Tanha HM, Law MH, Ingold N
… +7 more, Olsen CM, Pandeya N, Milne RL, MacInnis RJ, Whiteman DC, Cust AE, Steinberg J
Eur J Hum Genet
· 2026 Feb · PMID 41526671
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Polygenic risk scores (PGS) have the potential to support enhanced, risk-based screening for breast cancer. Previous studies for many diseases found that genome-wide PGS (GW-PGS) outperform PGS derived by applying hard G...Polygenic risk scores (PGS) have the potential to support enhanced, risk-based screening for breast cancer. Previous studies for many diseases found that genome-wide PGS (GW-PGS) outperform PGS derived by applying hard GWAS significance thresholds. To support future breast cancer risk predictions, we compared the predictive performance of two existing PGS (including PGS313, a leading hard-thresholding PGS) and five newly developed GW-PGS (applying different methods to recent GWAS). We evaluated the performance of PGS Z-scores and of predicted 5-year absolute breast cancer risks based on age alone or age and PGS, across three large cohorts from the UK (UK Biobank) and Australia (QSkin, Melbourne Collaborative Cohort Study). Performance was assessed using discrimination (AUC) and calibration metrics, with dedicated evaluations for European, South Asian and African genetic ancestry groups, different age groups and for UKB, by pre-baseline mammogram screening history. Z-scores from three GW-PGS (LDpred2, PRS-CS, PRS-CS) yielded improved discrimination over PGS313, especially in European and South Asian ancestry groups (AUC improvements 2-18%, p < 0.029). Incorporating PGS substantially improved absolute risk predictions compared to age-only models, with the strongest evidence in European-ancestry groups (AUC improvements 15-39%, p < 10⁻⁴) and similar trends in non-European groups. No PGS outperformed all others across all ancestry groups. Estimated relative risk for highest GW-PGS risk groups (e.g. top 5% LDpred2) was ~2.5-fold population-average risk, similar to previous estimates for individuals with pathogenic variants in ATM and CHEK2 genes. These findings support the potential of PGS for risk-based breast cancer screening, noting that current GW-PGS may not substantially improve breast cancer risk predictions compared to PGS313.
Kleine Schaars K, Nijenhuis M, Soree B
… +11 more, de Boer-Veger NJ, Buunk AM, Guchelaar HJ, Houwink EJF, Risselada A, Rongen GAPJM, van Schaik RHN, Swen JJ, Touw D, Deneer VHM, van Westrhenen R
Eur J Hum Genet
· 2026 Mar · PMID 41526670
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The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline des...The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene-drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being "potentially beneficial". Genotyping prior to treatment can be considered on an individual patient basis.
Bylstra Y, Lim WK, Teo JX
… +8 more, Menezes M, Hodgson J, Yap F, Chambers JC, Yeo KK, Tan P, Amor DJ, Jamuar SS
Eur J Hum Genet
· 2026 Mar · PMID 41520097
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The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We invest...The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.
Mackley MP, Dickson MA, Szuto A
… +9 more, Anderson J, Chitayat D, Hayeems RZ, Mendoza-Londono R, Ng E, Offringa M, Wang YW, Ly LG, Chad L
Eur J Hum Genet
· 2026 Mar · PMID 41520096
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Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnost...Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnostic yield and potential to influence treatment and care planning decisions, little is known about how families experience rGS in the ICU and the emotional and contextual factors influencing their testing-related decisions. We conducted semi-structured interviews with twenty-three parents of infants who consented to rGS in an ICU at two tertiary hospitals in Toronto, Ontario, Canada; all interviews took place in close proximity to the decision to pursue rGS. Parents' experiences with rGS and the related genetics consultation demonstrated a complex interplay of emotional, pragmatic, relational, and temporal 'sense-making' to grasp what was happening. Overall, parents felt overwhelmed in the ICU. Some de-prioritized genetic testing compared to other aspects of care while others reflected negatively or ambivalently on rGS or felt that it was implicitly expected that they pursue it. We conclude that an rGS approach tailored to the ICU setting is needed. Consideration should be given to distributing complex decisions (such as those relating to primary vs. secondary findings) across multiple briefer visits, and alleviating decisional burden by reframing rGS as one of the many shared decisions made with families in this setting.
