Kiljańczyk M, Daneberga Z, Tooming M
… +20 more, Urbańczyk K, Pöyhönen M, Kahre T, Foretova L, Tham E, Milagre T, Melegh B, Haanpää MK, Blatnik A, Wimmer K, de Putter R, Wadt K, Houdayer C, Holinski-Feder E, Kattamis A, Klink B, Høberg-Vetti H, Blanco Guillermo I, Hoogerbrugge N, Lubiński J
Germline genetic testing practices for hereditary cancer vary across the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) member countries. We surveyed experts in genetic testing from 20 EU memb...Germline genetic testing practices for hereditary cancer vary across the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) member countries. We surveyed experts in genetic testing from 20 EU member countries and Norway to assess multi-gene panel usage, availability of genome-wide sequencing, first-tier testing approaches, implementation of polygenic risk scores, and the roles of non-genetic healthcare professionals. National experts and members of the ERN GENTURIS completed a structured questionnaire covering founder germline pathogenic variants (gPV) testing, panel testing for common genetic tumour risk syndromes, use of whole-exome sequencing (WES) and whole-genome sequencing, polygenic risk score implementation, use of formalin-fixed paraffin-embedded tumour samples, laboratory accreditation, and the clinical roles of physicians, genetic counselors and nurses. Significant inter-country heterogeneity was observed. Most countries rely on next-generation sequencing (NGS) multi-gene panels. Founder gPV testing is first-line in a few high-prevalence populations (e.g., BRCA1/2 founders). All 21 countries offer NGS panel tests for hereditary breast and ovarian cancer, and ≥19 countries do so for colorectal and prostate cancers. However, NGS panel size and gene composition exhibit substantial variability. WES is available in 12 countries on a routine basis. Most countries implemented genetic testing on stored tumour tissue from deceased patients. In all countries, clinical geneticists can order germline genetic tests, and in 9 countries, any physician can do so. These findings show differences in accessibility to germline genetic testing of hereditary cancer in Europe. We propose EU-wide guidance via pathways, standards of care, and sharing of best practices to further optimize access to hereditary cancer genetic molecular diagnostics.
Smith HS, Vu M, Dangouloff T
… +16 more, Schubert C, Level C, Lamsal R, Christensen KD, Stark Z, Goranitis I, Aujla M, Westover T, Ponte A, Shah N, Servais L, Bailey M, Lavelle TA, Grosse SD, Norris S, Buchanan J
Affordability and value-for-money are key factors that will inform decisions about implementation of genomic newborn screening (gNBS) as a population-based program. Given the methodological and data-related challenges to...Affordability and value-for-money are key factors that will inform decisions about implementation of genomic newborn screening (gNBS) as a population-based program. Given the methodological and data-related challenges to evaluating health and economic outcomes of gNBS, there is a need for discussion and knowledge sharing amongst investigators responsible for conducting such evaluations. The International Consortium on Newborn Sequencing (ICoNS) includes academic and commercial gNBS pilot and implementation programs, and the ICoNS Economics Subcommittee assembles health economists who are involved in the evaluation of these programs. This paper summarizes the reported approaches taken by gNBS researchers to assess the health, psychosocial, and economic outcomes of gNBS and provides recommendations for reporting of gNBS economic evaluations developed by an international working group of health economists. We surveyed 12 ICoNS-affiliated project investigators involved in the design of health economics and outcomes evaluation protocols, the results of which were supplemented through ICoNS Economics Subcommittee discussion. Investigators reported making economic evaluation methodological design choices that reflect both the gNBS study design and adaptation to local policy questions and stakeholder input. Investigators reported plans to conduct cost-effectiveness analyses (n = 7, 58%) and/or cost-utility analyses (n = 5, 42%). Recommendations for reporting gNBS economic evaluations include aspects of genetic condition identification, screening and follow-up care pathways, and health and cost outcomes. Going forward, making transparent study design choices and sharing lessons learned could advance understanding of outcomes in a methodologically complex context and inform researchers planning to design similar studies in the future.
