Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.
Hum Mutat
; 41(2): 403-411, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-31660661
ABSTRACT
We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1c.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, RNA-sequencing 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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Artrogriposis
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Empalme Alternativo
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Predisposición Genética a la Enfermedad
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Conectina
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Genes Recesivos
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Enfermedades Musculares
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Hum Mutat
Asunto de la revista:
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Australia