A homozygous TTN gene variant associated with lethal congenital contracture syndrome

Abstract

Pathogenic variants in the TTN gene have been reported to cause various cardiomyopathies and a range of skeletal muscle diseases, collectively known as titinopathies. We evaluated a consanguineous family multiple members affected with a lethal congenital contracture syndrome. Using exome sequencing, we identified a homozygous c.36122delC (p. P12041Lfs*20) variant in exon 167 in the fetal IC isoform of TTN. The finding expands the phenotypes that can be caused by pathogenic variants TTN, which should be considered in lethal congenital contracture syndromes, arthrogryposis multiplex congenita, congenital myopathies, and hydrops fetalis.

Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

“…Junctional reads bridging exons 181 and 170 are detected in adult skeletal muscle (Savarese et al, ), inferring the novel frameshift variants found in families A and F affect transcripts expressed in skeletal muscle. Of note, exons 213‐217 are not expressed at significant levels in cardiac tissue (Savarese et al, ) and reported individuals with a metatranscript‐only pathogenic TTN variant did not present with a cardiac phenotype (herein and in Chervinsky et al, ; Fernández‐Marmiesse et al, ; Oates et al, ).…”

“…Genetic diagnosis of a recessive congenital titinopathy was further complicated for Families A and F whose second TTN frameshift variants involved metatranscript‐only exons (exons 181 and 170, respectively). In support of pathogenicity, there are several recent reports of autosomal recessive congenital titinopathies associated with variants within metatranscript‐only exons 163, 172, 181, 201 (Oates et al, ), 197 (Fernández‐Marmiesse et al, ), and 167 (Chervinsky et al, ). Junctional reads bridging exons 181 and 170 are detected in adult skeletal muscle (Savarese et al, ), inferring the novel frameshift variants found in families A and F affect transcripts expressed in skeletal muscle.…”

“…Although, in the context of a myopathy, typically only variants in exons described in the skeletal muscle isoform N2A (NM_133378.4) are considered. However, six pathogenic variants in TTN exons not included within the described skeletal muscle isoform N2A (NM_133378.4) are recently reported affecting 10 different families with recessive congenital titinopathies (Chervinsky et al, ; Fernández‐Marmiesse et al, ; Oates et al, ). These pathogenic variants in TTN metatranscript‐only exons support emerging evidence that there are numerous developmental TTN transcripts isoforms yet to be formally described (Savarese et al, ).…”

Fetal arthrogryposis: Challenges and perspectives for prenatal detection and management

“…Once AMC is identified and an approximate clinical diagnosis allows for the assignment to an etiological subgroup, genetic testing can help distinguish among an expanding number of conditions, depending on test availability. However, genome‐wide sequencing studies in the last years have shed light on a seemingly endless list of diseases or disease phenotypes, and an exploding number of genes and molecular pathways, that can be associated with contractures (Abiusi et al, ; Aggarwal, Das Bhowmik, Tandon, & Dalal, ; Beecroft et al, ; Chai et al, ; Chervinsky et al, ; Filges et al, ; Hall & Kiefer, ; Hunter et al, ; Nguyen et al, ; Stevenson, Vincent, Spellicy, Friez, & Chaubey, ). For the time being, genetic testing, however, will be complicated by the limited time during pregnancy for molecular studies, and its added value will therefore also largely depend on the dating of the pathological ultrasound finding.…”

Centronuclear myopathy due to a de novo nonsense variant and a maternally inherited splice‐site variant in TTN: A case report

“… 5 , 6 Recessive TTN mutations cause a wide range of muscle disease with or without cardiomyopathy which have been reported under different terms in the past, such as recessive early‐onset myopathy with fatal cardiomyopathy, centronuclear myopathy (CNM), core myopathy with heart disease, and arthrogryposis multiplex congenita with myopathy and others. 3 , 7 , 8 , 9 , 10 , 11 , 12 …”