Constitutional methylation of the MLH1 promoter is a rare cause of Lynch Syndrome likely to be overlooked in daily clinical practice, as MLH1 methylation is common in sporadic tumors. We present four unrelated Danish and...Constitutional methylation of the MLH1 promoter is a rare cause of Lynch Syndrome likely to be overlooked in daily clinical practice, as MLH1 methylation is common in sporadic tumors. We present four unrelated Danish and Australian patients with Lynch syndrome phenotypes and constitutional MLH1 methylation including two patients with methylation levels indicating mosaicism. The clinical features, immunohistochemistry, MLH1 promoter methylation status and genomic analysis of probands and family members are presented. The patients varied greatly in their clinical presentation and included multiple tumors, and a breast cancer and a dermal lipofibroma, tumors not classically related to Lynch syndrome. However, these patients are difficult to distinguish from other Lynch patients based on the clinical presentation. Awareness of this rare phenomenon and systematic testing of potential carriers is paramount to detect this condition and crucial to estimate the risk of cancer and optimize care for patients and their families.
Velchev JD, Krebsová A, Votýpka P
… +16 more, Zoubková V, Amsel BJ, Wildiers A, Verrijcken A, Laga S, Gerber BL, Yildiz H, Fransen E, Meester JAN, Boeckx N, Alaerts M, Voorendt M, Kempers M, Van Laer L, Loeys BL, Verstraeten A
Thoracic aortic dissection (TAD) is a life-threatening condition with a significant genetic contribution. This study evaluated the clinical implications of diagnostic screening of 368 TAD patients for (likely) pathogenic...Thoracic aortic dissection (TAD) is a life-threatening condition with a significant genetic contribution. This study evaluated the clinical implications of diagnostic screening of 368 TAD patients for (likely) pathogenic (LPP) variants in 23 TAD-associated genes and sought to identify genotype-phenotype correlations. Clinically relevant causative variants were identified in 12.5% of patients. Most patients were explained by LPP variants in FBN1 (n = 13), ACTA2 (n = 8), COL3A1 (n = 6), and TGFBR1 (n = 5), and all identified LPP variants were found in the genes identified by the ClinGen Aortopathy Expert Panel to be definitively or strongly associated with heritable aortopathy. LPP patients had a significantly younger age at dissection and had almost a two-fold increase in risk of dissection at any age compared to those without a rare genetic variant (HR, 1.98; 95% CI, 1.4-2.8; p < 0.001). COL3A1 LPP variant-harboring patients were particularly young, with a median age at dissection of 22 years. Patients with more than one variant of uncertain significance (VUS) experienced dissection at younger ages compared to single VUS-harboring individuals (p = 0.002). Presence of the MYH11 NM_001040113.2:c.3787_3789del (p.Lys1263del) VUS was indicative of a younger age at dissection. In conclusion, our study demonstrated the clinical utility of current genetic testing in TAD patients. Yet, it highlights the need for improved VUS interpretation and their consideration as risk factors. Further improvements in the screening approaches are needed to increase clinical utility and, hence, mitigate TAD morbidity and mortality by identification of at-risk individuals.
Existing systematic reviews of the health economic evidence for whole-exome and whole-genome sequencing (WES/WGS) are outdated or restricted to specific diseases or populations. This systematic review aims to provide an...Existing systematic reviews of the health economic evidence for whole-exome and whole-genome sequencing (WES/WGS) are outdated or restricted to specific diseases or populations. This systematic review aims to provide an update on the health economic evidence for these sequencing options across a broad spectrum of clinical applications. We searched bibliographic databases (PubMed/EMBASE/MEDLINE/EconLit), the International Health Technology Assessment database, the Tufts cost-effectiveness analysis registry, and appraisals by the National Institute for Health and Care Excellence and the Scottish Medicines Consortium. We included studies reporting cost and/or cost-effectiveness results of WES and/or WGS, published between July 2016 and May 2024. Outcome-only studies were excluded. Summary information on study characteristics and findings was extracted, tabulated, and analysed. 130 studies were included. Availability of health economic evidence varied between geographic regions and clinical applications. 82 studies evaluated WES/WGS as diagnostic tools, but only five assessed prenatal, newborn, or healthy population screening. Many studies did not follow common methodological and reporting guidelines. Overall, WES/WGS can be cost-effective depending on the clinical and geographical context. The evidence base has grown significantly since 2016, but further evidence is needed, particularly for using these technologies for screening.
