Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure, and death. Recent studies suggest that early-onset AF increases the risk of developing heart failure and...Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure, and death. Recent studies suggest that early-onset AF increases the risk of developing heart failure and dilated cardiomyopathy. This study aimed to identify genetic variants in a large set of 34 cardiomyopathy genes among early-onset AF individuals. We conducted targeted sequencing of cardiomyopathy-associated genes in 478 individuals from a Danish cohort with early AF onset. Additionally, we analyzed whole exome sequencing data from 375,869 individuals from the UK Biobank, including 29,267 individuals with AF. Of the Danish individuals with early-onset AF, 8.8% carried pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes. The prevalence of rare P/LP variants in the UK Biobank analysis ranged from 3.85% in the group with early AF onset to 1.03% in the group without AF diagnosis. Results were largely consistent when excluding individuals with no prior cardiomyopathy or heart failure diagnosis. This suggests that genetic testing for cardiomyopathy could be relevant in selected individuals with early AF diagnosis.
Al Shamsi B, Al Momen M, Al Kindy F
… +5 more, Al-Kalbani S, Al-Futaisi A, Al-Awadi M, Al Abri Y, Al-Thihli K
Eur J Hum Genet
· 2026 Jun · PMID 42056474
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SLC52A3-related Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurodegenerative disorder characterized by progressive motor and sensory impairment, with high mortality rate if left untreated. We hereby report the la...SLC52A3-related Brown-Vialetto-Van Laere syndrome (BVVL) is a rare neurodegenerative disorder characterized by progressive motor and sensory impairment, with high mortality rate if left untreated. We hereby report the largest cohort with SLC52A3-related BVVL from the Arabian Peninsula. A total of 23 patients, 16 females and 7 males, with genetically confirmed BVVL diagnosis at two tertiary centers from the region were retrospectively reviewed. Most patients were clinically ascertained (13/23), while 10 patients were diagnosed pre-symptomatically. 20 patients were homozygous for SLC52A3: c.634C>T (p.Arg212Cys) variant and 3 patients were homozygous for SLC52A3: c.1325_1326del. Facial diplegia was the commonest clinical feature (12/13), while moderate to severe hearing loss and dysarthria were seen in (10/13) patients. Symptomatic patients were treated with riboflavin doses ranging between 15 and 100 mg/Kg/day, with a median of 26 mg/Kg/day. Pre-symptomatic patients were treated with doses lower than that (as low as 5 mg/Kg/day). Patients were followed for 6 months to 12 years, with a median of 4 years. Most patients have shown significant or near-total recovery with residual symptoms (11/13), while 9/10 patients diagnosed pre-symptomatically remained symptom-free, and 2 symptomatic patients showed complete resolution of symptoms. The study emphasizes the significant interfamilial and intrafamilial variability of BVVL, and it stresses the impact of early treatment with riboflavin in the prevention of morbidity and mortality associated with this condition. The study also provides the longest cumulative follow-up of pre-symptomatically treated patients reported to date, providing preliminary evidence for the role of riboflavin in the prevention of morbidities associated with this condition.
Horton R, Weller S, Ballard L
… +1 more, Lucassen A
Eur J Hum Genet
· 2026 Jun · PMID 42056473
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Over the past two decades, genetic testing has undergone major shifts in its accessibility and in its nature. Historically, it primarily involved analysis of single genes selected on the basis of symptoms or family histo...Over the past two decades, genetic testing has undergone major shifts in its accessibility and in its nature. Historically, it primarily involved analysis of single genes selected on the basis of symptoms or family history, and was available only to a few. Now, options range from diagnostic clinical genomic tests, to broader screens offered to 'healthy' populations, to direct-to-consumer tests offering to explore ancestry. As genetic testing becomes an increasingly 'everyday' encounter, we sought to explore how the topics of genetics (and genomics) were considered in the Mass Observation Project, an archive of writing by 'ordinary' people about everyday life in Britain. 55% of the 147 respondents had personal experience of genetic testing or knew someone who had, typically to explore ancestry. Responses often gave the sense of genetic testing as a powerful tool in healthcare with results that were fairly definitive. Genomic testing was typically written about as an amplification of genetic testing, generating information of similar solidity. Writers threaded together personal experiences with insights drawn from a wide variety of media, often quite old, in outlining their ideas. While many positioned genetics as outside their remit, respondents engaged in depth with the opportunities and challenges raised, advocating for ethical/societal considerations to form a key part of decision-making regarding genetics. Our analysis shows that people without prior experience of clinical genetic testing may yet have a wealth of experiences and exposures sculpting their expectations as to what testing stands to bring. Consent conversations may benefit from exploring these.
