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The Italian Society of Human Genetics (SIGU) Working Group on Pharmacogenomics has released recommendations for the implementation, interpretation and reporting of germline pharmacogenetic testing in clinical practice within the Italian National Health Service (SSN). These guidelines outline the key principles for the responsible use, reporting, and interpretation of pharmacogenetic data, emphasizing clinical validity, clinical utility, cost-effectiveness, and ethical considerations. With the aim of promoting a systematic standardized, and evidence-based implementation of germline pharmacogenetic testing in Italy, SIGU strongly recommends addressing the following points: (1) Pharmacogenetic testing should be performed based on validated scientific evidence, primarily following Association for Molecular Pathology (AMP) and Dutch Pharmacogenetics Working Group (DPWG) guidelines, and restricted to gene-drug pairs with ClinPGx clinical annotation level 1 A. (2) Patients must be appropriately informed and provide specific consent, particularly when pharmacogenetic data are derived as secondary findings from diagnostic next generation sequencing (NGS) analyses. (3) Testing should prioritize clinically actionable variants that influence therapeutic efficacy or prevent severe adverse drug reactions. (4) The interpretation and reporting of results must be carried out by a qualified geneticist in collaboration with clinical pharmacologists to ensure appropriate therapeutic recommendations. (5) The implementation of pharmacogenetic testing should be supported by robust quality assurance procedures in laboratories, in line with international standards. (6) The inclusion of pharmacogenetic tests in the Italian LEA (Essential Levels of Assistance) should be updated in accordance with international evidence and EMA-AIFA recommendations. (7) Further pharmaco-economic and psychosocial research is needed to evaluate the impact of pre-emptive versus reactive testing strategies on patient outcomes and healthcare sustainability.

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Haemochromatosis is a genetic disorder of iron homeostasis. It can be caused by mutations in genes encoding the iron-regulatory hormone hepcidin (HAMP), and/or genes that regulate hepcidin expression (HFE, HJV, TFR2), or a gain-of-function mutation in the gene encoding hepcidin receptor ferroportin (FPN1/SLC40A1). HFE-related haemochromatosis is prevalent predominantly in individuals of northern European descent. These mutations result in dysregulated levels or activity of hepcidin, leading to high iron-saturation of transferrin followed by progressive liver iron accumulation in the absence of anaemia. To enable and enhance the understanding of haemochromatosis in both researchers and prospective medics, this review collates and discusses the genetic basis and consequent pathophysiology of the different types of haemochromatosis within a single, comparative review. The discussion is supported by figures and a summary table that compares the haemochromatosis types for prevalence, clinical manifestations, primary organs affected, iron-related biochemical parameters and mechanisms of iron loading. Also, gain-of-function ferroportin mutation is compared to ferroportin disease, which is a loss-of-function ferroportin mutation, and shows a tendency to anaemia. Essentially, HFE-related haemochromatosis (common type) and TFR2-related haemochromatosis (rare type) show late-onset, milder and gradual iron loading, and often involve liver and joint damage. In contrast, HJV- and HAMP-related haemochromatosis (rare types) show severe and rapid iron loading in the first three decades of life, with notable cardiac and endocrine complications. Hepcidin levels are more markedly decreased in HJV-related haemochromatosis compared to HFE and TFR2 types. There are minimal to absent levels of hepcidin in HAMP-related haemochromatosis.

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.

There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey of scope, curation, reporting and sharing practices of diagnostic laboratories performing somatic testing in Australia and New Zealand. Laboratories with accreditation (n = 41) were invited in 2023 to complete a semi-structured, 25-question interview. Responses were received for 27 laboratories (66% response rate) offering solid tumour, haematological malignancy and non-cancer services. Only 36% of laboratories offered tests capturing the full breadth of variants, from single-nucleotide variants to gene fusions. Knowledge sharing was rare, with only one laboratory submitting variant classifications to a public knowledge base. Most laboratories (96%) conducted somatic testing in oncology. Of cancer laboratories, 35% offered testing considered capable of comprehensive genomic profiling (CGP). Almost half of cancer laboratories had already adopted the 2022 ClinGen/CGC/VICC oncogenicity guidelines, and 84% were using AMP/ASCO/CAP 2017 clinical significance guidelines. Only 47% of mixed discipline cancer laboratories reported biomarkers such as tumour mutational burden, with wide variation in reporting of matched therapy options. Our study has generated a unique overview of somatic laboratory practices in the region, and areas for global standardisation in somatic molecular testing and reporting. We also provide a model for practice and guideline uptake assessment, for application by other country-wide networks. This is particularly relevant in anticipation of CGP mainstreaming, with the increasing complexity of sequencing interpretation for laboratories and clinicians.

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.

