Swaroop Aradhya

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 .

The identification of numerous genetically based epilepsies has resulted in the widespread use of genetic testing to inform epilepsy etiology. Our study aims to investigate whether a difference exists in the diagnostic evaluation and healthcare‐related cost expenditures of pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis through multigene epilepsy panel (MEP) testing and comparing those who underwent early (EGT) versus late genetic testing (LGT). Testing was defined as early (less than 1 year), or late (more than 1 year), following clinical epilepsy diagnosis. A retrospective chart review of pediatric individuals (1–17 years) with epilepsy of unknown etiology who underwent multigene epilepsy panel (MEP) testing identified 28 of 226 (12%) individuals with a pathogenic epilepsy variant [EGT n = 8 (29%); LGT n = 20 (71%)]. The average time from clinical epilepsy diagnosis to genetic diagnosis was 0.25 years (EGT), compared with 7.1 years (LGT). The EGT cohort underwent fewer metabolic tests [EGT n = 0 (0%); LGT n = 16 (80%) (P < 0.01)] and invasive procedures [EGT n = 0 (0%); LGT n = 5 (25%) (P = 0.06)]. Clinical management changes implemented due to genetic diagnosis occurred in 10 (36%) patients [EGT n = 2 (25%); LGT n = 8 (40%) (P = 0.76)]. Early genetic testing with a MEP in pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis is associated with fewer non‐diagnostic tests and invasive procedures and reduced estimated overall healthcare‐related costs.Plain language summary: This study aims to investigate whether a difference exists in the diagnostic evaluation and cost expenditures of pediatric patients (1‐17 years) with epilepsy of unknown cause who are ultimately diagnosed with a genetic cause of epilepsy through multigene epilepsy panel testing and comparing those who underwent early testing (less than 1 year) versus late testing (more than 1 year) after clinical epilepsy diagnosis. Of the 28 of 226 individuals with a confirmed genetic cause of epilepsy on multigene epilepsy panel testing, performing early testing was associated with fewer non‐diagnostic tests, fewer invasive procedures and reduced estimated overall healthcare‐related costs.

Genomic sequencing has led to the identification of many rare, novel DNA variants in diverse populations. To determine whether a variant is associated with disease, laboratory geneticists follow guidelines for weighing clinical information, population allele frequency, in silico projections of molecular effects, and other evidence.¹ Classifying variants as pathogenic or likely pathogenic (P/LP) helps clinicians confirm diagnoses, provide prognoses, refine treatment strategies, and address risks for family members.² However, as evident in the National Institutes of Health’s ClinVar database,³ many variants are classified as variants of uncertain significance (VUSs) because available evidence at the time of their discovery is not sufficient to establish their involvement in disease. VUSs can be reassessed when additional evidence emerges, sometimes leading to reclassification as P/LP or benign or likely benign (B/LB).

Cover legend: Aradhya etal., Am J Med Genet C Semin Med Genet 2023, 10.1002/ajmg.c.32057. image