Common Diseases in Clinical Cohorts – Not Always What They Seem

October 28, 2025

Publication: New England Journal of Medicine

23 October 2025

Fedik Rahimov, Benjamin M Jacobs, John S Lee, Naim A Mahi, Andrew Blumenfeld, Ammar J Alsheikh, Ali Abbasi, Mark Reppell, Valerie L Pivorunas, Haukur J Sigurðsson, Stephen Sawcer, Heath Guay, Jeffrey F Waring, Howard J Jacob, Nizar Smaoui

Abstract

Background: Misdiagnosis or underdiagnosis of rare diseases in patients with diagnoses of common diseases can lead to delayed or inappropriate treatments, thereby complicating the management of both rare and common conditions. Despite advances in molecular diagnostic techniques, the effect of rare diseases on the diagnosis of common diseases in research and clinical trials has not been comprehensively investigated.

Methods: We used exome- and genome-sequencing data from participants in the U.K. Biobank, a research study, and five clinical trials involving patients who had received a primary diagnosis of multiple sclerosis, inflammatory bowel disease, or atopic dermatitis to assess the incidence of monogenic rare diseases that often manifest with clinical symptoms overlapping with those of these common diseases.

Results: We identified 153 U.K. Biobank participants who carried a rare variant that contributes to a molecular diagnosis of a monogenic disorder – 53 of 1850 (2.86%) with a diagnosis of multiple sclerosis, 75 of 6681 (1.12%) with a diagnosis of inflammatory bowel disease, and 25 of 998 (2.50%) with a diagnosis of atopic dermatitis. We replicated the findings regarding such rare disease-causing variants in two independent cohorts – one including patients with a diagnosis of multiple sclerosis, and the other patients with a diagnosis of inflammatory bowel disease – who had undergone genome sequencing for research and for clinical trials, respectively. By combining genome and transcriptome analyses, we showed that molecular diagnosis can potentially elucidate mechanisms of inadequate response to therapeutic intervention.

Conclusions: Our study shows the value of systematic genome sequencing in understanding the phenotypic heterogeneity of common diseases and identifying failure to diagnose rare diseases and highlights the benefits of deep molecular phenotyping in clinical trials and patient care.

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Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk

October 20, 2025

Publication: Nature Medicine

16 October 2025

Stefanie Zorn, Rebecca Bounds, Alice Williamson, Katherine Lawler, Ruth Hanssen, Julia Keogh, Elana Henning, Miriam Smith, Barbara A. Fielding, A. Margot Umpleby, Summaira Yasmeen, Maria Marti-Solano, Claudia Langenberg, Martin Wabitsch, Tinh-Hai Collet & I. Sadaf Farooqi

Abstract

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.

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Polygenic and developmental profiles of autism differ by age at diagnosis

October 14, 2025

Publication: Nature

01 October 2025

Xinhe Zhang, Jakob Grove, Yuanjun Gu, Cornelia K. Buus, Lea K. Nielsen, Sharon A. S. Neufeld, Mahmoud Koko, Daniel S. Malawsky, Emma M. Wade, Ellen Verhoef, Anna Gui, Laura Hegemann, APEX Consortium, iPSYCH Autism Consortium, PGC-PTSD Consortium, Daniel H. Geschwind, Naomi R. Wray, Alexandra Havdahl, Angelica Ronald, Beate St Pourcain, Elise B. Robinson, Thomas Bourgeron, Simon Baron-Cohen, Anders D. Børglum, Hilary C. Martin & Varun Warrier

Abstract

Although autism has historically been conceptualized as a condition that emerges in early childhood, many autistic people are diagnosed later in life. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (r_g = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

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Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis