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.

Preimplantation genetic testing (PGT) as a reproductive technology to prevent the transmission of genetic anomalies to offspring has been available for decades. In the Netherlands, a National Indications Committee was tasked with guiding decisions on using PGT from 2009. The multidisciplinary Committee employs a per-indication approach for evaluating conditions caused by specific pathogenic variants, using a decisional framework, and arrives at its advice through discussion. This paper reflects on the Committee's journey in safeguarding the ethical and societal acceptability of the use of PGT in the Netherlands. We performed a quantitative and qualitative analysis of relevant documentation of the Committee, issued between 2009 and 2024. The Committee advised positively on applying PGT for 134 of 192 (70%) indications. Its advice was based on the criteria 'severity and nature of the disease', 'risk' and 'treatment options' for the majority of indications. Only in a few cases, the Committee make a normative statement about severity. There was no trend observed in requests over the years and the Committee's modus operandi remained consistent. In 15 years, the Committee has shaped the application of PGT for a broad variety of genetic conditions. Through its per-indication approach, it has been able to assess a complex interplay of disease characteristics and provide consistent guidance to medical practitioners in decision-making about the use of PGT. It has served as a robust model to safeguard the ethical and societal acceptability of PGT for a future in which new and rare genetic conditions will continuously be identified.

Secondary findings (SF) identified in massive parallel sequencing raise important clinical and healthcare related questions. To get an overview on current practices of European healthcare providers (HCP), we conducted a cross-sectional survey study among 39 stakeholders-predominantly senior medical and laboratory geneticists-from 15 European countries participating in the European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS). Respondents reported considerable heterogeneity in SF management and reporting, even within countries. While 31% of responding HCP return findings from all 81 genes on the American College of Medical Genetics and Genomics (ACMG) recommended SF list version 3.2, 41% restrict SF disclosure, often excluding genes associated with cardiological or metabolic disorders or with limited clinical actionability. A further 26% do not report ACMG-listed SF at all. Notably, 70% of HCP also assess additional cancer-predisposition genes beyond the ACMG list, using in-house gene lists or national guidelines. Most HCP restrict reporting to (likely) pathogenic variants (90%) and find SF in less than 5% of genetic analyses (59%). Consent procedures and patient information practices varied, with most HCP employing opt-in consent models and genetic counselling primarily delivered by medical geneticists and genetic counsellors. Major institutional challenges raised by participants, include lack of harmonised guidelines, concerns about patient anxiety, and insufficient resources for follow-up care. The findings of this study highlight the need for robust, evidence-based European guidelines to ensure clinically relevant and patient-centred SF management.

Comprehensive genomic profiling (CGP) has significantly advanced cancer genomics by enabling broad detection of clinically relevant genomic alterations across diverse cancers. In the context of BRCA1/2, CGP has expanded analysis beyond conventional testing for hereditary breast and ovarian cancer (HBOC), thereby identifying otherwise unrecognized variants. Nevertheless, the high prevalence of variants of uncertain significance (VUS) remains a major obstacle to clinical implementation. To address this challenge, we analyzed 2172 CGP tests performed at Hiroshima University Hospital and affiliated institutions in Japan. BRCA1/2 VUS identified through CGP were systematically prioritized using an integrative framework combining in silico prediction and functional evidence. From 526 BRCA1/2 variants, 153 were classified as VUS. Our variant prioritization filter based on ten in silico predictors narrowed these to 10 candidates, including two splice-site and eight missense variants, most of which were concordant with prior functional studies. Among these, the significance of BRCA2:c.67 G > C (p.D23H, NM_000059.4) had remained unclear. Functional analysis demonstrated exon 2 skipping consistent with loss of function, and clinical observations from two patients carrying this variant showed that therapeutic responses aligned with the biology of homologous recombination deficiency. These findings present a proof-of-concept framework for prioritizing and interpreting BRCA1/2 VUS detected in real-world CGP testing. By integrating multiple in silico predictors with functional evidence, this approach enables systematic prioritization and interpretation of BRCA1/2 VUS and may be broadly applicable to variant assessment in hereditary cancer predisposition genes.

Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle of Willis (CoW) - influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate&#x2009;=&#x2009;0.95, standard error&#x2009;=&#x2009;0.25). All lead SNPs demonstrated nominal association (p&#x2009;<&#x2009;0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.

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.