Clancy J, Toivonen J, Lauronen J
… +5 more, Partanen J, Blood Service Biobank, FinnGen, Arvas M, Ritari J
Eur J Hum Genet
· 2026 Jun · PMID 42045633
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The healthy donor effect (HDE) refers to the lower mortality observed among blood donors compared to the general population. While HDE arises due to healthier individuals being more likely to donate, the extent to which...The healthy donor effect (HDE) refers to the lower mortality observed among blood donors compared to the general population. While HDE arises due to healthier individuals being more likely to donate, the extent to which it is influenced by genetic differences remains unclear. To elucidate the genetic basis of HDE, we conducted a genome-wide association study (GWAS) involving 53,688 active blood donors with extensive donation histories and 228,060 controls from biobank cohorts within the FinnGen project. We identified 46 fine-mapped genome-wide significant loci associated with several health-related endpoints, plasma protein levels and laboratory measurements. Genetic correlation analyses across FinnGen endpoints revealed that blood donors are genetically protected against several diseases beyond those affecting donation eligibility. Using the correlated endpoints as exposures in multivariable Mendelian randomization (MVMR) to inform priors for Bayesian GWAS, we found that 25 of the fine-mapped loci exert a direct effect on blood donorship (BD) rather than acting through disease mediation, suggesting a genetic contribution to maintaining a health state conducive to long-term donation. We also performed MVMR analyses of laboratory traits. The results indicated that normal liver function, blood glucose, and low inflammation independently increase the likelihood of becoming a blood donor, while iron levels showed no causal relationship. Functional enrichments among the proteins regulated by the 46 fine-mapped variants included mainly red cell antigen-related cell adhesion processes. In conclusion, our findings demonstrate that HDE is partly explained by genetic factors, involving both direct health-promoting effects and indirect eligibility selection.
Lu L, Jiang S, Wang Y
… +3 more, Liu S, Lu J, Gu Y
Eur J Hum Genet
· 2026 Jun · PMID 42045632
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This study explores public attitudes toward genetic sequencing (GS) services in China and identifies key factors influencing adoption. Although GS has the potential to strengthen precision public health, its uptake may b...This study explores public attitudes toward genetic sequencing (GS) services in China and identifies key factors influencing adoption. Although GS has the potential to strengthen precision public health, its uptake may be constrained by societal and attitudinal barriers. We used a sequential mixed-methods design, combining focus group discussions with a structured ranking questionnaire. A total of 28 participants (mean age 48.9 years) were included. The qualitative analysis identified five major themes reflecting participants' understanding, concerns, and expectations regarding GS. Quantitatively, the most influential factors for adoption were the characteristics of genomic information and financial accessibility. Demographic differences were observed: men prioritized cost, whereas women emphasized clarity of information; older adults focused on affordability, whereas younger participants valued transparency and the utility of information. Psychological concerns also emerged as an important barrier, including fears of genetic discrimination and emotional distress arising from the implications of genetic information. In contrast to European studies that often highlight privacy and data protection, participants in this study placed greater emphasis on informational and financial considerations. Despite the modest sample, thematic saturation was reached and the mixed-methods approach provides complementary qualitative and quantitative evidence. Addressing public concerns through transparent communication, education, psychological support, and affordability-focused policies will be important to facilitate integration of GS into healthcare systems. These findings provide culturally grounded evidence to inform precision public health in China and similar contexts.
