Variants in TTN are frequently identified in the genetic evaluation of patients with LGMD.  However, since only one specific TTN variant is known to cause LGMD (the recessive 11-bp insertion/deletion found in LGMD2J) such variants are often considered incidental and/or variants of uncertain clinical significance (VUS).

To review, classify, and investigate the clinical significance of TTN variants identified in patients with limb-girdle muscular dystrophy (LGMD) phenotypes who underwent next-generation sequencing (NGS) in a tertiary care clinic.  

TTN variants (laboratory-classified as pathogenic, likely pathogenic, or VUS) were aligned, mapped, and adjudicated. Variants considered potentially causative of the LGMD phenotype were investigated via segregation analysis and family studies.

Among LGMD patients who underwent NGS in a tertiary care clinic, 20 patients with one or more variants in TTN were identified.  Missense TTN variants, classified as VUS by the laboratory, were identified in 5/20 (25.0%); these were not investigated.  Two patients (2/20; 10.0%) had pathogenic TTN missense variants associated with HMERF.  The remainder (13/20; 65.0%) had other variants in TTN, including truncating mutations and deletions, that were variously classified by laboratories as VUS, or likely pathogenic for cardiac disease; these were investigated via segregation analysis and family studies whenever possible.  In 4/20 cases (20.0%), truncating or deletion variants affecting the A-band were shown to segregate in a dominant fashion with a LGMD phenotype; in each pedigree, at least one affected person with LGMD was also found to have dilated cardiomyopathy (DCM).

Truncating and deletion variants in TTN may cause autosomal dominant LGMD with DCM.  The clinical spectrum of titinopathies may be broader than previously recognized and pathogenic variants in TTN may account for a portion of the 60% of LGMD cases which are currently genetically uncharacterized.  This study shows the value of segregation and family studies in the interpretation of NGS findings.