Newborn bloodspot screening identifies babies with serious health conditions in a 2-stage process. Positive screening identifies those who need diagnostic tests. Although screening can improve physical health outcomes, r...Newborn bloodspot screening identifies babies with serious health conditions in a 2-stage process. Positive screening identifies those who need diagnostic tests. Although screening can improve physical health outcomes, research suggests that this initial screen positive stage has a profound psychological impact on families. This review systematically identifies, appraises, and synthesises the qualitative research on the impact of initial "positive screen" results on intrafamilial support systems. Studies fulfilled the inclusion criteria if they were research papers conducted with parents receiving an initial positive screen result and mentioned the impact on intrafamilial support systems. MEDLINE (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) databases were searched for qualitative research using search terms mapped onto the SPIDER framework. Title and abstracts were screened, and full texts independently reviewed by two researchers. A narrative synthesis of 25 papers was conducted and quality was appraised. All positive screen results, irrespective of diagnostic outcome, have consequences for intrafamilial support systems. Negative consequences included parents becoming the medical expert for other family members, family members becoming more distant through reducing communication, and parents questioning whether they want future children. Others experience reinforcement of strong intrafamilial support systems when family members displayed proactivity, offered reassurance, and provided adequate support in a timely manner. The synthesis findings imply screen positive results have a profound impact across family networks beyond the parent/couple dynamic, and whether this is positive or negative is complex. Further research is warranted to investigate how impact could be better addressed.
Genetic testing in hereditary cancer is evolving from single-gene-focused approaches in affected individuals to multi-gene panel testing for affected individuals and unaffected relatives. The widespread use of multi-gene...Genetic testing in hereditary cancer is evolving from single-gene-focused approaches in affected individuals to multi-gene panel testing for affected individuals and unaffected relatives. The widespread use of multi-gene panel testing has led to the identification of individuals with two or more pathogenic or likely pathogenic variants in hereditary cancer susceptibility genes (CSGs), termed Multilocus Inherited Neoplasia Allele Syndrome (MINAS) carriers. It remains unclear whether MINAS carriers are at increased risk of multiple, atypical, or more severe cancer phenotypes, and currently, there is no consensus on how best to identify and manage cancer risk. In this retrospective study, we identified 54 MINAS carriers at Princess Margaret Cancer Center in Toronto, Canada. Demographic, clinical, and genetic data were extracted from medical records. Group comparisons were performed using Fisher's exact or chi-square tests for categorical variables and independent t tests for age at cancer diagnosis. Statistical significance was set at p ≤ 0.05. The majority of affected MINAS carriers had a cancer consistent with the expression of at least one pathogenic variant. Approximately 28% of MINAS carriers were diagnosed with one atypical cancer. The most frequent gene pair combinations included hereditary breast cancer genes, with some carriers exhibiting earlier age of breast cancer onset than single CSG variants reported in the literature. Our study indicates that the cancer spectrum associated with CSGs is expanding and suggests that more intensive cancer surveillance for subgroups of MINAS carriers with hereditary breast cancer CSGs may be warranted.
Pharmacogenomics holds promise for enhancing drug safety and efficacy, paving the way for more precise, patient-centered therapeutic approaches and supporting personalized medicine and prevention. However, its routine in...Pharmacogenomics holds promise for enhancing drug safety and efficacy, paving the way for more precise, patient-centered therapeutic approaches and supporting personalized medicine and prevention. However, its routine integration into healthcare remains limited. A European multidisciplinary expert workshop was held in Amsterdam in January 2025, to share experiences regarding the priorities to further implement pharmacogenomic-guided treatment and prevention into clinical practice. A qualitative content analysis was conducted to identify key themes to support improved implementation of pharmacogenomics. The analysis drew on inputs from a multi-stakeholder workshop involving 55 participants from 10 European countries, representing policy, healthcare, academia, patient organizations and industry. The paper is centered around three central pillars to implement pharmacogenomics: evidence, acceptance, and integration into healthcare systems. Based on the expert presentations and discussions, five key priorities were identified for advancing pharmacogenomics: 1) the need for robust clinical and health economic evaluations to support funding and reimbursement decisions, 2) education and training for healthcare professionals, and raising awareness of pharmacogenomics among policymakers and the public, 3) investment in information technology and data infrastructure for interoperable storage and clinical decision making, 4) harmonizing regulatory and reimbursement policies, and 5) ensuring equitable access of pharmacogenomics. Findings underscore the need of a closer alignment through e.g. a dedicated network to move pharmacogenomics from an emerging innovation to a standard component of personalized medicine across Europe. Multidisciplinary collaboration throughout the implementation pathway will be crucial to advance pharmacogenomic-guided treatment and prevention as key part of personalized medicine.