Gazzin A, Calvo M, Rondot F
… +31 more, Reynolds G, Leoni C, Niceta M, Dentici ML, Digilio MC, Lepri F, Monda E, Carelli I, Trevisson E, Scala I, Mancano G, Andreucci E, Stanzial F, Brancati F, Zampino G, Tarani L, Paparella R, Carli D, Villar AM, Banaudi E, Massuras S, Cardaropoli S, Daniele P, Airulo E, Riggi C, Calcagni G, Ferrero GB, Limongelli G, De Luca A, Tartaglia M, Mussa A
Eur J Hum Genet
· 2026 Feb · PMID 41507607
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Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic...Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases from a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.
Muto V, Fasano G, Radio FC
… +21 more, Pedalino C, Carvetta M, Coppola S, Zara E, Petrini S, Schluth-Bolard C, Bilbault C, El Chehadeh S, Gérard B, de Saint-Martin A, Koboldt DC, Sites E, Curry C, Herget T, Höing AS, von Elsner L, Barr EE, Hodoglugil U, Slavotinek A, Tartaglia M, Lauri A
Eur J Hum Genet
· 2026 Mar · PMID 41507605
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We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor sk...We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects. In vitro and in vivo analyses documented impaired Golgi integrity, vesicle trafficking, and brain and body axes development. Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants. Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology. Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly. These findings expand the ARF3-related Golgipathy mutational spectrum, strengthen previous observations linking variants with dominant negative behavior to a markedly severe phenotype, and underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction.
Vibert R, El Baroudi Y, Vecten M
… +8 more, Buffet A, Verkarre V, Gimenez-Roqueplo AP, Richard S, Favier J, Barlier A, Giraud S, Burnichon N
Eur J Hum Genet
· 2026 Mar · PMID 41507604
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Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene p...Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene panels (MGP) to characterize RCC linked to hereditary syndromes. The current French guidelines of the national reference network for hereditary renal cancers (PREDIR) recommend genetic testing for patients meeting specific clinical criteria. This study evaluates the diagnostic yield and the relevance of current criteria, the utility of MGP testing, and the added value of tumor analyses. We retrospectively analyzed 2057 RCC patients who underwent germline MGP testing across three French hospital laboratories. Tumor analysis results from 140 patients were also evaluated. The overall rate of germline pathogenic/likely pathogenic variants was 3.5%, with 39% in syndromic cases and 1.2% in apparently sporadic cases. Tumor analyses identified somatic pathogenic variants in 56.3% of cases. Our data support that the likelihood of identifying a germline PV is low in patients with sporadic single clear cell RCC, and that the clinical utility of testing all patients with other sporadic subtypes appears limited. This suggests a need to revise current testing criteria in patients with sporadic single RCC, for example, by lowering the age threshold for genetic testing from 45 to 40 years in clear cell RCC, and to 50 years in other subtypes. We also suggest incorporating tumor analyses to distinguish hereditary RCC from sporadic cases driven by tumor-specific pathogenic variants.
Forrest LE, Forbes Shepherd R, Spelman T
… +10 more, Keogh L, Young MA, Powell S, Beard C, Salmon L, Warwick L, Williams R, Burke J, D'Souza R, James PA
The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on wome...The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on women's reproduction, intimate partner relationships, and sexual functioning. Australian women aged 18-40 years who had predictive BRCA1/2 testing, received either a positive or negative result, and had no personal cancer history, completed an online survey that used a case-control design. Outcome measures included childbearing, use of reproductive technologies, relationship status, and sexual functioning. 579 women participated (62.0% with a BRCA1/2 PV; 38.0% without a BRCA1/2 PV). More women with a BRCA1/2 PV had children compared to those who did not (49.0% c.f., 40.5%; p = 0.045). BRCA1/2 status did not predict whether women were partnered at survey completion (Odds Ratio 1.20; 95% CI 0.80, 1.78) or their sexual functioning over the previous month (β-coefficient -0.08; 95% CI -1.15, 0.98). Women with a BRCA1/2 PV were more likely to have children after genetic testing (OR 1.83: 95% CI 1.05, 3.21) and were more likely to have a greater number of children after genetic testing (β-coefficient 0.41; 95% CI 0.10, 0.73) compared to women without a BRCA1/2 PV, after adjustment for confounders. Receiving a positive predictive BRCA1/2 result is associated with an increased likelihood of childbearing and having a greater number of children compared to receiving a negative predictive BRCA1/2 result. These findings contribute to the evidence base to inform long-term follow-up for women after predictive BRCA1/2 testing.
