Yi-Lee Ting

Primary immunodeficiencies (PI), or inborn errors of immunity (IEI), are a clinically heterogeneous group of more than 550 monogenic disorders for which early molecular diagnosis is essential to guide management and improve outcomes. To address global barriers to genetic testing, the Jeffrey Modell Foundation implemented Jeffrey’s Insights, a no-cost next-generation sequencing (NGS) program delivered through the global Jeffrey Modell Centers Network. From 2019 to 2025, 5,991 patients across 59 countries underwent NGS testing, resulting in a molecular diagnostic yield of 22.7%. Molecular diagnostic yields were highest in Australia and New Zealand (40.9%), Asia (31.6%), and the Middle East and Africa (31.3%). Among 1,482 patients with clinician-reported follow-up, NGS altered diagnosis (38.1%), management (37.0%), treatment (32.8%), and genetic counseling (50.6%), and improved clinical outcomes (31.3%). Physicians reported on healthcare utilization and barriers to care prior to testing. These findings underscore the value of NGS as an available first-tier test for suspected PI and highlight the need for broader global access to genomic diagnostics.

Genetic testing for cardiomyopathy and arrhythmia (CM/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM/ARRH genetic testing. This was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results. Among 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives? care. Of these, 75 (55.1%) received recommendations for the patient?s own care, most frequently additional diagnostic tests/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66/138, 47.8% vs 9/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009). The results from CM/ARRH genetic testing on affected patients influenced cardiologists? medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM/ARRH impact health outcomes.

BACKGROUND: Truncating variants (TTNtvs) in the titin ( TTN ) gene have been associated with cardiomyopathies or arrhythmias (C/A) and autosomal recessive neuromuscular diseases (NM). However, the clinical significance of TTNtvs across the entire coding sequence of TTN has not been comprehensively assessed. The purpose of this study was to examine the burden of TTNtvs in C/A and NM cases compared with controls in the genome aggregation database. METHODS: This was a retrospective study of probands who underwent multigene testing (49 740 C/A panel, 24 514 NM panel) that included TTN from November 2017 to October 2021. Burden testing was performed using controls in the genome aggregation database v3.1.2 database, and the analysis was stratified by exon/band location and exon usage in cardiac or skeletal muscle. Frequency and odds ratio of TTNtv alleles in C/A or NM cases and genome aggregation database controls were measured. RESULTS: There were 2446 (4.9%) C/A and 482 (2.0%) NM cases with 2446 and 528 TTNtv alleles, respectively. TTNtvs in all bands were significantly enriched in both C/A and NM cases compared with controls. A significant enrichment of TTNtvs in C/A was observed for exon 358 of the M-band (odds ratio, 2.55 [95% CI, 1.85–3.54]) but not the other M-band exons. CONCLUSIONS: In the largest single-site cohort of C/A and NM cases with TTNtvs, an enrichment of TTNtvs across TTN was observed. These findings expand the clinically relevant regions of TTN .