complex class I molecules that persisted in progenitor cells after macroscopic inflammation resolution.”
The researchers also identified a population of macrophages—immune cells that engulf and digest cellular debris—with high expression of the gene ITGA4. These cells were key drivers of inflammation through the JAK/STAT pathway, which carries signals from the cell surface to the nucleus to switch genes on and off. “ITGA4+ macrophages were identified as key inflammatory drivers, showing enriched JAK–STAT signaling and cytokine expression (interleukin-6 (IL-6), IL-12 and IL-23),” the investigators stated. Drugs that block this pathway, known as JAK inhibitors, are already used to treat IBD, which points to these macrophages as a likely target of therapies.
Co-first author Tobi Alegbe, PhD, at the Wellcome Sanger Institute and Open Targets, said “For inflammatory bowel diseases like Crohn’s and ulcerative colitis, it’s still unclear what is going wrong in the gut cells to cause inflammation. We have been able to compare gut cells of hundreds of people with and without IBD. This has given us new insight into the genes and cell types that are involved during active disease, and lays the groundwork for similar approaches to understand diseases of other major organs like eczema and asthma.”
Co-senior author Carl Anderson, PhD, at the Wellcome Sanger Institute, said “What makes this study different is that we designed replication in from the start and found that even with hundreds of patients and standardized protocols, fewer than half of the gene expression changes we detected in one cohort replicated in the other. That’s a sobering finding for the field. The biology that did replicate consistently points to the gut lining itself as a key player in Crohn’s with a molecular signature in epithelial cells that persists even after inflammation has resolved. We don’t yet know what that persistence means, but it likely influences how the gut responds to future inflammatory insults.”
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STAT+: Verge Labs’ new AI model solves patient stratification problems for neurology clinical trials
As the saying goes, one man’s trash is another man’s treasure. Or as Verge Labs might put it, one company’s failed clinical trial … is that same company’s new AI benchmarking dataset.
Over a decade ago, Alice Zhang co-founded Verge Genomics with the idea that by looking at the network of genes causing neurodegenerative diseases like Parkinson’s, ALS, or Alzheimer’s, the company would be able to come up with better drugs. The company did target discovery work, for example, coming up with two targets that Eli Lilly nominated to its internal pipeline in 2024. Verge also had its own pipeline, where it was pursuing an ALS drug — that is, until its Phase 1b trial failed last month.
The company published a postmortem explaining what exactly went wrong with the trial, in which a third of the patients dropped out because they could not tolerate the drug. “While the temptation is strong, when a trial doesn’t meet the anticipated end points, to kind of look away and not talk about it, we think there are a lot of learnings that can come — not just for us, but for the field and for ALS broadly — that’s really important to share. That’s not done very often,” Zhang told STAT in an interview.
STAT+: Human Cell Atlas leader’s tie to 10x Genomics raises conflict-of-interest questions
A decade since its founding, the International Human Cell Atlas Consortium is hosting a high-profile meeting in Boston this week, with panels featuring more than two dozen prominent academics and biotech industry leaders, including Genentech’s Aviv Regev, David Altshuler of Vertex Pharmaceuticals, and Eric Lander from the Broad Institute. The event, which is expected to draw hundreds of scientists from across the globe, comes at an inflection point in the HCA’s ambitious aim to build a comprehensive reference map of all the different types of cells that make up a human body.
Later this year, the HCA expects to deliver a first draft — the completion of single-cell atlases across all of the major organs and tissues — that promise to boost researchers’ understanding of how the body works. So far the HCA has focused on building a reference of healthy cells and the genes they express. In its next phase, it plans to tackle disease, and that means amassing knowledge about where particular cells are located, who their neighbors are, and who they’re communicating with — a rapidly emerging field known as spatial biology.
It’s embarking on this expansion when the field is awash in new technology options from companies like Vizgen, Bruker, Illumina, Takara Bio, Bio-Techne, and 10x Genomics, a Bay Area company whose single-cell RNA sequencing technology was the workhorse of the HCA’s first phase. Scientists who want to join this effort will be faced with decisions about which commercially available solutions to use.
A novel de novo QRICH1 variant causing Ververi–Brady syndrome with infantile epileptic spasms syndrome: clinical and genetic analysis
ObjectiveThis study aims to investigate the clinical phenotype and genetic etiology of a case of Ververi–Brady syndrome (VBS) with infantile epileptic spasms syndrome (IESS) caused by a novel de novo variant in the QRICH1 gene.MethodsClinical data were retrospectively collected from a pediatric patient admitted to Hunan Children’s Hospital on July 28, 2025, due to intermittent nodding episodes for 10 days. Trio-based whole-exome sequencing (trio-WES) was performed for the proband and his parents. Candidate variants were validated by Sanger sequencing and assessed for pathogenicity. Relevant literature was reviewed to summarize genotype–phenotype correlations.ResultsThe patient, a 5-month-and-22-day-old male infant, presented with facial dysmorphism, global developmental delay, and IESS. After treatment with adrenocorticotropic hormone (ACTH) and vigabatrin, seizures were fully controlled and developmental outcomes improved. Trio-WES identified a novel heterozygous frameshift variant in the QRICH1 gene (NM_198880.3: c.1282dup, p. Gln428Profs*27), which was de novo and absent in both parents. According to the ACMG/AMP guidelines, this variant was classified as pathogenic (PVS1 + PS2 + PM2_Supporting). A literature review identified 11 relevant articles, encompassing a total of 46 patients (including the present case) with 41 distinct QRICH1 variants: 10 missense, 11 nonsense, 17 frameshift, and 3 splicing mutations. Common clinical features included developmental delay, nonspecific facial dysmorphism, hypotonia, autism spectrum disorder, epilepsy, and scoliosis.ConclusionQRICH1 variants underlie Ververi–Brady syndrome. Here we describe a patient with QRICH1-related Ververi–Brady syndrome presenting with IESS. Combined treatment with ACTH and vigabatrin was followed by seizure freedom, electroencephalographic (EEG) improvement, and developmental gains in this patient. This report expands the genotypic and phenotypic spectrum of the disorder.