Ratnaike TE, Kule ME, Paramonov I
… +4 more, Matalonga L, Polavarapu K, Olimpio C, Horváth R
Eur J Hum Genet
· 2026 Mar · PMID 41454053
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Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenot...Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.
Koebbe LL, Hess T, Haas SL
… +40 more, Gockel I, Piessen G, Latiano A, Pereira C, Malecka-Wojciesko E, Mokrowiecka A, Boccia S, Majewski M, Alakus H, Lanas Á, Pastorino R, Goetze TO, Elbe P, Kreuser N, Palmieri O, Tavano F, Bruns CJ, Glehen O, B D'Journo X, Gronnier C, Fabre JM, Sulpice L, Bujanda L, Moreira L, Heilmann-Heimbach S, Billmann M, Noethen MM, Cannizzaro R, Ghidini M, Hamann L, Aragones N, Dinis-Ribeiro M, Medeiros R, Al-Batran SE, Leja M, Kupcinskas J, García-González MA, Maj C, Venerito M, Schumacher J
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline ex...Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in CDH1 and ATM were enriched among GC cases. Beyond GC, ATM LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, ATM should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with ATM PVs occur alongside GC.
Eur J Hum Genet
· 2026 Feb · PMID 41444428
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Protein glycosylation defects can present with early-onset brain malformations and muscular dystrophy or milder, late-onset muscular dystrophy. Here, we report a new glycosylation defect with an atypical phenotype of lat...Protein glycosylation defects can present with early-onset brain malformations and muscular dystrophy or milder, late-onset muscular dystrophy. Here, we report a new glycosylation defect with an atypical phenotype of late-onset, progressive, severe brain atrophy and muscular dystrophy in a 47-year-old man. Exome sequencing revealed a homozygous highly deleterious c.478G>T (p.G160W) variant in the B3GNT4 gene. A knock-in mouse model replicated the patient's muscle histology. B3GNT4 is expressed at very low levels in the thalamus, and this region was selectively preserved in the patient. The study demonstrates the first disease associated with one of the seven B3GNT galactosyltransferases and the importance of B3GNT4 in adolescence to adult muscle and CNS development.
Hereditary diffuse gastric cancer (HDGC) and Lynch syndromes are dominant hereditary diseases caused by pathogenic germline variants in specified genes, and characterised by a broad spectrum of malignancies. Whereas HDGC...Hereditary diffuse gastric cancer (HDGC) and Lynch syndromes are dominant hereditary diseases caused by pathogenic germline variants in specified genes, and characterised by a broad spectrum of malignancies. Whereas HDGC is associated with CDH1 and CTNNA1 variants and defined by an increased risk of diffuse gastric cancer and lobular breast cancer, Lynch syndrome results from alterations in mismatch repair genes, whose main manifestations include colorectal, endometrial, ovarian, breast, prostate, stomach, and urological tumours. Remarkably, a huge difference remains in the knowledge surrounding the molecular mechanisms that drive these disorders, and in current approaches for patient management. In fact, the HDGC narrative is still in its early stages when compared with Lynch syndrome, which accumulates more than a century of research. Herein, we propose an analogy between HDGC and Lynch syndromes, highlighting intricacies across genetic origin, variant effects, cellular landscapes, and associated clinical outcomes. Further, we postulate that the history of Lynch syndrome may be useful to advance HDGC aetiology, namely strategies for identification of new candidate genes, rules for variant interpretation, sources of phenotypic heterogeneity, and improved surveillance protocols. This collected data will impact clinical perspectives, as well as future research programs addressing HDGC unmet challenges.
