Gaudillat L, Patay L, Santenard J
… +8 more, Baurand A, Beaudouin A, Salvi D, Level C, Faivre L, Nowak F, Peyron C, Thauvin-Robinet C
Eur J Hum Genet
· 2026 Mar · PMID 41366566
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The 2025 French Genomic Medicine Initiative (PFMG2025) aims to make clinical genome sequencing (GS) widely accessible across France through the deployment of dedicated care pathways for rare diseases (RDs), cancer geneti...The 2025 French Genomic Medicine Initiative (PFMG2025) aims to make clinical genome sequencing (GS) widely accessible across France through the deployment of dedicated care pathways for rare diseases (RDs), cancer genetic predisposition (CGP), and cancers. This framework includes the establishment of two national GS laboratories, the definition of seventy priority pre-indications and the integration of new digital tools for e-prescription. To support these transformations, the French Ministry of Health created an innovative and internationally unprecedented role: Genomic Pathway Manager (GPM). These professionals are positioned at the interface between clinical practice, operational organisation of care pathways, and interdisciplinary coordination. They assist clinicians in prescribing GS analyses, coordinating sampling processes, and managing multidisciplinary meetings. This study provides the first nationwide assessment of the GPM role, assessing their professional profiles, activities, and job satisfaction. A quantitative questionnaire was distributed in May 2023 to all GPMs recruited, with a 90% response rate (36/40). Results show considerable heterogeneity in GPM profiles and responsibilities across different institutions. Most GPMs actively contribute to data entry in prescription systems (90%), participate in multidisciplinary meetings (85%), and train clinicians (80%). GPMs with genetic counsellor (GC) training are significantly involved in patient information sessions, enhancing the overall efficiency of the prescription process. Although GPMs expressed high job satisfaction, challenges remain, including geographical disparities, role standardization, and the need for continuous training. GPMs have proven to be key players in streamlining genomic medicine pathways. This study offers unique insights into an emerging role that may inspire similar developments in other countries.
Horowitz-Cederboim S, Hoffman-Lipschuetz R, Durst R
… +9 more, Shpitzen S, Shauer A, Zwas DR, Rosenbluh C, Antman I, Eilat A, Harel T, Tomer O, Meiner V
Eur J Hum Genet
· 2026 Apr · PMID 41345255
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Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous familie...Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.
Dolling H, Rowitch S, Bromham M
… +6 more, Archer S, O'Curry S, Rowitch DH, Raymond FL, Hughes C, Baker K
Eur J Hum Genet
· 2026 Feb · PMID 41326621
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As early rapid genomic sequencing (rGS) is adopted in paediatric medicine, there is an urgency to understand and address family support needs. This mixed methods study (Peregrin*) examined the experiences of 96 parents,...As early rapid genomic sequencing (rGS) is adopted in paediatric medicine, there is an urgency to understand and address family support needs. This mixed methods study (Peregrin*) examined the experiences of 96 parents, 1-5 years after receiving trio rGS results for their child with a severe early-onset condition. Quantitative outcome measures assessed parental well-being, life satisfaction, and family impact, comparing results to non-clinical population data, between mothers and fathers, and according to child's diagnostic outcome. Qualitative semi-structured interviews explored parents' satisfaction with support, engagement with support networks, and unmet needs. Quantitatively, mothers exhibited elevated anxiety and depression relative to population norms, and there was a lack of strong correlation in well-being metrics within couples. Parents of children with a genomic diagnosis reported poorer well-being, explained by greater medical complexity. Qualitatively, insufficient support was more frequently reported by those whose child had received a genomic diagnosis (36%) compared to those without (6%). Families drew on a range of formal and informal support sources, including condition-specific groups, though these were accessed by a minority of fathers. These findings highlight persistent and evolving support needs in families affected by complex childhood health conditions, which persist after rGS. Parents' support needs are highly individual, vary over time and across children's illness trajectory. There remain important gaps between parental needs and support, impacting on family well-being.
Coenen MJH, Nijenhuis M, Soree B
… +11 more, de Boer-Veger NJ, Buunk AM, Guchelaar HJ, Houwink EJF, Risselada A, Rongen GAPJM, Swen JJ, Touw DJ, van Westrhenen R, Deneer VHM, van Schaik RHN
Eur J Hum Genet
· 2026 Jan · PMID 41318725
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The Dutch Pharmacogenetics Working Group (DPWG) describes gene-drug interactions to facilitate pharmacogenetic implementation in clinical practice. The current guideline describes the gene-drug interactions for TPMT, NUD...The Dutch Pharmacogenetics Working Group (DPWG) describes gene-drug interactions to facilitate pharmacogenetic implementation in clinical practice. The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). Evidence based recommendations were obtained via a literature review of published studies. This literature review showed that gene variants leading to a decreased activity of TPMT and/or NUDT15 result in higher risk of toxicities, especially bone-marrow depression. For intermediate metabolisers (IM) of TPMT or NUDT15, it is advised to start with 50% of the normal dose when treated with azathioprine or 6-mercaptopurine. For poor metabolisers (PM), it is advised to start with an alternative treatment or to reduce the dose to 10% of the normal dose. For thioguanine, a dose of 75% of the normal dose is advised for TPMT IM and 50% of the normal dose for NUDT15 IM. Alternative treatment or a start dose reduction is advised for PM. A start dose of 6-7% can be used for TPMT PM and of 10% for NUDT15 PM. For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation.
KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of...KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.
Silva A, Haghshenas S, van der Laan L
… +15 more, Levy MA, Relator R, McConkey H, Kerkhof J, Skinner SA, Faivre L, Lespinasse J, Vitobello A, Valenzuela I, Scheffer IE, Russ-Hall SJ, Myers KA, Tedder ML, Sadikovic B, Cooley Coleman JA
Eur J Hum Genet
· 2026 Jan · PMID 41291199
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Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL), also known as MEF2C-related disorder or MEF2C haploinsufficiency syndrome (MCHS), is a condition caused by pathogen...Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL), also known as MEF2C-related disorder or MEF2C haploinsufficiency syndrome (MCHS), is a condition caused by pathogenic variants in the Myocyte Enhancer Factor-2C (MEF2C) gene. This study aimed to identify a DNA methylation episignature specific to NEDHSIL and explore its similarities with other known episignatures. Genome-wide DNA levels were assessed in a cohort of patients with MEF2C mutations and controls, and differentially methylated CpG sites were identified. A bioinformatic analysis yielded a classifier that was trained against controls and other known episignature disorders within the EpiSign Knowledge Database. The classifier demonstrated high accuracy, sensitivity, and specificity in classifying NEDHSIL samples. Furthermore, functional annotation and comparative analysis revealed similarities between the NEDHSIL episignature and other genetic neurodevelopmental disorders. This study provides evidence for a DNA methylation episignature specific to NEDHSIL and highlights the potential utility of this epigenetic biomarker for diagnosing and understanding molecular pathophysiology of neurodevelopmental disorders associated with MEF2C mutations.
Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health...Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; M = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental (M = 65.8), physical (M = 67.5), and general (M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores (M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = -0.491, 95% CI -0.76, -0.22, p < 0.001) and general HRQOL (β = -0.466, 95% CI -0.77, -0.16, p = 0.004), but not mental HRQOL (p = 0.102). CC-LFS accounted for significant proportions of unique variance in general (R = 17.7%, p = 0.004) and physical HRQOL (R = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs' psychosocial health.
de Vries JM, Arduç A, Waisfisz Q
… +5 more, B Tan-Sindhunata M, Faas BH, van Leeuwen E, Linskens IH, Pajkrt E
Eur J Hum Genet
· 2026 Feb · PMID 41272104
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This study evaluates the diagnostic genetic yield in fetuses sonographically suspect of having isolated clubfoot. We conducted a retrospective study on all fetuses with apparently isolated clubfoot on initial ultrasound,...This study evaluates the diagnostic genetic yield in fetuses sonographically suspect of having isolated clubfoot. We conducted a retrospective study on all fetuses with apparently isolated clubfoot on initial ultrasound, examined between January 2021 and December 2024. Clubfoot was classified as isolated when no additional structural anomalies were observed on initial imaging. Among 218 cases, 140 (64%) were classified as isolated. Prenatal genetic testing was performed in 64 of these cases (46%), of which 61 (95%) underwent both copy number variant (CNV) and single nucleotide variant (SNV) analysis. In 38 of the 61 (62%) cases targeted investigation of the DMPK gene was carried out too. Pathogenic or likely pathogenic causative variants were identified in six of the 61 (9.8%) pregnancies: two of the 26 tested (7.7%) with unilateral clubfoot and four of the 35 tested (11.4%) with bilateral clubfoot. These include SNVs in TRPV4, PTPN11, BBS2, and MED13L (4/61 = 6.6%) and two CNVs, a de novo 22q11.23 deletion, and a de novo 5q21.1q31.1 deletion (2/61 = 3.3%). One case remained unsolved due to the identification of a variant of uncertain significance (VUS) in PIEZO2. Three cases revealed unsolicited findings unrelated to the indication for testing. Our findings highlight the diagnostic yield of prenatal CNV- and SNV-testing in cases of suspected isolated clubfoot, but does not support systemic testing for DMPK. Although broad genetic testing can support diagnosis and counseling, challenges remain in interpreting results and managing unsolicited findings.