Leveraging existing genomic data to opportunistically screen for secondary findings (SFs) can identify individuals at increased genetic risk who may be missed by criteria-based testing. While some guidelines support retu...Leveraging existing genomic data to opportunistically screen for secondary findings (SFs) can identify individuals at increased genetic risk who may be missed by criteria-based testing. While some guidelines support returning actionable SFs with professional support, there is a gap in consistent practice regarding the return process. This study reports the outcomes of opportunistic genomic screening in an Australian biobank. Whole genome sequencing data from 1057 healthy participants in the Tasmanian Ophthalmic Biobank (TOB), all of white European ancestry, underwent opportunistic screening for pathogenic (P) or likely pathogenic (LP) variants affecting genes in the ACMG SF v3.0 list. Variants of interest were manually curated, and only P/LP variants were returned. Actionable SFs (P/LP variants) were identified in 3.6% (38/1057) of participants. The most common genes were HFE (haemochromatosis), LDLR (Familial Hypercholesterolemia), and TP53 (Li-Fraumeni syndrome). Of the 38 participants with a variant, 27 received their result, with two-thirds being newly informed. Ten participants were referred to clinical genetics for diagnostic confirmation, while seven declined to proceed. Opportunistic screening identified a clinically significant incidence of actionable SFs in a healthy biobank cohort. There was high participant interest in receiving results, although subsequent uptake of clinical referral remains a challenge.
Kaplan G, Smith DM, Wan MW
… +3 more, Slevin H, Burkitt-Wright E, Garg S
Eur J Hum Genet
· 2026 Jun · PMID 42020528
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Pregnancy in the context of Neurofibromatosis 1 (NF1) may be emotionally complex due to uncertainties surrounding inheritance and the condition's variable presentation. This study aimed to explore how expectant parents w...Pregnancy in the context of Neurofibromatosis 1 (NF1) may be emotionally complex due to uncertainties surrounding inheritance and the condition's variable presentation. This study aimed to explore how expectant parents with NF1 experience pregnancy and relate to their unborn child. Fourteen participants took part in individual semi-structured interviews, and data were analysed using reflexive thematic analysis. Participants described how decisions around conception and genetic testing were influenced by personal and medical history, perceived severity of NF1, and concerns about potential impact on their child. Participants described how ongoing uncertainty contributed to feelings of anxiety, guilt, and emotional restraint, which they managed through internal strategies such as seeking reassurance, information, and acceptance, as well as through external support networks. Notably, internal representations of the unborn child were sometimes shaped by cautious and emotionally regulated engagement in response to uncertainty. In a condition like NF1, where uncertainty may complicate prenatal bonding, adapting psychological interventions that have been used antenatally to promote early bonding and support later parenting outcomes could help strengthen emotional wellbeing and the developing parent-infant relationship.
D'Alessio AM, Indrieri A, Vitiello G
… +12 more, Morleo M, Schelley S, Enns GM, Passarelli C, Tammaro R, Tiranti V, Peron C, Deb W, Novelli A, Isidor B, Iolascon A, Franco B
Mitochondrial disorders (MDs) are a diverse group of genetic conditions primarily affecting the oxidative phosphorylation (OXPHOS) system and cellular energy production. Among MDs, Linear Skin Defects with Multiple Conge...Mitochondrial disorders (MDs) are a diverse group of genetic conditions primarily affecting the oxidative phosphorylation (OXPHOS) system and cellular energy production. Among MDs, Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), or Microphthalmia with Linear Skin Lesions (MLS) syndrome, is a rare X-linked dominant male-lethal disorder characterized by ocular malformations, linear skin defects, and multisystem developmental anomalies. These features are associated with pathogenic variants in genes related to mitochondrial function, including HCCS, COX7B, and NDUFB11 or chromosomal rearrangements of the Xp22 region encompassing HCCS. Despite progress, genotype-phenotype correlations remain insufficiently defined. In this study, we report three novel mutations in three patients with LSDMCA, broadening the phenotypic spectrum of the disorder. Whole exome sequencing revealed pathogenic missense variants in HCCS [NM_005333.5: c.625 G > C; p.(Asp209His)] and COX7B [NM_001866.3: c.221 C > T; p.(Pro74Leu)] in two unrelated patients. Functional studies confirmed that the COX7B variant impairs mitochondrial respiratory chain (MRC) function. A third patient harbored a novel frameshift pathogenic variant in NDUFB11 [NM_001135998.3: c.145_152dup; p.(Thr52Glnfs*66)], further implicating mitochondrial dysfunction in LSDMCA pathogenesis. Notably, the COX7B variant was identified in a biological male (46, XY) without X-chromosome structural rearrangements, marking the first such reported case of LSDMCA. Our data suggest that certain missense variants, resulting in mild impairment of the gene product, may allow male survival, thereby expanding the known phenotype of this rare disorder. This report advances our understanding of genotype-phenotype correlations in LSDMCA and highlights the impact of mitochondrial dysfunction during embryonic development.