Genomic science is a central feature of the UK government's current 10-year health plan for England, which places significant emphasis on prediction and prevention. Although NHS prevention strategies have long been aimed...Genomic science is a central feature of the UK government's current 10-year health plan for England, which places significant emphasis on prediction and prevention. Although NHS prevention strategies have long been aimed at catching diseases earlier and at a more treatable stage, genomics until now has focussed largely on diagnosis and treatment. At present, there is limited evidence on how patients and publics engage with uncertain and probabilistic genomic information. While the public health benefits of this turn towards genomic screening may take time to establish, insights can be gained from recent large-scale diagnostic initiatives that also offered a screening element. This article draws on a qualitative longitudinal study of 100,000 Genomes Project participants, within which decision-making around the option to receive Additional Findings (AFs) was discussed. By focusing on future health risks in asymptomatic individuals, AFs can be understood as an opportunistic form of screening. Analysis identified three interrelated themes: ambivalence, reflecting anxiety and uncertainty surrounding decisions to receive AFs; inevitability and participant's own perceptions of patterns of future risk within families; and legacy, capturing motivations framed in collective and relational terms. Participants' accounts reflected enduring expectations of genomic medicine as a source of certainty and clarity, which sits uneasily alongside probabilistic and uncertain forms of knowledge such screening approaches are likely to produce. Understanding how individuals and families conceive of the potential and pitfalls of employing genomic tests in screening contexts is vital as a range of countries pilot or adopt genomic tools in population health services.
Ploem C, de Wert G, Soriano Longarón S
… +10 more, Niebuur J, Christiaans I, Birnie E, Henneman L, Rigter T, Cornel M, Stemkens D, Yntema H, Van der Hout S, Plantinga M
Genome-wide screening can be offered at various stages of life and serve multiple purposes, including early detection of treatable conditions, achieving health benefits, or enhancing reproductive choices. Although genome...Genome-wide screening can be offered at various stages of life and serve multiple purposes, including early detection of treatable conditions, achieving health benefits, or enhancing reproductive choices. Although genome-wide screening offers many new possibilities, determining which genomic data to analyse, how to interpret results, and how to communicate findings, presents significant challenges. In our research, we explored considerations for responsible genome-wide screening by combining a normative analysis of three different settings (population screening, opportunistic screening, and direct-to-consumer genetic testing) with an exploration of stakeholder views (among 25 professionals and 15 potential users of screening). In doing so, we focused on the proportionality criterion and four key screening issues: (1) dealing with unsolicited, secondary and uncertain findings; (2) information and consent; (3) privacy, storage, and (re)use of data; and (4) non-participation in screening. Our findings show broad consensus on the need for a cautious approach towards genome-wide screening. The proportionality criterion requires that benefits outweigh harm on both individual and societal level. Although genome-wide testing offers a range of possible expansions of screening, evidence for the proportionality of an expansion is not always available. The expansion of direct-to-consumer genetic testing raises the most concerns in terms of proportionality. In all screening settings, the position of and advocacy for newborns and children deserve special attention. Given the already scarce resources and personnel in healthcare, responsible implementation of genome-wide screening must be grounded in well-defined normative frameworks, supported by pilot studies that critically evaluate harms and benefits on both individual and societal level.
Many people will have had no formal education on health-related genomic testing, so information from media sources may constitute a major influence in shaping ideas and expectations around genomic tests. We undertook a f...Many people will have had no formal education on health-related genomic testing, so information from media sources may constitute a major influence in shaping ideas and expectations around genomic tests. We undertook a framing analysis of 186 UK news items discussing health-related genomic testing in the context of various recent UK-based initiatives: the 100,000 Genomes Project; Our Future Health; the Generation Study; the Deciphering Developmental Disorders Study; and the NHS Genomic Medicine Service. We found that news items tended to frame genomic tests as the fruit of amazing technological progress. Tests were frequently described as 'reading' the genetic code and in the context of newborn screening, diagnosis and prediction were often treated as almost synonymous. Genomics was positioned as standing to give us all a healthier future. A decision to contribute genomic data to a research database was typically framed as virtuous, though some items discussed privacy concerns in depth. A clear diagnosis was achieved in 88% of instances where diagnostic genomic testing of a specific symptomatic person was discussed, with little attention afforded to those who had experienced less impressive outcomes. In summary, UK news items tended to celebrate the very best of genomic testing, but in doing so, they potentially engender an expectation that dramatically beneficial results come as standard. Providers of genomic tests need to be mindful of the backdrop of promotional media discourse when patients are making decisions around testing and ensure that consent conversations help patients anticipate potential limitations and challenges as well as benefits.
