Recognizable Pattern of Arthrogryposis and Congenital Myopathy Caused by the Recurrent TTN Metatranscript-only c.39974-11T > G Splice Variant

Abstract

Introduction:Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in TTN (Titin). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as “metatranscript-only” and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974-11T>G) in TTN with a second truncating TTN variant has been linked to arthrogryposis multiplex congenita and myopathy. Methods: Via exome sequencing we identified the TTN c.39974-11T>G splice variant in trans with one of three truncating variants (p.Arg8922*, p.Lys32998Asnfs*63), p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed. Results: All five patients presented with generalized muscular hypotonia, reduced muscle bulk and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy one day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement in the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs. Conclusion:The recurrent TTN c.39974-11T>G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213-217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic worku

The crucial role of titin in fetal development: recurrent miscarriages and bone, heart, and muscle anomalies characterize the severe end of titinopathies spectrum

“…27,28 Together with our knowledge of the titinopathies spectrum, the number of clinicians involved in the diagnosis and management of these not-so-rare diseases is constantly growing. 29,30 Ever since TMD was discovered 31 , it has been mainly the neurologists who dealt with titinopathies. In recent years, following the publication of the first cases of congenital titinopathies, child neurologists, neonatologists, paediatricians have been increasingly involved.…”

Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript-only titin variant

“…Here we describe a 36 year-old patient with a congenital myopathy with distal arthrogryposis evolving toward a more diffuse contractile phenotype with rigid spine and moderate non-progressive muscular weakness, harboring the novel pathogenic c.36400A > T mutation in the titin meta-transcript-only exon 170. From a clinical stand-point similar phenotypes, but with higher degree of severity, have been previously reported in congenital titinopathies [ 13 ] and, more specifically, in children with meta-transcript-only exons titin mutations [ 10 , 11 ]. To date, our patient is the longest surviving among those previously reported in the literature with a metatrasncript-only exon titin mutation.…”

“…Congenital titinopathies are an emerging group of a potentially severe form of congenital myopathy caused by biallelic mutations in titin (TTN) [ 1 , 2 ]. Moreover, variants found in exons only included in the inferred complete isoform (IC) were described as pathogenic and referred as ‘metatranscript-only variants’ [ 6 , 8 – 11 ]. Here we present the oldest documented patient with a congenital myopathy with rigid spine linked to a pathogenic novel homozygous variant c.36400A > T, p.Lys12134* in exon 170 of titin .…”