October 10, 2025

Publication: Neuron

10 October 2025

Bongsoo Park, Alexandra M. Nicaise, Dimitrios Tsitsipatis, Liviu Pirvan, Daniel Zucha, Andi Munteanu, Pranathi Prasad, Miguel Larraz Lopez De Novales, Cristian Bulgaru, Rafael Kollyfas, Julia Whitten, Cory M.Willis, Luka Culig, Joseph Llewellyn, Rosana-Bristena Ionescu, Magdy Mekdad, Madalena B. C. Simões-Abade, Grzegorz Krzak, Jinshui Fan, Supriyo De, Matthew O.Ellis, Marta Suarez Cubero, Angeliki Spathopoulou, Luca Peruzzotti-Jametti, Tommaso Leonardi, Gabriel Balmus, Frank Edenhofer, Myriam Gorospe, Lukas Valihrach, Irina Mohorianu, Stefano Pluchino, Isabel Beerman

Summary

Progressive multiple sclerosis (PMS) involves a persistent, maladaptive inflammatory process with numerous cellular drivers. We generated induced neural stem cells (iNSCs) from patient fibroblasts through a direct reprogramming protocol that preserved their epigenome,which revealed a PMS-specific hypome-thylation of lipid metabolism and interferon(IFN) signaling genes.S ingle-cell multi-omics uncovered a novel, disease-associated radial glia-like cell (DARG) subpopulation in PMS cell lines exhibiting senes-cence and potent IFN responsiveness driven by specific transcription factors. Functionally, PMS iNSCs induced paracrine senescence and inflammation onto control cells, which was inhibited upon senolytic treatment. We identified inPMS brains a distinct population of senescent, IFN-responsive DARGs that developmentally aligned with the trajectories of iNSCs in vitro and spatially associated with inflammatory glia in chronically active lesions. DARGs may sustain smoldering inflammation, unveiling a previously unrecognized cellular axis that could un-derpin mechanisms in neurodegeneration. This discovery offers novel insights into disease mechanisms and highlights potential therapeutic targets.

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Clinical potential of whole-genome data linked to mortality statistics in patients with breast cancer in the UK: a retrospective analysis

October 8, 2025

Publication: The Lancet Oncology

07 October 2025

Daniella Black, Helen Ruth Davies, Gene Ching Chiek Koh, Lucia Chmelova, Marko Cubric, Georgia Chalivelaki Chan, Andrea Degasperi, Jan Czarnecki, Ping Jing Toong, Yasin Memari, James Whitworth, Salome Jingchen Zhao, Yogesh Kumar, Shadi Basyuni, Giuseppe Rinaldi, Scott Shooter, Vladyslav Dembrovskyi, Rosie Davies, Maria Chatzou Dunford, Ellen Copson, Carlo Palmieri, Åke Borg, John Ambrose, Catey Bunce, Alona Sosinsky, Prabhu Arumugam, Matthew Arthur Brown, Johan Staaf, Nicholas Turner, Serena Nik-Zainal

Background

Breast cancer is the most frequently diagnosed cancer in women. Survival is generally considered favourable, yet some patients remain at risk of early death. We aimed to assess whether comprehensive whole-genome sequencing (WGS) linked to mortality data could add prognostic value to existing clinical measures and identify patients who might respond to targeted therapeutics.

Methods

In this integrative, retrospective analysis, 2445 breast cancer tumours were analysed (any stage and molecular subtype) collected from 2403 patients recruited through 13 National Health Service Genomic Medicine Centres or hospitals in England affiliated to the 100 000 Genomes Project (100kGP) between 2012 and 2018. 2208 (90%) cases were linked with clinical data; mortality data were obtained for 1188 patients. Following high-depth WGS of tumour and matched normal DNA, comprehensive WGS profiling was performed, seeking driver mutations, mutational signatures, and compound algorithmic scores for homologous recombination repair deficiency (HRD), mismatch repair deficiency, and tumour mutational burden. Data from 1803 additional patients with breast cancer from three independent cohorts were used to validate various findings. To evaluate the prognostic value of WGS features, univariable and multivariable Cox regression on data from patients was performed with stage I–III, ER-positive, HER2-negative breast cancer with a cancer-specific mortality endpoint (around 5-year follow-up).