Mulhern S, Morrish AM, Connell V
… +2 more, Hickerton C, Macciocca I
Eur J Hum Genet
· 2026 Mar · PMID 41392322
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Inherited cardiac conditions (ICCs), like inherited cardiomyopathies (ICMs) and long QT syndrome (LQTS), are serious genetic conditions that carry a risk of sudden death. Predictive genetic testing (PT) is routinely avai...Inherited cardiac conditions (ICCs), like inherited cardiomyopathies (ICMs) and long QT syndrome (LQTS), are serious genetic conditions that carry a risk of sudden death. Predictive genetic testing (PT) is routinely available, however, the impact of this testing during the adolescent period is understudied. To understand the lived experience of young people who have undergone PT for ICCs, semi-structured, in-depth interviews were conducted with young people who underwent PT for an ICC between the ages of 10-17 years between January 2009 and July 2020. Their parents were also invited to participate. Participant experiences and views relating to the PT process were explored. Inductive thematic analysis was used to elicit a deep understanding of the experiences and needs of this cohort. Nineteen predictively tested young people were interviewed (8 tested for ICM, 11 for LQTS; of these, 11 were gene-positive) as well as 15 parents. Three intersecting themes were identified: 'it's a family affair' (impact of/on family relationships and experience of the condition); 'post-test day-to-day implications' (impact of integrating gene-status on self-perception); and 'needing developmentally-appropriate intervention and support' (recognising the evolving needs of the young person as an individual and within their family unit). Young people, regardless of their gene status, require individualised support and follow-up. Family structure and experience influences perception and understanding of the PT process, highlighting the need to appropriately involve, support and educate all family members.
de Wert G, van El CG, Clarke A
… +14 more, Cordier C, Fellmann F, Genuardi M, Hentze S, Kayserili H, Macek M, MacLeod R, Melegh B, Mendes Á, Rial-Sebbag E, Stefánsdóttir V, Tranebjærg L, Ulph F, Forzano F
Eur J Hum Genet
· 2026 Feb · PMID 41392321
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Cascade testing (CT) is an effective instrument for identifying an index patient's relatives at high risk of a heritable condition enabling informed decision-making on preventive interventions and reproductive choice. Ho...Cascade testing (CT) is an effective instrument for identifying an index patient's relatives at high risk of a heritable condition enabling informed decision-making on preventive interventions and reproductive choice. However, CT remains underutilised and faces barriers. Discussions are ongoing on how to optimise informing family members and testing uptake in a responsible manner. The European Society of Human Genetics (ESHG) contributes to this debate and provides recommendations based on an ethical analysis of when CT is justified, or may be less compelling, considering proportionality and the judicious use of finite resources. ESHG underscores the strong consensus regarding the 'moral architecture' of CT in cases of a high risk of serious, avoidable harm. In such cases, a more active approach towards CT is suggested, including a more directive approach in counselling, more active support for the proband, direct contacting, and balancing confidentiality when this is necessary to avoid a high risk of serious harm, taking account of national regulations and jurisdictions. In contrast, more caution is advised in more complex cases where the balance of benefits and harms of CT is less clear, such as when penetrance is low, and actionability or medical treatment is limited. This more cautious approach does not call for directivity, direct contact or the relaxing of medical confidentiality. The focus, then, shifts to cascade counselling, rather than cascade testing. In some cases, CT may not be proportional or appropriate given the balance between benefits and harms, also in view of available resources.
Implementation of genomics in newborn screening is rapidly becoming a reality through accelerated clinical research and investment in genomic sequencing programs. The perspectives of parents who have experienced genetic...Implementation of genomics in newborn screening is rapidly becoming a reality through accelerated clinical research and investment in genomic sequencing programs. The perspectives of parents who have experienced genetic screening and technologies can inform effective clinical translation and co-design of a model of care for future programs. Semi-structured interviews were undertaken with 23 parents of children diagnosed with genetic conditions. Data were evaluated using inductive content analysis methods. Parents valued expeditious, contemporary and accurate information from specialists to manage uncertainties and aid decision-making upon receiving a genomic diagnosis, alongside coordination and collaboration with local services to provide child and family centred care. Integration of psychosocial support into genomic NBS programs was highlighted as an important strategy to mitigate potential psychological risks of receiving a newborn genomic screening result. Integrating genomic NBS in current health ecosystems requires a model that provides care and support across the healthcare journey for the child and family. Information provision and consent at screening facilitates familial understanding of the implications of genomic screening. Equitable access to post screening care and expertise is essential to optimise health and psychosocial outcomes for the child and family and maintain parental acceptability.