This paper continues our development of methods for discovery of genetic modifiers of the Duchenne muscular dystrophy (DMD) phenotype. DMD is an X-linked recessive disorder involving progressive muscle tissue loss with r...This paper continues our development of methods for discovery of genetic modifiers of the Duchenne muscular dystrophy (DMD) phenotype. DMD is an X-linked recessive disorder involving progressive muscle tissue loss with replacement by fat and fibrotic tissue, leading in most cases to loss of ambulation (LOA) by early to mid-adolescence. The standard pharmacologic treatment is corticosteroid administration, which increases average LOA by 2-3 years. There is variation in LOA due to specific DMD mutations, some of which permit the production of residual or partial dystrophin protein and lead to milder phenotypes. But there is also believed to be variation due to genetic modifiers acting even in patients whose DMD mutations preclude dystrophin production altogether, based in part on animal models, and several genes have been implicated as potential modifiers of LOA in DMD patients. Here we consider whether the mechanism of action of any of these genes might be to influence LOA by modifying the effects of corticosteroid exposure. We develop and evaluate a novel statistic, the PPI; we consider the issue of potential "phenocopies," or individuals whose late LOA might be due to residual dystrophin production; and we apply our approach to 12 candidate SNPs using our DMD dataset. We find evidence of genotype x steroid interaction effects for 4 out of the 12 SNPs we tested, which can be linked to the TGF-β pathway. These results corroborate the hypothesis that modifiers in the TGF-β pathway affect LOA by modulating the efficacy of corticosteroid administration.
Reproductive genetic carrier screening (RGCS) provides people with information about the likelihood of having children with serious inherited genetic conditions. The perspectives of people who have experience with a gene...Reproductive genetic carrier screening (RGCS) provides people with information about the likelihood of having children with serious inherited genetic conditions. The perspectives of people who have experience with a genetic condition are important in understanding the acceptability of RGCS. Through the Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission), over 10,000 reproductive couples were offered screening for genetic conditions associated with ~1300 genes. Of those who took part, some had previously had a prenatal, neonatal or paediatric diagnosis of a genetic condition in their offspring or had a genetic condition themselves. Although these participants knew their carrier status for the condition in their family, they had RGCS to determine if they had an increased chance for children with any of the other conditions screened. These participants were invited to take part in semi-structured interviews to explore their perspectives. Thematic analysis from interviews with 19 people from 17 reproductive couples demonstrated positive attitudes towards making RGCS widely accessible. Participants valued being offered screening for additional conditions. A sense of doing 'due diligence' to protect future children from potential harm caused by a genetic condition was a strong motivator to undergo RGCS. There was a willingness to accept short-term anxiety that RGCS can create because of the peace of mind it can provide. Participant's discourse demonstrated complex prior experiences leading to heightened risk perception and highlighted that, although they valued and and were supportive of screening, people with experience of genetic conditions may benefit from additional support to navigate RGCS.