Findings

Among 2445 tumours in the 100kGP breast cancer cohort, genomic characteristics with immediate personalised medicine potential in 656 (26·8%) was observed, including features reporting HRD (298 [12·2%] total cases and 76 [6·3%] ER-positive, HER2-negative cases), highly individualised driver events, mutations underpinning resistance to endocrine therapy, and mutational signatures indicating therapeutic vulnerabilities. 373 (15·2%) cases had WGS features with potential for translational research, including compromised base excision repair and non-homologous end-joining dependency. Structural variation burden (hazard ratio 3·9 [95 CI% 2·4–6·2]; p<0·0001), high levels of APOBEC signatures (2·5 [1·6–4·1]; p<0·0001), and TP53 drivers (3·9 [2·4–6·2]; p<0·0001) were independently prognostic of customary clinical measures (age at diagnosis, stage, and grade) in patients with ER-positive, HER2-negative breast cancer. A prognosticator was developed for ER-positive, HER2-negative breast cancer capable of identifying patients who require either increased intervention or therapy de-escalation, validating the framework in the independent Swedish Cancerome Analysis Network-Breast (SCAN-B) dataset.

Interpretation

Breast cancer genomes are rich in predictive and prognostic value. A two-step model is proposed for effective clinical application. First, the identification of candidates for targeted therapies or clinical trials using highly individualised genomic markers. Second, for patients without such features, the implementation of enhanced prognostication using genomic features alongside existing clinical decision-making factors.

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Polygenic risk score for breast cancer risk prediction in Asian BRCA1 and BRCA2 pathogenic variants carriers

October 2, 2025

Publication: npj Breast Cancer

30 September 2025

Mei-Chee Tai, Joe Dennis, Sue K. Park, Sung-Won Kim, Jong Won Lee, Nur Tiara Hassan, Ava Kwong, Mikael Hartman, Sook-Yee Yoon, Joanne Ngeow, Yin-Ling Woo, Boyoung Park, Zhi-Lei Wong, Goska Leslie, Manjeet K. Bolla, Daniel R. Barnes, Michael T. Parsons, Penny Soucy, Jacques Simard, Nur Aishah Mohd Taib, Cheng-Har Yip, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Soo-Hwang Teo & Weang-Kee Ho

Abstract

Polygenic risk scores (PRS) have been shown to be predictive of breast cancer (BC) risk in European BRCA1 and BRCA2 pathogenic variant (PV) carriers, but their utility in Asian populations has not been evaluated. In this study, we evaluated the association of two breast cancer PRS developed for the East Asian general population and three versions of a PRS developed for the European general population in 604 BRCA1 (390 affected by breast cancer) and 785 BRCA2 (552 affected by breast cancer) PV female carriers of Asian ancestry. Only the Asian-based PRS, constructed using approximately 1 million single-nucleotide variations (SNVs), showed a significant association with breast cancer risk (Hazard Ratio per standard deviation (95% Confidence Interval) is 1.47 (1.10–1.95) for BRCA1 and 1.43 (1.04–1.95) for BRCA2). Incorporating this PRS into risk prediction models may improve cancer risk assessment among PV carriers of Asian ancestry.

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Identifying people with potentially undiagnosed dementia with Lewy bodies using natural language processing

October 1, 2025

Publication: NJP Aging

18 July 2025

Mohamed Heybe, Lucy Gibson, Annabel C Price, Rudolf N Cardinal, John T O’Brien, Robert Stewart, Christoph Mueller

Abstract

Natural language processing (NLP) can expand the utility of clinical records data in dementia research. We deployed NLP algorithms to detect core features of dementia with Lewy bodies (DLB) and applied those to a large database of patients diagnosed with dementia in Alzheimer’s disease (AD) or DLB. Of 14,329 patients identified, 4.3% had a diagnosis of DLB and 95.7% of dementia in AD. All core features were significantly commoner in DLB than in dementia in AD, although 18.7% of patients with dementia in AD had two or more DLB core features. In conclusion, NLP applications can identify core features of DLB in routinely collected data. Nearly one in five patients with dementia in AD have two or more DLB core features and potentially qualify for a diagnosis of probable DLB. NLP may be helpful to identify patients who may fulfil criteria for DLB but have not yet been diagnosed.

