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

Abstract

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3′ splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNAsequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons. K E Y W O R D S alternative splicing, arthrogryposis, congenital titinopathies, intronic splice variant, TTN metatranscript-only

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…Solving many of these cases required going beyond standard analysis approaches or additional omics approaches, highlighting the impact of CMG sequencing and variant detection. [14][15][16] The CMGs have contributed to the discovery of 778 phenotypic expansions associated with previously established disease genes. Such discoveries represent an important contribution to both the research and clinical fields, as the full phenotypic spectrum of a 9 .…”

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…Solving many of these cases required additional data types, including RNA-seq or targeted splicing assays, long-read sequencing, and methylation analysis. [14][15][16][17] The CMGs have contributed to the discovery of 778 phenotypic expansions associated with previously established disease genes. Such discoveries represent an important contribution to both the research and clinical fields because the full phenotypic spectrum of a Mendelian disease, or the set of phenotypes associated with a genomic locus, may not be fully revealed at the time of the initial disease-gene discovery.…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…A good example of the aforementioned issues with interpretation of splicing variants is represented by the recently identified recurrent TTN intronic splice-site variant (c.39974-11T>G) [84]. A large segregation in eight families where the variant, in trans with a second causative variant, co-segregated with the disease and a comprehensive analysis of expression data strongly suggested the pathogenic role of the identified variant [84].…”