Long-Read DNA Test Could Replace 15 Existing Tests for Rare Diseases
Researchers in the Netherlands have developed a DNA test for rare diseases that can provide much more comprehensive results than standard diagnostics in a shorter amount of time. A study published today in the New England Journal of Medicine reports that this new approach could replace 15 other genetic tests with a single analysis while increasing the number of patients who successfully receive a diagnosis.
Taken together, all rare diseases affect approximately 400 million people worldwide. Of the more than 7,000 rare diseases that have been identified so far, about 80% are caused by genetic mutations. Obtaining a diagnosis can be critical for people suspected of having a rare disease, offering them perspective for the future, better guidance and treatment, and less uncertainty. However, these patients often have to undergo multiple rounds of testing and wait years before receiving a definitive answer.
The new test is based on long-read genome sequencing, a technology that can read significantly longer stretches of DNA before assembling them into a complete genome. While conventional genomic tests typically read fragments around 300 nucleotides long, long-read sequencing can analyze stretches of up to 20,000 nucleotides at a time. The longer reads make it easier to accurately assemble the full genome, providing a more complete picture of the patient’s genetic makeup.
“Thanks to long reads, we obtain an even more complete view of DNA and can detect complex and hard-to-find abnormalities. We then link these to specific conditions,” says Alexander Hoischen, PhD, professor of genomic technologies at Radboud University Medical Center. “In this way, our knowledge grows and we can make more diagnoses.”
In addition, the test can detect epigenetic modifications in the genome that affect gene function without altering the underlying DNA sequence. Although these modifications can be responsible for some rare disorders, conventional testing methods are currently unable to detect them.
“With current diagnostics, this requires additional specialized tests, but with long reads we capture these modifications as a bonus—two in one,” explains Christian Gilissen, PhD, professor of genome bioinformatics at Radboud University Medical Center.
Earlier this year, the technology was used as part of the National Undiagnosed Hackathon, where over 140 experts across the Netherlands came together to search for a diagnosis for 33 families. Long-read sequencing was used to map their DNA in detail, leading to five new confirmed diagnoses within two days as well as strong suspicion of a diagnosis for another eight families.
As the number of rare disease diagnoses continues to rise, this new test could make the diagnostic process much faster and more efficient. Long-read sequencing could also help researchers identify and investigate the genetic drivers of rare conditions, many of which remain largely understudied.
Based on these findings, Lisenka Vissers, PhD, professor of translational genomics at Radboud University Medical Center, calls for the technology to be adopted worldwide as the first choice diagnostic approach when testing patients suspected to have a rare genetic disorder.
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Maternal Blood Test Allows Comprehensive Genetic Fetal Screening
A technique called non-invasive fetal sequencing (NIFS), developed by scientists at Harvard University, allows accurate and comprehensive genetic screening of a fetus using only a blood test from the expectant mother.
At the European Society of Human Genetics conference in Gothenburg this week, the researchers report that the technique allowed them to identify 97% of all the genetic variants normally identified using more invasive testing during pregnancy such as amniocentesis or chorionic villus sampling.
Non-invasive prenatal testing (NIPT) that focuses on cell free DNA in maternal blood has been offered for some time but has only historically tested for a limited set of mutations, mostly conditions with chromosome number abnormalities such as Down syndrome, as these were easiest to detect accurately in the small amount of fetal DNA found in maternal blood.
However, a combination of improvements in sequencing accuracy and coverage and other advances such as developments in machine learning can now help interpret such tests and it is now possible to detect a wide range of genetic variants in the fetus using only maternal blood.
In this study, the team applied NIFS to 565 pregnancies at a median gestational age of 17.5 weeks. Blood samples were sequenced to a high level of coverage (an average of 860x), and ensemble machine learning was used to call heterozygous, hemizygous, and homozygous sequence variants, and copy number variants across the full exome. The NIFS results were validated against matched genome sequencing from invasive procedures in 388 samples.
The researchers looked at nearly 7.9 million fetal variants, and the test had a median sensitivity of 94.0% and precision of 94.9% for detecting these mutations. The test identified 97.2% of the reportable fetal variants that could be found by invasive testing.
Notably, the NIFS test was more sensitive at detecting de novo and paternal variants at around 97% or higher and less sensitive at detecting inherited maternal variants at around 95%.
“The test performed really well in capturing all of the clinically relevant variants found by invasive genome sequencing that would have been missed by all current non-invasive tests,” said presenting scientist Christopher Whelan, PhD, a senior computational scientist working at the Broad Institute of Massachusetts Institute of Technology and Harvard, in a press statement.
“There were also some unexpected discoveries, such as twin pregnancies with abnormal tissue, and evidence that some mothers had received a bone marrow transplant from a male donor that confounded NIPT results. This provided further evidence of the strength of the technique.”
Whelan works in the lab of Michael Talkowski, PhD, the director of the Center for Genomic Medicine at Massachusetts General Hospital, who was also involved in the research. Talkowski is co-founder of the diagnostics company First Genomic Insights, which is developing this test for commercialization. If successful it will likely be the first U.S. company to bring an exome scale non-invasive prenatal test like this to the market.
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