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The presymptomatic and early manifestations of semantic dementia

September 24, 2025

Publication: Brain

23 September 2025

David J Whiteside, Matthew A Rouse, P Simon Jones, Ian Coyle-Gilchrist, Alexander G Murley, Katherine Stockton, Laura E Hughes, Richard A I Bethlehem, Varun Warrier, Matthew A Lambon Ralph, Timothy Rittman, James B Rowe

Abstract

People with semantic dementia (SD) or semantic variant primary progressive aphasia typically present with marked atrophy of the anterior temporal lobe, and thereafter progress more slowly than other forms of frontotemporal dementia. This suggests a prolonged prodromal phase with accumulation of neuropathology and minimal symptoms, about which little is known. To study early and presymptomatic SD, we first examine a well-characterised cohort of people with SD recruited from the Cambridge Centre for Frontotemporal Dementia. Five people with early SD had coincidental MRI prior to the onset of symptoms, or were healthy volunteers in research with anterior temporal lobe atrophy as an incidental finding. We model longitudinal imaging changes in left- and right-lateralised SD to predict atrophy at symptom onset. We then assess 61,203 participants with structural brain MRI in the UK Biobank to find individuals with imaging changes in keeping with SD but with no neurodegenerative diagnosis. To identify these individuals in UK Biobank, we design an ensemble-based classifier, differentiating baseline structural MRI in SD from healthy controls and patients with other neurodegenerative diseases, including other causes of frontotemporal lobar degeneration. We train the classifier on a Cambridge-based cohort (SD n=47, other neurodegenerative diseases n=498, healthy controls n=88) and test it on a combined cohort from the Neuroimaging in Frontotemporal Dementia study and the Alzheimer’s Disease Neuroimaging Initiative (SD n=42, other neurodegenerative n=449, healthy control n=127).

From our case series, we find people with marked atrophy three to five years before recognition of symptom onset in left- or right-predominant SD. We present right-lateralised cases with subtle multimodal semantic impairment, found concurrently with only mild behavioural disturbance. We show that imaging measures can be used to reliably and accurately differentiate clinical SD from other neurodegenerative diseases (recall 0.88, precision 0.95, F1 score 0.91). We find individuals with no neurodegenerative diagnosis in the UK Biobank with striking left-lateralised (prevalence ages 45-85 4.8/100,000) or right-lateralised (5.9/100,000) anterior temporal lobe atrophy, with deficits on cognitive testing suggestive of semantic impairment. These individuals show progressive involvement of other cognitive domains in longitudinal follow-up. Together, our findings suggest that (i) there is a burden of incipient early anterior temporal lobe atrophy in older populations, with comparable prevalence of left- and right-sided cases from this prospective unbiased approach to identification, (ii) substantial atrophy is required for manifest symptoms, particularly in right-lateralised cases, and (iii) semantic deficits across multiple domains can be detected in the early symptomatic phase.

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Surgery for pineal cysts with symptoms in the absence of hydrocephalus: a prospective cohort study

September 24, 2025

Publication: eClinicalMedicine – part of The Lancet

22 September 2025

Riccardo Masina, Jessica Harding, Wendi Qian, Tomasz Matys, Maria Harrington, Anna Hill, Jeff Faux, Christopher Quelch, Ihor Tysh, Thanasis Paschalis, Amber Steele, Kieren Allinson, Alexis Joannides, Angelos Kolias, Martin Taphoorn, Linda Dirven, Thomas Santarius

Abstract

There is mounting evidence for surgery as an effective treatment in selected patients with non-hydrocephalic symptomatic pineal cyst (nhSPC) syndrome. We present the first prospective cohort study of surgical PC resection to treat nhSPC syndrome.

Methods

CamProS-PC is an observational, single-centre, prospective cohort study. Patients were eligible if aged >18 years, PC size >10 mm, had severe symptoms refractory to medical treatment, without ventriculomegaly. Patient-reported data were collected preoperatively, and 3 and 12 months postoperatively. MR imaging was performed before and 12 months after surgery. The primary outcome was improvement in Role Functioning (RF) at 12 months. Secondary outcomes were changes in other domains of Health-Related Quality of Life (HRQoL) and symptoms at 3 and 12 months, and safety of the intervention. CamProS-PC is registered (ISRCTN51545574) and has been completed.

