Background: Genetic testing is valuable to confirm molecular diagnosis in nearly 60% of cases suspected of hypertrophic cardiomyopathy (HCM). However, the interpretation of variants, especially those of uncertain significance (VUSs), remains challenging for laboratories and clinicians. In April 2024, the ClinGen Cardiomyopathy Variant Curation Expert Panel (VCEP) adapted the ACMG/AMP criteria for eight of the sarcomeric genes ( MYH7 , MYBPC3 , TNNI3 , TNNT2 , TPM1 , ACTC1 , MYL2 , and MYL3 ), providing a refined framework for variant interpretation in these genes. This retrospective study re‐evaluated 69 VUSs identified in 84 HCM patients between 2017 and 2024, aiming to resolve uncertainty and reduce the VUS rate. Methods: Here, two groups of curators reinterpreted variants with the most recent data using the Cardiomyopathy VCEP specifications until a consensus was reached. To streamline the process, we created a semiautomated decision support tool based on these gene‐specific rules. Results: The application of the Cardiomyopathy VCEP specifications resulted in the reclassification of 17.4% ( N = 12/69, 95% CI: 10.2%–28.0%) of VUS, whereas the new data alone were not sufficient. Out of the reclassified variants, 91.7% ( N = 11/12) were downgraded to benignity (involving 17 patients), and 8.3% were upgraded to pathogenicity (involving one patient), with a mean reclassification time of 68.3 months, corresponding to 5.7 years. The most applied criteria were related to population (PM2 = 55 % ; BA1/BS1 = 16 % ), bioinformatic prediction (PP3 = 45 % ; BP4 = 25 % ), and critical domains (PM1 = 21 % ). However, most codes suffer from a lack of evidence (segregation data, functional assays, and case‐control studies). When comparing this curation with classifications in public databases, 13.3% ( N = 8/60) and 16.2% ( N = 11/68) of variants listed as having inconclusive significance in ClinVar and CardioClassifier were, respectively, reclassified in this study. Conclusion: Using gene‐specific ACMG/AMP criteria reduces the rate of VUS, increasing diagnostic yield, and informing clinical management in the context of HCM. Nonetheless, ongoing efforts to generate evidence and promote standardization remain essential to improve variant interpretation.

Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs.

Silvia Caroselli, M.Sc., Marco Fabiani, Ph.D., Caterina Micolonghi, M.D., Camilla Savio, M.Sc., Giacomo Tini, M.D., Ph.D. , Beatrice Musumeci, M.D., Erika Pagannone, M.D., Aldo Germani, Ph.D., Fabio Libi, M.Sc., Vincenzo Visco, M.D., Antonio Pizzuti, M.D., Camillo Autore, M.D., Simona Petrucci, M.D., Ph.D., Speranza Rubattu, M.D., and Maria Piane, Ph.D.. Ann Lab Med -0001;0:. https://doi.org/10.3343/alm.2024.0201

Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant acquired risk factors for DCM (hypertension, diabetes, smoking habit, and/or previous alcohol and cocaine abuse) and with a family history of both DCM and sudden cardiac death. The left ventricular systolic function, as assessed by standard echocardiography, was 20%. The genetic analysis performed using TruSight Cardio panel, including 174 genes related to cardiac genetic diseases, revealed a novel nonsense TTN variant (TTN:c.103591A > T, p.Lys34531*), falling within the M-band region of the titin protein. This region is known for its important role in maintaining the structure of the sarcomere and in promoting sarcomerogenesis. The identified variant was classified as likely pathogenic based on ACMG criteria. The current results support the need of genetic analysis in the presence of a family history, even when relevant acquired risk factors for DCM may have contributed to the severity of the disease.

Hereditary cardiomyopathies (CMPs), including Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Dilated Cardiomyopathy (DCM), and Hypertrophic Cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in Next-Generation Sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated to CMPs. Nowadays, a set of core genes is included in diagnostic panels for ARVC, DCM, HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines, provides a thorough overview of the genetic landscape of minor genes in CMPs and offers insights for future research and translation to clinical practice. Given the increasing knowledge on these less-understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life.