Warren A, Andreou D, Warren D
… +2 more, Wieland J, Mantzouratou A
Eur J Hum Genet
· 2026 Feb · PMID 41266756
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Endometriosis is a chronic, estrogen-driven inflammatory disorder affecting approximately 10% of reproductive-aged women globally. Despite increasing genomic insights into advanced-stage disease, the genetic underpinning...Endometriosis is a chronic, estrogen-driven inflammatory disorder affecting approximately 10% of reproductive-aged women globally. Despite increasing genomic insights into advanced-stage disease, the genetic underpinnings of early-stage endometriosis remain poorly understood, limiting opportunities for timely diagnosis and intervention. This study explores the contribution of regulatory variants, including those derived from ancient hominin introgression, and their interaction with modern environmental exposures in shaping endometriosis susceptibility. We conducted a dual-phase literature review to identify genes implicated in endometriosis pathophysiology and endocrine-disrupting chemical (EDC) sensitivity. Five genes (IL-6, CNR1, IDO1, TACR3, and KISS1R) were selected based on tissue expression, pathway involvement, and EDC reactivity. Whole-genome sequencing (WGS) data from the Genomics England 100,000 Genomes Project were analysed in nineteen females with clinically confirmed endometriosis. Variant enrichment, co-localisation, and linkage disequilibrium analyses were conducted, and functional impact was evaluated using public regulatory databases. Six regulatory variants were significantly enriched in the endometriosis cohort compared to matched controls and the general Genomics England population. Notably, co-localised IL-6 variants rs2069840 and rs34880821-located at a Neandertal-derived methylation site-demonstrated strong linkage disequilibrium and potential immune dysregulation. Variants in CNR1 and IDO1, some of Denisovan origin, also showed significant associations. Several of these variants overlapped EDC-responsive regulatory regions, suggesting gene-environment interactions may exacerbate risk. These findings propose a novel perspective of endometriosis susceptibility, in which ancient regulatory variants and contemporary environmental exposures converge to modulate immune and inflammatory responses. This integrative approach identified new potential biomarkers for early-stage detection of endometriosis.
Sheen D, Willis A, Fehlberg Z
… +3 more, Southey M, Goranitis I, Young MA
Eur J Hum Genet
· 2026 Jan · PMID 41266755
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The increasing use of genomic testing in clinical and research contexts raises how best to manage additional findings (AFs). This systematic review of the preferences of clinical patients and research participants for wh...The increasing use of genomic testing in clinical and research contexts raises how best to manage additional findings (AFs). This systematic review of the preferences of clinical patients and research participants for what and how AFs should be returned, aims to inform development of guidelines and policies that are inclusive of test recipients. Framework analysis was used to systematically review qualitative and quantitative studies exploring preferences for AFs in clinical and research contexts and identify key themes. Eighty-seven studies were included involving a total of 71,486 study participants. The right to choose whether and what AFs to receive was highly supported. Actionable findings and findings with familial implications were highly desired across studies. Additionally, a substantial number of studies identified mixed interest in findings currently not returned, including non-actionable findings and variants of unknown significance (VUS). Penetrance and certainty influenced perceived relevance and decisions regarding what to receive, with varying thresholds identified within studies. This review identified a consistent desire for systematic support for test recipient decision-making and managing AFs. The findings of this review support existing emphasis on recipient choice. However, recipient strength of preference for a broad variety of findings indicates that a minimum acceptable return of actionable findings should be established in national guidelines and the feasibility of offering other types of findings should be explored.
Pang J, Barnett W, Purdie J
… +9 more, Della-Vedova JA, Woodward A, Bell DA, Hooper AJ, Chan DC, Martin AC, Nowak KJ, Garton-Smith J, Watts GF
Eur J Hum Genet
· 2026 Feb · PMID 41249832
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Familial hypercholesterolaemia (FH) is a common, co-dominant cause of premature coronary artery disease that remains under-recognised worldwide. Genetic testing, the most accurate diagnostic method, is particularly valua...Familial hypercholesterolaemia (FH) is a common, co-dominant cause of premature coronary artery disease that remains under-recognised worldwide. Genetic testing, the most accurate diagnostic method, is particularly valuable in the cascade testing of close blood relatives, but there is little experience in general practice. We developed a tertiary-primary shared care model to identify genetic FH among first-degree relatives (FDRs) of FH index cases. Service and clinical outcomes were assessed. From a total of 153 FDRs of 90 adult FH index cases, 105 (corresponding to 64 index cases) undertook genetic testing by their general practitioner (GP). Median age of the FDRs was 14.8 years (range 3-79 years), 54% being male, 80% Caucasian, 61% children/adolescents, and 80% progeny. The number of new FDRs with a pathogenic variant per index case was 0.89 (95% CI, 0.69-1.10), with an uptake and yield of testing of 95% and 50%, respectively. Relatives with a pathogenic variant had significantly higher LDL-cholesterol than those without (5.9 ± 1.8 vs. 2.7 ± 0.9 mmol/L, p < 0.001). Among 31 relatives initiated on treatment after a genetic diagnosis, a 46% reduction in LDL-cholesterol was achieved with 45% attaining guideline-directed goals. Genetic cascade testing of FDRs of index cases with FH is feasible and effective in a shared-care model in which GPs are supported by a tertiary centre. These preliminary findings inform the development of centralised and sustained models of care, with implications for the detection of FH in communities.