Findings

Between January 2019 and May 2023, 122 consecutive patients were screened and 40 were recruited and underwent PC resection. No loss of follow-up occurred. Mean age was 38 [SD 28–49] with 80% (32/40) females. At baseline, all patients reported headaches, 95% (38/40) dizziness, and 98% (39/40) reported impairment of vision, 98% (38/40) sleep, 90% (36/40) concentration, 88% (35/40) memory, 68% (27/40) speech, and 60% (24/40) hearing. At 12 months postoperatively, HRQoL was improved across all functional scales: RF mean difference 46 [SD 11–80, p < 0.0001] points, Physical 22 [SD −1 to 45, p < 0.0001], Emotional 35 [SD −2 to 71, p < 0.0001], Cognitive 38 [SD 3–73, p < 0.0001], and Social 50 [SD 14–87, p < 0.0001]. Global Health Status improved by 32 [SD 4–61, p < 0.0001] points. Symptoms improved overall in 95% (38/40) of patients. Most benefits were already seen at 3 months. Complications occurred in 23% (9/40) of patients; one was permanent (diplopia). All patients were alive at last follow-up.

Interpretation

CamProS-PC demonstrated significant benefit to HRQoL and symptoms one year after PC resection with overall acceptable safety profile.

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Reduced-energy diet in women with gestational diabetes: the dietary intervention in gestational diabetes DiGest randomized clinical trial

September 10, 2025

Publication: Nature Medicine

19 February 2025

Laura C. Kusinski, Danielle Jones, Nooria Atta, Elizabeth Turner, Suzanne Smith, Linda M. Oude Griep, Kirsten Rennie, Emanuella De Lucia Rolfe, Stephen J. Sharp, Vern Farewell, Helen R. Murphy, Roy Taylor & Claire L. Meek

Abstract

Reduced-energy diets promote weight loss and improve long-term outcomes in type 2 diabetes but are untested in gestational diabetes. We aimed to identify if weight loss in pregnancy improves perinatal outcomes in gestational diabetes. We performed a multicentre parallel, randomized, controlled, double-blind trial of energy restriction in women with singleton pregnancies, gestational diabetes and body mass index ≥25 kg m⁻². Participants were randomized to receive a standard-energy control diet (2,000 kcal d⁻¹) or reduced-energy intervention diet (1,200 kcal d⁻¹) from enrollment (29 weeks) until delivery, provided as weekly diet boxes (40% carbohydrate, 35% fat, 25% protein). The randomization was performed in a 1:1 ratio, stratified by center and blinded to the participants and study team. Primary outcomes were maternal weight change from enrollment to 36 weeks and offspring birth weight. In total, 425 participants were randomized to the control (n = 211) or intervention (n = 214). Outcome data were available for 388 of 425 (90.1%) participants at 36 weeks and 382 of 425 (89.8%) at delivery. There was no evidence of a difference in maternal weight change to 36 weeks between groups (intervention effect −0.20 (95% confidence interval −1.01, 0.61); P > 0.1) and offspring standardized birth weight (intervention effect 0.005 (−0.19, 0.20); P > 0.1). A reduced-energy diet was safe in pregnancy. ISRCTN registration no. 65152174.

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Common Diseases in Clinical Cohorts – Not Always What They Seem

Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk

Polygenic and developmental profiles of autism differ by age at diagnosis

Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis

Clinical potential of whole-genome data linked to mortality statistics in patients with breast cancer in the UK: a retrospective analysis

Background

Methods

Findings

Interpretation

Polygenic risk score for breast cancer risk prediction in Asian BRCA1 and BRCA2 pathogenic variants carriers

Identifying people with potentially undiagnosed dementia with Lewy bodies using natural language processing

The presymptomatic and early manifestations of semantic dementia

Surgery for pineal cysts with symptoms in the absence of hydrocephalus: a prospective cohort study

Reduced-energy diet in women with gestational diabetes: the dietary intervention in gestational diabetes DiGest randomized clinical trial

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