Classifying germline variants in hereditary cancer genes remains challenging and requires integrating diverse lines of evidence. BoostDM is a computational method originally developed to identify somatic cancer driver mutations by detecting signals of positive selection. Given the functional overlap between somatic and germline pathogenic variants in cancer genes, we evaluated the utility of BoostDM for interpreting germline variants in hereditary cancer genes. We assessed BoostDM's performance across six genes with dual roles in sporadic and hereditary cancer (ATM, BRCA1, BRCA2, CDH1, PTEN, TP53), using gene-specific BoostDM models. A total of 1275 germline single nucleotide variants with expert-reviewed pathogenic and benign classifications were included. BoostDM scores were compared to those from AlphaMissense and REVEL, two leading pathogenicity predictors for missense variants. BoostDM correctly classified 74.5% of pathogenic/likely pathogenic and 98.6% of non-synonymous benign/likely benign variants overall. It performed particularly well for non-synonymous, non-missense variants (92.3% sensitivity). For missense variants, BoostDM correctly identified 46% of pathogenic and 95.5% of benign variants. While BoostDM did not outperform AlphaMissense or REVEL, it demonstrated high specificity (99.5%) and positive predictive value (PPV&#x2009;=&#x2009;98%) for missense variants with high scores (&#x2009;>&#x2009;0.5). Gene-specific performance varied, with TP53 showing the most robust results. In conclusion, BoostDM predictions are not a replacement for ACMG/AMP-guided germline variant classification, especially for missense changes. However, its high specificity and PPV suggest that high BoostDM scores can provide supportive evidence of pathogenicity, prompting further clinical and functional investigation.

Core myopathies are congenital diseases with clinical, pathological and genetic heterogeneity. Main histological features are fiber "cores" showing a focally reduced oxidative enzyme activity. Dusty Core Disease (DuCD) differs from Central Core Myopathy for the presence of irregular areas, without clear borders and round/ovoidal shape, and myofibrillar disorganization characterized by reddish purple granular material depositions. This disorder is defined clinically by severe phenotypes with early onset of disease and molecularly by low level of RyR1 in muscle. Until now DuCD was associated only to biallelic recessive RYR1 mutations. We analyzed the clinical aspects, pathological features and mutational spectrum of four DuCD patients, belonging to our cohort of Congenital Myopathy probands. Molecular analysis detected 5 different RYR1 pathogenic variants, two of them so far unreported. Patients presented a heterogeneous phenotype ranging from severe recessive infantile forms to moderate dominant adult-onset presentations. Histological, immunological and ultrastructural techniques were employed to validate these dominant cases, which expand our knowledge on the inheritance of this subgroup of diseases.

Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.

Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.

Abnormal RNA splicing is an underrecognized driver of pathogenicity in germline TP53 - the cause of Li-Fraumeni syndrome (LFS). We re-evaluated exonic single-nucleotide variants (SNVs) that yield missense or synonymous changes for spliceogenic effects by integrating SpliceAI prediction, in-vitro minigene assays, and analysis of tumor RNA-seq from TCGA, and assessed genotype-phenotype correlations using clinical data from multiple databases and national registries. We identified 58 spliceogenic exonic SNVs (SE-SNVs) across the TP53 gene (40 missense, 18 synonymous). Experimental validation confirmed aberrant splicing for 15 out of 17 tested variants, most often through cryptic splice-site activation that introduced frameshifts and premature termination. Clinically, carriers of SE-SNVs previously considered as mild or of low-pathogenicity by protein-based assays showed earlier onset and LFS-signature cancers, indicating that splicing disruption can override amino-acid effects. The recurrent c.375&#x2009;G&#x2009;>&#x2009;A (p.(Thr125&#x2009;=&#x2009;)) showed heterogeneous effect: with both childhood/adolescent and adult onset, consistent with partial, variable retention of canonical splicing. These data reveal a substantial burden of spliceogenic pathogenicity in TP53 and strong support integrating splicing prediction, functional validation, and transcript-level evidence into variant interpretation and risk stratification in LFS.

Hereditary cancer syndromes are among the most common inherited disorders and contribute to nearly 10% of solid tumours. While genetic testing is now central to diagnosis, surveillance, and cascade prevention, its impact is constrained by the persistent challenge of variants of uncertain significance (VUS), which comprise almost 40% of reported hereditary cancer syndrome-associated variants in ClinVar. These unresolved classifications undermine the interpretive power of testing, limiting its translational and preventive potential. In this review, we examine the foundations of variant interpretation, the role of expert-guided specifications, and emerging methods for VUS reclassification, including population-level data, RNA- and protein-based functional assays, computational predictors, and long-read sequencing. We further highlight how systematic re-evaluation structures and curation infrastructures translate new evidence into clinical practice. We conclude with an outlook on future directions to reduce the burden of VUS and increase the clinical utility of hereditary cancer syndrome testing.

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 PPIGxE; 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-&#x3b2; pathway. These results corroborate the hypothesis that modifiers in the TGF-&#x3b2; pathway affect LOA by modulating the efficacy of corticosteroid administration.