The inherited arrhythmia syndrome, Brugada Syndrome (BrS), is a leading cause of autopsy negative sudden death: the sudden arrhythmic death syndrome. Historically, BrS was believed to exhibit a Mendelian (autosomal domin...The inherited arrhythmia syndrome, Brugada Syndrome (BrS), is a leading cause of autopsy negative sudden death: the sudden arrhythmic death syndrome. Historically, BrS was believed to exhibit a Mendelian (autosomal dominant) mode of inheritance, caused by rare variants in SCN5A, the gene coding for the alpha subunit of the main cardiac sodium voltage channel. Challenges to this paradigm have arisen. For example, the majority of BrS cases do not exhibit rare variants in SCN5A. Moreover, genotype-phenotype mismatch in families has been observed. These findings suggest a more complex genetic architecture underpinning BrS. Subsequent large genomic studies of international patient cohorts have shown an unexpectedly high contribution of common genetic variation to its phenotypic development and severity. This has led to an alternative disease hypothesis whereby BrS develops as result of accumulated genetic and environmental risk surpassing a 'disease threshold' - the higher the accumulated risk, the more severe the clinical phenotype. Whilst expansion of standard clinical genetic testing to include an assessment of common variation might assist with diagnosis and phenotypic severity prediction in BrS, its incorporation into clinical practice presents inherent challenges which require careful consideration.
Eur J Hum Genet
· 2026 Jan · PMID 41203982
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Genetic counselling (GC) for familial colorectal cancer (fCRC) has been previously shown to improve outcomes such as emotional distress and screening adherence. This is the first randomised clinical trial to evaluate the...Genetic counselling (GC) for familial colorectal cancer (fCRC) has been previously shown to improve outcomes such as emotional distress and screening adherence. This is the first randomised clinical trial to evaluate the efficacy of GC for fCRC. We included individuals affected or at-risk for fCRC (Lynch syndrome, APC-associated polyposis, other risk-associated pathogenic variants and clinically defined fCRC). Participants were randomised to (1) standard care or (2) standard care and genetic counselling. Measures include empowerment, anxiety, depression, knowledge, emotional distress, perceived social support, risk perception. Eighty-two individuals participated in the study. The average age was 44.81 years old, with 52.4% women. There was a significant effect in the counselling group (42/82) on post-intervention empowerment scores compared to the control group (40/82) (p = 0.004, d = 0.71), and similarly for depression (p = 0.025, d = 0.40), anxiety (p = 0.036, d = 0.35) and knowledge (p = 0.016, d = 0.25). Exploratory analysis show that several sociodemographic, affective and cognitive variables are moderating the improvement in empowerment following genetic counselling. Our data show significant improvements for both primary endpoint (empowerment) and secondary endpoints (knowledge, depression, anxiety, emotional distress). Genetic counselling is an effective intervention for fCRC both when the diagnosis is part of a syndrome or clinically defined, and both for affected or at-risk individuals.
Language in clinical genetics is never neutral. The terms used to describe genetic concepts, like mutation or variant, sporadic or hereditary, patient or counselee not only shape scientific discourse but also profoundly...Language in clinical genetics is never neutral. The terms used to describe genetic concepts, like mutation or variant, sporadic or hereditary, patient or counselee not only shape scientific discourse but also profoundly affect how individuals understand their risks, experience counselling, and make decisions. Terminology carries ethical weight, influencing perceptions of identity, stigma, and inclusion. Precision and empathy in language are therefore central to ethical and effective care. We propose the use of consistent terminology in communication that integrates three ethical responsibilities, promoting inclusivity through careful terminology, fostering psychosocial awareness by recognising that words can evoke fear or stigma, or offer reassurance and communicative clarity. This can be achieved by standardising professional terminology (e.g., variant, sporadic/hereditary) while co-constructing meaning with counselees. We recommend avoiding ambiguous labels like positive or negative, using precise qualifiers for variants and harmonising language across professional disciplines. Communication itself can be a clinical intervention, as careful paraphrasing and clarification both enhance understanding and provide emotional support. As genetic testing becomes increasingly mainstream in oncology, empathetic, precise, and patient-centred communication is essential. By fostering clarity and reducing stigma, language can support informed decision-making, trust, and ultimately, the ethical integration of genetics into everyday healthcare.