Nathan V, Akbar H, McInerney-Leo A
… +8 more, Gilroy D, Henders A, Naresh R, Choudhury N, Waqar M, Shah S, Yanes T, South Asian Genes and Health in Australia (SAGHA) research team
People of South Asian ancestry represent approximately 25% of the world's population, yet constitute less than 2% of global genomic databases, limiting our ability to provide equitable genomic healthcare for this populat...People of South Asian ancestry represent approximately 25% of the world's population, yet constitute less than 2% of global genomic databases, limiting our ability to provide equitable genomic healthcare for this population. The urgent need to improve representation of diverse populations in genomic research is widely recognised as an area of priority among the genetics community. Community engagement is a key first step to informing tailored recruitment strategies and genomic research participation. This study aimed to understand prior experience with, and attitudes towards, genomic research within the context of cardiovascular disease risk among people of South Asian ancestry residing in Queensland, Australia. Semi-structured focus groups were conducted between April and August 2023 (n = 60 individuals), which were recorded, transcribed verbatim and analysed using inductive and deductive approaches. Three thematic categories were developed: 'Engagement with Genomic Research', 'Cultural Connections' and 'Trust and Relationship Building'. While participants expressed positive views toward genomic research, only a few individuals had previously participated, primarily due to a lack of awareness and engagement from researchers in genomic studies. Fear of stigma and discrimination was a significant determinant towards genomic research engagement, which was multi-faceted and rooted in both community-level concerns and lived experiences of racial discrimination in Australia. Conversely, community partnership and establishing trustworthiness were critical facilitators for enhancing participation in genomic research. These findings will have important implications for designing culturally responsive community engagement strategies and will inform the development of recruitment protocols tailored to South Asian communities in Australia.
Newborn bloodspot screening (NBS) programs aim to identify babies at risk of developing serious conditions where an effective preventive or ameliorative intervention is available in infancy or early childhood. In recent...Newborn bloodspot screening (NBS) programs aim to identify babies at risk of developing serious conditions where an effective preventive or ameliorative intervention is available in infancy or early childhood. In recent decades, new testing technologies have been introduced into NBS to expand the number of screened conditions. This now also includes the possible introduction of genomic sequencing. Those who support genomic newborn screening (gNBS) do so on the rationale that a wider range of treatable conditions will be able to be screened for, and that gNBS will enable more equitable communication of actionable information to families. However, significantly increasing the number of conditions screened for may also increase expectations of screening coverage. Within a context of increased expectations of conditions being detected via gNBS, there is also the potential for actual or perceived 'missed cases', a situation where a newborn has (or will soon develop) a genetic condition that was not detected on screening. In this paper, we consider legal and ethical issues pertaining to missed cases in gNBS. We argue that certain missed cases in gNBS constitute neither a legal nor moral harm, especially where gNBS is delivered within a systematic screening program rather than via a commercially marketed test. However, should gNBS be introduced, engaging with key interest-holders such as parents and policy-makers will be vital to ensure that the scope and limitations of gNBS are both appreciated and accepted, and that public trust in this important population screening program is maintained.