With the advent of novel gene therapies, rare genetic diseases once lacking treatments are now being considered for newborn screening programmes (NBS). Wilson and Jungner criteria (drawn on worldwide to guide screening p...With the advent of novel gene therapies, rare genetic diseases once lacking treatments are now being considered for newborn screening programmes (NBS). Wilson and Jungner criteria (drawn on worldwide to guide screening programme evaluation) necessitate effective interventions for a recommendation of screening. Spinal muscular atrophy (SMA) is an example of a condition for which the case for NBS has rapidly gathered pace in recent years. With the introduction of disease-modifying therapies (that are most efficacious when delivered pre-symptomatically), many countries are now piloting or implementing SMA NBS. Despite this, the acceptability of SMA NBS remains underexplored. To address this gap, surveys and interviews were conducted with four key groups: i) general public, ii) SMA families, iii) parents of screened babies iv) healthcare professionals. Survey responses from 9,511 respondents were analysed: 5,604 from the public, 250 from SMA families, 3,541 from parents and 116 from healthcare professionals. Fifty-three qualitative interviews were conducted with 56 participants: 10 public; 12 SMA parents; 9 adults with SMA; 9 parents of screened babies (including one positive result) and 16 healthcare professionals. Support for SMA NBS was found to be consistently high: 90% of public, 99% of SMA parents and adults, 98% of parents of screened babies and 97% of healthcare professionals supported its national implementation. Concerns centred on the impact of diagnoses through NBS, anxiety and treatment ineligabilty for adult-onset SMA. However, these were not considered barriers. SMA NBS is widely acceptable to relevant stakeholder groups, though rapid, comprehensive and high-quality support for families is essential following diagnosis.
Cystine stones are caused by pathogenic variants in SLC3A1 or SLC7A9. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these...Cystine stones are caused by pathogenic variants in SLC3A1 or SLC7A9. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these impact genetic prevalence estimates. Due to the disease rarity, direct patient recruitment and observation is impractical. We applied a population genetics approach to estimate genetic burden and prevalence. Pathogenic variants were identified from the 2022 Human Gene Mutation Database and intersected with population variants from the 1000 Genomes Project Phase 3. Allele frequency, carrier rate, and affected rate were calculated. Results were compared to prior data, and simulations were performed across varying initial allele frequencies. We identified 116 and 76 novel pathogenic variants in SLC3A1 and SLC7A9, respectively. Pathogenic allele frequencies increased by +0.12% (SLC3A1) and 0.16% (SLC7A9), leading to fold-changes in genetic prevalence of 1.51x and 2.78x. The combined updated prevalence is 1 in 17,612, a 1.74x increase. Simulations confirmed the fold-change magnitude. In rare diseases, even modest discovery of new variants can significantly increase genetic prevalence. As shown in cystine stone, this helps narrow-but not close-the gap with clinical prevalence. Further efforts are needed to bridge this gap and guide treatment development.
Ceroni F, Reis LM, Watkins F
… +10 more, Bax DA, Fischer MC, Jeganathan K, Jewell R, Martin JS, Salt A, Seese SE, Thomson J, Semina EV, Ragge NK
Eur J Hum Genet
· 2026 Jun · PMID 41946911
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KDM2B encodes an epigenetic regulator that binds to promoter-associated CpG islands via its CxxC zinc-finger domain, protecting them from DNA methylation. It also helps establish transcriptional programs essential for de...KDM2B encodes an epigenetic regulator that binds to promoter-associated CpG islands via its CxxC zinc-finger domain, protecting them from DNA methylation. It also helps establish transcriptional programs essential for development by recruiting the non-canonical Polycomb Repressive Complex 1.1 to lineage-specific genes. Heterozygous variants in KDM2B were recently associated with a neurodevelopmental disorder. Notably, some individuals with variants in the CxxC domain also exhibited congenital heart, kidney and/or structural eye anomalies. By screening 706 families with developmental eye disorders, we identified two cases with KDM2B-CxxC variants, NM_032590.5:c.1841G>C;p.(Arg614Pro) and NM_032590.5:c.1880G>C;p.(Cys627Ser), both resulting in a characteristic KDM2B DNA episignature. Both individuals exhibited complex structural eye defects, with neurodevelopmental, cardiac and renal anomalies variably present. These cases strengthen the association between KDM2B-CxxC variants and eye, kidney and heart malformations and highlight the importance of testing this gene and its episignature in individuals with structural eye disorders, especially when accompanied by congenital cardiac and/or renal anomalies.
