Genetics in Medicine最新文献

Recent advances in personalized therapies for germline genetic disorders are expanding the clinical utility of genome sequencing beyond diagnosis and risk assessment. In this perspective, we introduce interventional genomics as a clinical paradigm in which germline genomic testing serves as the starting point for personalized treatment planning that integrates established and emerging therapeutic options. Drawing lessons and parallels from oncology, we propose embedding structured treatment insights into germline genomic reports, supported by a standardized lexicon of pathogenic mechanisms, therapeutic feasibility frameworks, and dedicated informatics tools. To translate this vision into clinical practice, we also propose the establishment of multidisciplinary Interventional Genomics Boards and explore the infrastructure needed to support such diagnosis-to-treatment workflows in the clinic. We also highlight the need to train a new class of clinicians with expertise in genomic interpretation and therapeutic design. Such clinicians must be able to interface with preclinical development efforts, clinical trial execution, and the rapidly evolving regulatory frameworks that govern genomic therapies. Finally, regulatory complexities and access-related challenges that will affect equitable implementation across diverse clinical settings are also discussed.

Purpose: Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease (chILD). Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of chILD. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants.

Methods: Phenotypic data was collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, WB, and flow cytometry.

Results: Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For one participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular LB. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation.

Conclusions: Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) affects 1:1000, causing 5-10% of kidney failure. The primary disease gene, PKD1, has six pseudogenes with 97-99% homology, a >12kb transcript, high GC content, and polypyrimidine tracts. While long-range PCR with Sanger sequencing has been the "gold-standard", next-generation sequencing (NGS) is increasingly used.

Methods: We performed exome sequencing (ES) on 203 ADPKD patients in 171 families from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort, with prior "gold standard" results: n=157 PKD1, n=27 PKD2, n=19 with no pathogenic variant detected. Clinical geneticists, blinded to genotype, reviewed ES data. We assessed effects of pipeline modifications, exome capture reagents, pseudogene alignment, and deeper ES or genome sequencing (GS) for unsolved cases.

Results: Optimized ES identified 95.5% of defined PKD1 pathogenic variants, all PKD2 variants, and at least 9 of 19 "unsolved" cases. Standard pipelines on research-grade ES missed at least 22 PKD1 variants due to GATK HardFiltering or alternative locus annotation. Higher-depth ES achieved 100% PKD1 variant detection. GS identified a balanced translocation t(1;16)(q31.1;p13.3).

Conclusion: NGS matches "gold-standard" sensitivity, and considers additional disease genes. ES plus GS solve 96% of well-phenotyped ADPKD. We outline practical considerations for NGS on PKD1.

Background: Thoracic aortic aneurysms (TAA) are typically asymptomatic until rupture or dissection, with research indicating up to 20% may have a genetic basis. This study evaluates the prevalence of hereditary aortopathies and the utility of genetic testing in adults with TAA applying current ACC/AHA guidelines.

Methods: We assessed 1,323 consecutive adult patients presenting for TAA evaluation between July 2022 and April 2025 at a large aortic center, enrolling 426 patients who underwent guideline-driven genetic testing. Median(IQR) age was 57 (50-64) years, 22.8% were female, and 11.3% had BAV. Mean aortic diameter was 4.6±0.48cm; 67.1% had TAA and 2.1% had dissections. Statistical analyses assessed the prevalence of genetic aortopathies and risk factors.

Results: Of the 426 patients, 2.6% had diagnostic tests identifying pathogenic variants, 68.3% tested negative, and 29.1% had variants of unknown significance(VUS). Diagnostic tests were significantly associated with younger age(p=0.05) and root aneurysms(p<0.001). No VUS associations were demonstrated. Gender and BAV were not associated with diagnostic tests or VUS. TAA diagnosis <60 years and familial history had the highest utility of the ACC/AHA recommendations, but were not significant.

Conclusions: Our findings suggest a lower prevalence of genotype-positive TAA than previously reported in all TAA patients; highlighting the need for more refined genetic testing criteria focusing on high-risk individuals. Further research is essential to better define genetic testing's role in TAA management.

Kleefstra syndrome (KLEFS1) is a rare monogenic neurodevelopmental disorder (mNDD) with multisystem involvement, caused by disruption of EHMT1 function, resulting in significant burden on affected individuals and their families. The current shortage of and globally scattered syndrome-specific knowledge has led to significant disparities in the access to and provision of evidence-based and individual-centered expert care. To address the challenges and improve outcomes for individuals with KLEFS1, an international KLEFS1 guideline consortium was formed consisting of 43 participants, both clinical experts and patient-representatives, from 15 different countries. The primary goal of the consortium was to develop a comprehensive and high-quality guideline for KLEFS1, aiming to enhance patient care, establish a uniform minimum international standard of care, and support decision-making. The current clinical guideline is evidence-based and includes 66 tailored recommendations to improve KLEFS1 care. The comprehensive methodological approach ensures broad consensus and supports effective implementation. Furthermore, this guideline serves as a valuable methodological model for guideline development in the context of rare disorders.