Rare disease studies often rely on small, selected cohorts, are resource-intensive and difficult to scale. UK primary care electronic health record (EHR) databases provide population-based, longitudinal data, but their u...Rare disease studies often rely on small, selected cohorts, are resource-intensive and difficult to scale. UK primary care electronic health record (EHR) databases provide population-based, longitudinal data, but their use for rare genetic disease research has not been systematically examined. Through systematic mapping of publications from five UK primary care EHR databases (CPRD, OPCRD, QResearch, SAIL Databank and THIN), we found that only 0.82% (47 of 5754) of studies reported on rare genetic diseases. Of these, 77% (36 of 47) linked to external datasets. Study designs included case-control, cross-sectional and cohort studies. Cohort designs predominated, often with individual-level matched comparators. Case ascertainment was primarily based on routinely recorded diagnostic codes. Most studies examined a single disease, collectively encompassing 23 conditions. There was a skew towards multisystem, neurological, autosomal dominant and single-gene disorders, with relatively higher population frequencies and therapeutic tractability. Rare disease sample sizes ranged from 21 to 5059 (median 392). Important insights were revealed into phenotypic variation, phenotype expansion, complications and management outcomes, including findings not readily identifiable in traditional studies. Examples include higher prevalence of hereditary haemorrhagic telangiectasia in females, consistent with sex-modified phenotypic expression; non-skeletal complications and premature mortality in X-linked hypophosphataemia; and elevated malignancy risk in myotonic dystrophy type 1 with type 2 diabetes, potentially attenuated by metformin. In conclusion, UK primary care EHR databases are markedly underutilised for rare genetic diseases. For many conditions, limited availability of diagnostic codes is a constraint. However, their demonstrated capacity, scale, scope and population representativeness support wider use.
Robust evidence is required to support decision-making about incorporating genomics into healthcare; patient perspectives are crucial. Prior studies centre on people giving research consent for testing, yet significant d...Robust evidence is required to support decision-making about incorporating genomics into healthcare; patient perspectives are crucial. Prior studies centre on people giving research consent for testing, yet significant differences between research and clinical cohorts are well established. We investigated 1690 patients offered genomic testing during clinical care by a range of medical specialists, for rare diseases and cancer. Ninety per cent (1515) accepted testing. Of 74 decliners providing their reasons, 20 gave genomic-specific concerns. Impact and experiences of care were captured using surveys after consent (S1:RR 73%) and return of results (S2:RR 53%). We actively included those often missing from research, e.g. 8% of S2 respondents accepted telephone assistance - typically with interpreters - to complete surveys. Those who spoke English as an additional language were less likely to have received enough information at pre-test counselling (88% v 96%) and less likely to correctly answer questions about potential genomic test results. After receiving results, 10% (52/534) of respondents had moderate-high decision regret; predictors included English as an additional language and not receiving enough information at consent. Value from testing was quantified and compared: those with informative results valued their medical and personal utility; those with uninformative results derived social utility. Perceived personal control increased post-result for those with diagnostic results and decreased for those with uninformative results. Our results expand the evidence base available for genomic health technology assessment. On balance, genomic test results provide more value than harm, but equity issues need to be addressed to ensure all patients can benefit.
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder regarded as having near-complete penetrance, a view largely derived from clinically ascertained cohorts. As genomic newborn screening is piloted internat...Tuberous sclerosis complex (TSC) is a genetic multisystem disorder regarded as having near-complete penetrance, a view largely derived from clinically ascertained cohorts. As genomic newborn screening is piloted internationally, robust estimates of penetrance and expressivity in unselected populations are urgently needed. We analysed genome sequencing data from >900,000 adults in UK Biobank (UKB) and the All of Us Research Program (AoU), representing multiple genetic ancestries, to identify individuals carrying high-confidence ACMG/AMP (likely) pathogenic TSC1/TSC2 variants. Electronic health records and self-reported data were interrogated for TSC-related phenotypes, including diagnostic codes, and evidence of epilepsy, chronic kidney disease and other hamartomas. We identified 61 adults with (likely) pathogenic TSC1/TSC2 variants and phenotype data available. Only 20/61 (33%) had a recorded diagnosis of TSC and a further 8/61 (13%) had at least one TSC phenotype; 33/61 (54%) had no recorded TSC diagnosis, manifestations or suggestive medication history, despite median age ≥55 years (UKB ≥ 75 years) with extensive longitudinal healthcare data. Apparent reduced penetrance was observed for TSC1 in both cohorts (46.6% UKB, 46.1% AoU), consistent with previously reported milder phenotypes associated with this gene. Apparent TSC2 penetrance was also incomplete (27.8% UKB, 66.7% AoU, p = 0.038, not significant after Bonferroni correction). Borderline significant apparent penetrance differences between UKB and AoU were not explained by gene, variant class, or ClinVar designation, but may reflect healthy volunteer bias in UKB. Overall, these findings challenge the assumption of near-complete penetrance for (likely) pathogenic TSC1/TSC2 variants and have important implications for genomic newborn screening, variant interpretation and counselling of asymptomatic carriers.