Engel C, Rendek M, Assoumani J
… +74 more, Argilli E, Ariani F, Avice-Denizet AL, Bijlsma EK, Blanc P, Bruno LP, Callewaert B, Capra V, Carullo M, Chesneau B, Coppens S, Curry C, Dale B, Dahlen E, Delahaye-Duriez A, Denommé-Pichon AS, Demeer B, Dvořáková L, Fischer J, Geneviève D, Giacomini T, Handrup MM, Heron D, Hüning I, Iacomino M, Isidor B, Keren B, Kmoch S, Koolen DA, Kübler A, Laštůvková J, Le C, Levy J, Rizzo CL, Maitz S, Marlin S, Mignot C, Mirzaa G, Nagel I, Neuens S, Nosková L, Pao E, Pecková A, Plaisancie J, Porrmann J, Privitera F, Reis A, Renieri A, Rio M, Rippert A, Ryba L, Scala M, Schieving JH, Sherr EH, Shuen A, Sidlow R, Smol T, Soblet J, Striano P, Suri M, Syryn H, Tran Mau-Them F, Travessa AM, Van Gils J, Vasileiou G, Verseput JJA, Vilain C, Vincent-Delorme C, Vyhnálková E, Wakeling EL, Zacher P, Zara F, Kuentz P, Piard J
Saeedi S, Hirjikaka D, Clausen M
… +13 more, Luca S, Reble E, Kodida R, Assamad D, Chad L, Costain G, Faghfoury H, Silver J, Shastri-Estrada S, Smith M, Hayeems RZ, Bombard Y, Genetics Navigator Study Team
Roncato R, Perfler S, Gambron M
… +13 more, Zoroddu E, Miozzo MR, Angelini S, Gennarelli M, Stocco G, Conti V, Filippelli A, Borgiani P, Novelli G, Squassina A, Floris M, Cecchin E, Joint Italian Working Group on Pharmacogenetics Implementation
Pharmacogenetics enables personalization of drug therapy based on an individual's genetic profile. Despite clinical relevance, implementation of pharmacogenetics remains limited. In Italy, integration is fragmented, with...Pharmacogenetics enables personalization of drug therapy based on an individual's genetic profile. Despite clinical relevance, implementation of pharmacogenetics remains limited. In Italy, integration is fragmented, with heterogeneous practices and a lack of national coordination. A comprehensive assessment of the current landscape is essential. A nationwide survey was conducted between January and October 2025 to map laboratories providing pharmacogenetic testing. A structured questionnaire collected data on institutional characteristics, testing workflows, pharmacogene panels, analytical methodologies, interpretation procedures, and reimbursement. Forty-nine laboratories participated (response rate: 65%). Most were part of public institutions (82%), primarily general or research hospitals. Testing was predominantly performed in medical genetics units (39%) and focused on oncology, specifically DPYD (94%) and UGT1A1 (84%) for fluoropyrimidine and irinotecan therapies. Adherence to national (SIF/AIOM) and international (CPIC/DPWG) guidelines was generally high; compliance with AMP Tier 1 analytical standards varied substantially. Pharmacological counseling was provided by only 29% of laboratories, mainly by clinical pharmacology units. Considerable heterogeneity emerged in testing platforms, bioinformatics tools, and the use of CE-IVD-certified kits. Marked geographical disparities were evident, with pharmacogenetic activity concentrated in Northern Italy. This survey provides the first national overview of pharmacogenetics implementation in Italy, revealing variability in laboratory practices, interpretation standards, and clinical integration. While oncology-related testing is widely adopted and guideline adherence is increasing, the lack of a coordinated national framework restricts consistency and equitable access. Establishing a coordinated network of pharmacogenetic laboratories with harmonized standards for testing, reporting, and education is crucial for evidence-based pharmacogenetic care.