Hypertrophic cardiomyopathy (HCM) is a major contributor to morbidity and mortality in Noonan syndrome (NS), with a high risk of heart failure and arrhythmias. Lymphatic dysplasia represents another clinically significant manifestation often associated with significant morbidity. Emerging evidence suggests that MEK inhibitors may target these severe complications. Seven pediatric patients with molecularly confirmed NS and severe, treatment-refractory HCM and/or lymphatic effusions received oral trametinib treatment under compassionate use. Clinical, biochemical, and echocardiographic parameters were longitudinally assessed to evaluate efficacy and safety. Transcriptomic analysis of RAS/MAPK pathway-related gene expression was performed in a subset of patients at baseline, one week after treatment initiation, and during prolonged therapy. Trametinib treatment was maintained at doses ranging from 0.0075 to 0.033 mg/kg/day for 3–45 months. All patients showed a rapid decrease in NT-proBNP levels, followed by significant reductions in interventricular septal thickness and, when present, left ventricular outflow tract obstruction. In patients with lymphatic dysplasia, trametinib was associated with sustained reduction of pleural effusions and improved respiratory status. Treatment discontinuation led to progressive clinical and biochemical worsening, with improvement after reintroduction, when performed. Transcriptomic analysis demonstrated early modulation of RAS/MAPK pathway signatures in most patients. Adverse events were mild (grade 1), predominantly dermatological, and manageable with dose adjustments. These findings provide additional clinical and molecular evidence supporting trametinib treatment as a targeted therapeutic strategy for cardiac and lymphatic manifestations in NS. Prospective studies are needed to define long-term safety, optimal dosing, and treatment duration of MEK inhibition in NS and other RASopathies.
Genomic newborn screening (NBS) has emerged as a powerful complement to conventional screening; however, its clinical utility remains to be fully established. We conducted a prospective multicenter pilot study within the Seoul National University Hospital network from November 2025 to February 2026. A panel of 419 genes was curated by a multidisciplinary expert team based on early childhood onset, disease severity, the presence of an asymptomatic window, and the local availability of effective treatments. Genome sequencing was performed on 399 newborns, including six monozygotic twin pairs analyzed as single data points. In addition to 385 inborn neonates, 14 neonates referred because of abnormal conventional NBS results were included. As a result, the screen-positive rate was 1.3% (5/393). Two positive cases with variants in SLC25A15 and MYO15A were missed by conventional NBS, and we also identified three cases harboring pathogenic variants in arrhythmia-associated genes, a category inherently beyond the scope of conventional screening. Among 49 neonates with abnormal conventional NBS results, all were negative on genomic NBS. The median turnaround time from sample collection to final report was 26 days. Genomic NBS demonstrated favorable precision and complementary clinical utility beyond conventional screening. Regular multidisciplinary curation of target genes and long-term longitudinal follow-up are essential for successful clinical implementation.
Cornelia de Lange syndrome (CdLS) is a rare congenital disorder characterised by craniofacial features, growth retardation, limb anomalies, and intellectual disability. The condition arises from pathogenic variants in genes encoding cohesin complex components or regulators, most frequently NIPBL. Despite advances in genomic testing, approximately 30% of clinically diagnosed cases remain unresolved, suggesting the presence of non-coding variants. We investigated 10 classical CdLS patients negative for pathogenic variants in NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Genome-wide methylation profiling was performed to identify CdLS-specific epigenetic signatures. Episignature-positive cases underwent trio-based deep sequencing of the entire NIPBL locus while targeted NIPBL RNA sequencing was used to assess splicing. Whole-genome sequencing (WGS) was performed in episignature-negative individuals. Five of ten patients exhibited a positive CdLS episignature in blood, saliva, or skin. Deep sequencing identified de novo deep intronic NIPBL variants in all cases, and two additional variants in episignature-negative patients. Seven distinct intronic variants were identified across introns 4, 10, 21, and 32. In silico tools predicted the creation or activation of cryptic splice sites in six variants. RNA sequencing confirmed pseudoexon inclusion in three patients, leading to premature termination codons and predicted nonsense-mediated decay. Tissue-specific variation in aberrant transcript expression was observed between blood and fibroblasts. We conclude that deep intronic NIPBL variants represent an under-recognised cause of CdLS, frequently escaping detection by conventional exome analysis. Integration of methylation episignatures, deep intronic sequencing, and RNA analysis enhances diagnostic yield and provides insight into the regulatory architecture of cohesinopathies.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer predisposition syndrome in which uterine leiomyomas (ULs) are common, morbid, and often precede renal cancer diagnosis. We synthetized evidence on the clinical presentation, pathology, management, and reproductive outcomes of HLRCC-associated ULs. MEDLINE, Embase, Scopus, Web of Science Core Collection, and ClinicalTrials.gov were searched for peer-reviewed studies reporting original data on ULs in HLRCC. Two reviewers independently screened articles and extracted data. Individual patient data from 410 patients and aggregate data from 27 observational studies were included. Mean age at UL diagnosis was 32.4 years. Most patients (89.1%) had multiple fibroids, were symptomatic (88.1%), and commonly reported abnormal uterine bleeding (80.6%) or pelvic pain (41.2%). Average maximum fibroid size was 7.5 cm. Fumarate hydratase (FH) and/or S-(2-succino)cysteine (2SC) immunohistochemistry studies showed abnormal staining in >85% of tumors. Surgical intervention was required in 94.4% of patients; hysterectomy was most common (67.0%), at a mean age of 35.2 years, whereas myomectomy was performed in 27% at 27.7 years. Despite a family history of HLRCC-related features in 88.8% of patients, only 0.6% underwent germline FH testing before gynecologic diagnosis. Fertility and obstetric outcomes were sparsely reported. Uterine leiomyosarcoma was rare, with an uncertain syndromic association. HLRCC-associated ULs are genetically, morphologically, and clinically distinct from sporadic fibroids, yet remain under-recognized. Integrating age, multiplicity, symptoms, family history, and pathology-triggered FH/2SC immunohistochemistry into gynecologic practice would enable earlier germline testing, renal surveillance, and reproductive counseling. Prospective registries are needed to define genotype–phenotype relationships, fertility outcomes, and leiomyosarcoma risk.
