Novel compound heterozygous mutations in the TTN gene: elongation and truncation variants causing limb-girdle muscular dystrophy type 2J in a Han Chinese family.

Introduction: Limb-girdle muscular dystrophy (LGMD) is a group of clinically heterogeneous muscle disorders commonly manifesting proximal limb girdle muscle weakness. There have been more than 30 subtypes of LGMD associated with causative genes and limb-girdle muscular dystrophy type 2J (LGMD2J) is caused by mutations in the TTN gene.

Methods: We report a Han Chinese family with LGMD2J. The proband and his sister both presented with weakness in the proximal lower limbs bilaterally. Muscle biopsy and genetic analysis were performed.

Results: Muscle biopsy of the proband showed dystrophic changes accompanied by rimmed vacuoles. Whole-exome sequencing identified novel compound heterozygous mutations in the TTN gene, including elongation (c.107962_107963delAT, p.I35988Sfs*26) and truncation (c.99125_99128dupACAG, p.S33043Rfs*9) variants in the proband and his sister. Both two variants have never been reported. Notably, we are the first to identify an elongation mutation in the TTN gene, broadening the genetic mutation spectrum of LGMD2J.

Discussion: Several variants in the last exon of the TTN gene have been reported, one of which was associated with LGMD2J. Besides, LGMD2J should be distinguished from other myopathies caused by mutations in the TTN gene. The pathogenesis of and specific curative methods for LGMD2J remain to be further elucidated.